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Activated by regular exercise, immune cells in muscles found to fend off inflammation, enhance endurance in mice

The connection between exercise and inflammation has captivated the imagination of researchers ever since an  early 20th-century study  showed a spike of white cells in the blood of Boston marathon runners following the race.

Now, a new Harvard Medical School study published Friday in Science Immunology may offer a molecular explanation behind this century-old observation.

The study, done in mice, suggests that the beneficial effects of exercise may be driven, at least partly, by the immune system. It shows that muscle inflammation caused by exertion mobilizes inflammation-countering T cells, or Tregs, which enhance the muscles’ ability to use energy as fuel and improve overall exercise endurance.

Long known for their role in countering the aberrant inflammation linked to autoimmune diseases, Tregs now also emerge as key players in the body’s immune responses during exercise, the research team said.

“The immune system, and the T cell arm in particular, has a broad impact on tissue health that goes beyond protection against pathogens and controlling cancer. Our study demonstrates that the immune system exerts powerful effects inside the muscle during exercise,” said study senior investigator  Diane Mathis , professor of immunology in the Blavatnik Institute at HMS.

Mice are not people, and the findings remain to be replicated in further studies, the researchers cautioned. However, the study is an important step toward detailing the cellular and molecular changes that occur during exercise and confer health benefits.

Understanding the molecular underpinnings of exercise

Protecting from cardiovascular disease, reducing the risk of diabetes, shielding against dementia. The salutary effects of exercise are well established. But exactly how does exercise make us healthy? The question has intrigued researchers for a long time.

The new findings come amid  intensifying efforts  to understand the molecular underpinnings of exercises. Untangling the immune system’s involvement in this process is but one aspect of these research efforts.

“Our research suggests that with exercise, we have a natural way to boost the body’s immune responses to reduce inflammation.” Diane Mathis, professor of immunology in the Blavatnik Institute

“We’ve known for a long time that physical exertion causes inflammation, but we don’t fully understand the immune processes involved,” said study first author Kent Langston, a postdoctoral researcher in the Mathis lab. “Our study shows, at very high resolution, what T cells do at the site where exercise occurs, in the muscle.”

Most previous research on exercise physiology has focused on the role of various hormones released during exercise and their effects on different organs such as the heart and the lungs. The new study unravels the immunological cascade that unfolds inside the actual site of exertion — the muscle.

T cell heroes and inflammation-fueling villains

Exercise is known to cause temporary damage to the muscles, unleashing a cascade of inflammatory responses. It boosts the expression of genes that regulate muscle structure, metabolism, and the activity of mitochondria, the tiny powerhouses that fuel cell function. Mitochondria play a key role in exercise adaptation by helping cells meet the greater energy demand of exercise.

In the new study, the team analyzed what happens in cells taken from the hind leg muscles of mice that ran on a treadmill once and animals that ran regularly. Then, the researchers compared them with muscle cells obtained from sedentary mice.

The muscle cells of the mice that ran on treadmills, whether once or regularly, showed classic signs of inflammation — greater activity in genes that regulate various metabolic processes and higher levels of chemicals that promote inflammation, including interferon.

Both groups had elevated levels of Treg cells in their muscles. Further analyses showed that in both groups, Tregs lowered exercise-induced inflammation. None of those changes were seen in the muscle cells of sedentary mice.

However, the metabolic and performance benefits of exercise were apparent only in the regular exercisers — the mice that had repeated bouts of running. In that group, Tregs not only subdued exertion-induced inflammation and muscle damage, but also altered muscle metabolism and muscle performance, the experiments showed. This finding aligns with well-established observations in humans that a single bout of exercise does not lead to significant improvements in performance and that regular activity over time is needed to yield benefits.

The hind leg muscles of mice lacking Treg cells (right) showed prominent signs of inflammation after regular exercise, compared with those from mice with intact Tregs (left). The research showed such that this uncontrolled inflammation negatively impacted muscle metabolism and function.

Credit: Kent Langston/Mathis Lab, HMS

Further analyses confirmed that Tregs were, indeed, responsible for the broader benefits seen in regular exercisers. Animals that lacked Tregs had unrestrained muscle inflammation, marked by the rapid accumulation of inflammation-promoting cells in their hind leg muscles. Their muscle cells also had strikingly swollen mitochondria, a sign of metabolic abnormality.

More importantly, animals lacking Tregs did not adapt to increasing demands of exercise over time the way mice with intact Tregs did. They did not derive the same whole-body benefits from exercise and had diminished aerobic fitness.

These animals’ muscles also had excessive amounts of interferon, a known driver of inflammation. Further analyses revealed that interferon acts directly on muscle fibers to alter mitochondrial function and limit energy production. Blocking interferon prevented metabolic abnormalities and improved aerobic fitness in mice lacking Tregs.

“The villain here is interferon,” Langston said. “In the absence of guardian Tregs to counter it, interferon went on to cause uncontrolled damage.”

Interferon is known to promote chronic inflammation, a process that underlies many chronic diseases and age-related conditions and has become a tantalizing target for therapies aimed at reducing inflammation. Tregs have also captured the attention of scientists and industry as treatments for a range of immunologic conditions marked by abnormal inflammation.

The study findings provide a glimpse into the cellular innerworkings behind exercise’s anti-inflammatory effects and underscore its importance in harnessing the body’s own immune defenses, the researchers said.

There are efforts afoot to design interventions targeting Tregs in the context of specific immune-mediated diseases. And while immunologic conditions driven by aberrant inflammation require carefully calibrated therapies, exercise is yet another way to counter inflammation, the researchers said.

“Our research suggests that with exercise, we have a natural way to boost the body’s immune responses to reduce inflammation,” Mathis said. “We’ve only looked in the muscle, but it’s possible that exercise is boosting Treg activity elsewhere in the body as well.”

Co-investigators included Yizhi Sun, Birgitta Ryback, Bruce Spiegelman, Amber Mueller, and Christophe Benoist.

The work was funded by National Institutes of Health grants R01 AR070334, F32 AG072874, and F32 AG069363; and by the JPB Foundation.

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The end of inflammation? New approach could treat dozens of diseases.

Cancer, aging, and severe COVID-19 have all been linked to damage from inflammation. Now scientists are flipping their focus to find new drugs that may revolutionize treatments.

Growing up in Atlanta, Georgia, Lauren Finney Harden had always had allergies. But after she moved to New York City for her first job in 2007, inflammation “just exploded” throughout her body.

“I had insane full-body rashes and strange gastro issues. I’d get massive burps that made me feel like I needed to throw up, but nothing would come up but air,” she says. Eventually, she was diagnosed with lupus, a disease in which the immune system attacks the body’s own tissues and organs. She was put on a drug called prednisone, a corticosteroid that tamps down inflammation.

But the cure, at times, felt worse than the disease. “I looked four months pregnant all the time,” Finney Harden says, “and I’d get cold sores every other week; my body could not fight off anything.”

Finney Harden’s experience is unfortunately a common one with traditional autoimmune treatments like prednisone. A broad immunosuppressant , prednisone works by disabling the production of pro-inflammatory molecules that are crucial for the body to mount an immune defense. So while prednisone—and drugs like it—are adept at quickly snuffing out inflammation, they leave the body vulnerable to any bug it encounters, and they can come with toxic side effects.

“Simply stopping inflammation is not enough to return tissue to its normal state,” says Ruslan Medzhitov , a professor of immunobiology at Yale School of Medicine. This approach ignores the other side of the inflammation coin: resolution. Resolving inflammation is an active, highly choreographed process for rebuilding tissue and removing the dead bacteria and cells. When that process is disrupted, inflammatory diseases arise.

In the early 2000s researchers began to recognize the role of inflammation in conditions as varied as Alzheimer’s , cancer , diabetes , and heart disease , prompting them to recast inflammation as the unifying explanation for a myriad of ailments, including those we develop as we age. Even aging itself, and its associated pathologies, is driven by persistent inflammation .

“Until relatively recently, we believed that inflammation just stopped,” says Molly Gilligan, an internal medicine resident at Columbia University who studies how the immune system impacts cancer development. Immunologists thought that products of inflammation—molecules that trigger it and dead cells and tissue—are eventually metabolized, or spontaneously dissipate on their own.

The reality is more complicated, and recognizing that could have game-changing effects on how we treat a wide swath of diseases.

Why is inflammation dangerous?  

Inflammation evolved to serve an important function: It rids our bodies of stuff that doesn’t belong, including foreign invaders like bacteria and viruses, tumor cells, and irritants like splinters.

“A classic example of inflammatory onset is the bee sting—the site becomes hot, red, swollen, and painful,” says Derek Gilroy , a professor of immunology at University College London. This response comes from a series of biological changes: blood vessels dilate to deliver white blood cells to the site of injury, making tissues turn red. Fluid also floods the site, causing swelling. The molecules that trigger these vascular transformations precipitate the itching, pain, and fever associated with inflammation.

White blood cells, the body’s first responders, then swarm and kill the invaders. Under normal circumstances, this carnage is contained, with the initial inflammatory response subsiding within 24 to 48 hours.

When inflammation becomes chronic, though, the chemical weapons deployed by front-line immune cells often damage healthy tissue, and our bodies become collateral damage. The price exacted includes worn joints , damaged neurons , scarred kidneys , and more. Autoimmune diseases like rheumatoid arthritis and lupus, characterized by pain and worsening disability, have long been associated with persistent inflammation.

In extreme cases, such as the cytokine storms associated with sepsis or severe COVID-19, inflammation can destroy and disable multiple organs , leading to catastrophic system failure and death.

What happens after inflammation?

Medzhitov likens an infection to a broken pipe that has flooded an office with water. Fixing the pipe might stop water from streaming in, but it doesn’t restore the office to its previous, functional state. Similarly, inflammation has a clean-up phase known as resolution, and it proceeds in a series of highly coordinated steps.

Like inflammation’s onset, its resolution is orchestrated by an army of signaling molecules. Among the most intensely studied are the specialized pro-resolving mediators, or SPMs, which were discovered in the 1990s by Charles Serhan , a professor of anesthesia at Harvard Medical School. Serhan was inspired by his postdoctoral mentor, Bengt Samuelsson , who uncovered how fatty molecules called lipids trigger inflammation. Serhan was searching for similar molecules when he identified lipoxin. But to his surprise, rather than inciting inflammation, lipoxin seemed to hamper it.

Over the next several years, Serhan and his colleagues identified additional SPMs. These molecules are derived from essential fatty acids such as those omega-3s famously found in cold-water fish like salmon and sardines. But they are difficult to study in the lab. “One of the main challenges is that they have short half-lives, so the body metabolizes them very quickly,” Gilligan says. Because of this, researchers who work on them often turn to synthetic versions of the molecules, or mimetics, which are simpler, more stable, and cheaper to produce.

Catherine Godson , a professor of molecular medicine at University College Dublin, has long been interested in diabetes, given its impact on global public health as the most common cause of kidney failure. When she learned of SPMs, she was excited by the idea of encouraging resolution to treat diabetics, a “population with a particularly high risk for infection.”

In mice with diabetic kidney disease , scarring from kidney inflammation gradually destroys the organ. Her team is testing the therapeutic potential of a lipoxin mimetic in these and other animal models. They’ve also looked at the mimetic’s effect in human tissue   in lab cell cultures taken from patients with atherosclerosis, an inflammatory disease of the blood vessel wall. In both cases, inflammatory factors plummeted when the mimetic was introduced; for the mice, the kidneys recovered their function in a stunning reversal of established disease.

Gilroy notes, however, that the story on SPMs is incomplete. “While lipoxins are present at levels in the body that indicate that they’re important in resolution, other SPMs such as resolvins require more evaluation,” he says.

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Manipulating macrophages.

Scientists speculate that one way lipoxins and other pro-resolution molecules work is by interacting with immune cells called macrophages.

Because they’re so abundant during inflammation, macrophages have traditionally been thought of as pro-inflammatory cells, says Gerhard Krönke , an immunologist and rheumatologist at the University of Erlangen-Nürnberg. “But a paradigm shift in the last decade or so suggests that macrophages are pivotal players in the resolution of inflammation.”

Gilroy agrees, calling macrophages “linchpin cells at the juxtaposition of inflammation and resolution: It can go one way if we’re healthy and the other way if we’re not.”

Initially, when the danger posed by invaders is at its peak, the macrophages drawn to the area are inflammatory—secreting pro-inflammatory cytokines and amping up production of antimicrobial agents. But this balance shifts as the tide of the confrontation turns. After the number of viruses declines, the debris left behind—viral remnants, dead immune cells, and other waste—must be collected and cleared away before it sparks another cycle of inflammation. That’s when the macrophages switch gears.

Attracted by “eat me” signals expressed on the surface of dying cells, macrophages readily engulf and clear cellular corpses from the environment. But it’s not just about clearing the wreckage—this act also flips a genetic switch, reprogramming macrophages to restore balance to the system and heal the tissues.

“Macrophages start to produce factors that tell the local tissue, Don’t recruit any more inflammatory cells here, or, Let’s proliferate and start repairs there,” says Kodi Ravichandran , an immunologist at Washington University in St. Louis whose research focuses on how dead cells are cleared from the body.

Clearing away cellular debris  

Now consensus is building that many of the illnesses attributed to inflammation—both chronic and acute—can be traced to a failure in resolution. Often that translates into a failure to clear away dead cells.

“If you knock out receptors in the macrophages of mice that recognize dying cells, for example, they become incapable of eating up these cells, resulting in a lupus-like disease,” with symptoms such as arthritis and skin rash, says Krönke.  

A similar mechanism is at work in older people, says Gilroy. As we age, the body loses a protein that recognizes dying cells; this blocks macrophages’ ability to find and eat debris. Locked in a pro-inflammatory state, these macrophages continue to produce molecules that amplify the inflammatory response early on.

Perhaps COVID-19 has been more severe in older populations “because they’ve lost some of the pro-resolution pathways with age,” suggests Luke O’Neill , an immunologist at Trinity College Dublin. He notes that COVID-19 has also been problematic for people with genetic differences that impact immune function, resulting in overactive inflammatory responses or underactive pro-resolving ones. His group and others have demonstrated that macrophages primed for inflammatory action play a significant role in critical COVID-19 cases, and they are currently testing pro-resolving strategies to combat this effect.

Cancer’s course, too, is affected when inflammation fails to resolve. The soup of toxins, growth factors, and other inflammatory by-products that accompany inflammation spurs cancer’s growth and spread. Many conventional treatments end up exacerbating the problem, according to Dipak Panigrahy , an assistant professor of pathology at Beth Israel Deaconess Medical Center in Boston.

“Chemotherapy and radiation are like sledgehammers,” Panigrahy says. “They may kill the tumor, but the debris they create stimulates inflammation, which feeds circulating tumor cells that survive the treatment.”

A decade ago, Panigrahy was puzzling over this conundrum when he met Serhan at a conference on lipids in Cancún, Mexico. “I had just presented my research on cell death in cancer and how there’s no way to clear the resulting debris when I heard Serhan’s talk about how he discovered these lipids that eliminated debris,” he says. The two Boston-based researchers have shared a close collaboration ever since.

In proof-of-concept experiments conducted on mice, Panigrahy’s group was able to prevent tumors from recurring after surgery by dosing the animals with mimetics of resolvin, one of the pro-resolving mediators discovered in Serhan’s lab. Phase one clinical trials for pancreatic, brain, and colon cancers will begin this year, says Panigrahy.

Long COVID and inflammation

Although much work remains to decode its secrets, “long COVID likely results from a catastrophic failure of appropriate immune response and resolution,” Gilroy suggests.

Meg St. Esprit is part of a large cohort of COVID-19 survivors who continue to suffer symptoms months after the virus has passed. She and her family contracted the disease in November 2020, and for seven days the mother of four in Pittsburgh, Pennsylvania, was beset by a high fever and severe headaches. Debilitating fatigue, vertigo, and brain fog soon followed. But while her husband and children recovered, St. Esprit’s symptoms lingered, and new ones emerged.

Since her bout with COVID-19, she has developed blood clots and myocarditis—dangerous consequences of inflammation. It’s also as if her entire body has gone haywire. “Different parts of it regularly flare up now,” she says. “My thumb joints swell to twice their normal size, my knee puffs out like a grapefruit, and I’ve had hives more times than I can count.”

Drugs to tweak the natural inflammatory process would thus be a powerful tool in our arsenal for long COVID as well. Even now the hunt is on . O’Neill and colleagues, for example, are testing molecules in clinical trials that push macrophages to be pro-resolving. SPMs are being tested extensively in animal models of diseases like cancer and sepsis, and more modestly in small patient trials studying eczema and periodontal disease .

But Gilroy cautions that the answer may be more nuanced than anti-inflammatory versus pro-resolution, and that drugs targeting both approaches may be needed.

“It’s like driving a car at full speed,” he says. “In order to stop, you take your foot off the accelerator, which would be like dampening inflammation’s onset. And then you apply the brakes, or in other words, promote its resolution.”

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New research may explain unexpected effects of common painkillers.

(Illustration by Michael S. Helfenbein)

Non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen and aspirin are widely used to treat pain and inflammation. But even at similar doses, different NSAIDs can have unexpected and unexplained effects on many diseases, including heart disease and cancer.

Now, a new Yale-led study has uncovered a previously unknown process by which some NSAIDs affect the body. The finding may explain why similar NSAIDs produce a range of clinical outcomes and could inform how the drugs are used in the future.

The study was published May 18 in the journal Immunity.

Until now, the anti-inflammatory effects of NSAIDs were believed to arise solely through the inhibition of certain enzymes. But this mechanism does not account for many clinical outcomes that vary across the family of drugs. For example, some NSAIDs prevent heart disease while others cause it, some NSAIDs have been linked to decreased incidence of colorectal cancer, and various NSAIDs can have a wide range of effects on asthma.

Now, using cell cultures and mice, Yale researchers have uncovered a distinct mechanism by which a subset of NSAIDs reduce inflammation. And that mechanism may help explain some of these curious effects.

The research showed that only some NSAIDs — including indomethacin, which is used to treat arthritis and gout, and ibuprofen — also activate a protein called nuclear factor erythroid 2-related factor 2, or NRF2, which, among its many actions, triggers anti-inflammatory processes in the body.

“ It’s interesting and exciting that NSAIDs have a different mode of action than what was known previously,” said Anna Eisenstein , an instructor at the Yale School of Medicine and lead author of the study. “And because people use NSAIDs so frequently, it’s important we know what they’re doing in the body.”

The research team can’t say for sure that NSAIDs’ unexpected effects are due to NRF2 — that will require more research. “But I think these findings are suggestive of that,” Eisenstein said.

Eisenstein is now looking into some of the drugs’ dermatological effects — causing rashes, exacerbating hives, and worsening allergies — and whether they are mediated by NRF2.

This discovery still needs to be confirmed in humans, the researchers note. But if it is, the findings could have impacts on how inflammation is treated and how NSAIDs are used.

For instance, several clinical trials are evaluating whether NRF2-activating drugs are effective in treating inflammatory diseases like Alzheimer’s disease, asthma, and various cancers; this research could inform the potential and limitations of those drugs. Additionally, NSAIDs might be more effectively prescribed going forward, with NRF2-activating NSAIDs and non-NRF2-activating NSAIDs applied to the diseases they’re most likely to treat.

The findings may also point to entirely new applications for NSAIDs, said Eisenstein.

NRF2 controls a large number of genes involved in a wide range of processes, including metabolism, immune response, and inflammation. And the protein has been implicated in aging, longevity, and cellular stress reduction.

Said Eisenstein, “That NRF2 does so much suggests that NSAIDs might have other effects, whether beneficial or adverse, that we haven’t yet looked for.”

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Edmund K. LeGrand , University of Tennessee and Joe Alcock , University of New Mexico

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June 28, 2022

Long COVID symptoms linked to inflammation

At a glance.

• Prolonged inflammation after SARS-CoV-2 infections caused permanent damage to lungs and kidneys, affected the brain, and correlated with behavioral changes in hamsters.
• The results suggest a mechanism for the symptoms of Long COVID in people.

The effects of COVID-19 can persist long after the initial symptoms of the illness are gone. These effects, called post-acute sequelae of COVID-19 (or PASC), can include brain fog, fatigue, headaches, dizziness, and shortness of breath. Long COVID—when symptoms last weeks or months after the acute infection has passed—affects about 2.5% of COVID patients. While patients who were hospitalized are more susceptible, even those with mild cases can experience Long COVID.

A research team led by Drs. Benjamin tenOever at the NYU Grossman School of Medicine and Venetia Zachariou at the Icahn School of Medicine at Mount Sinai set out to understand the underlying biology of Long COVID. The researchers, who were supported in part by NIH, studied the golden hamster, a widely used small animal model for respiratory infections. The hamsters were exposed to SARS-CoV-2 via their nostrils. For comparison, another group was exposed to a flu virus, influenza A. Various samples were taken for analysis after 3, 14, and 31 days of infection.

Tissues from human donors who had COVID-19 at the time of death or had recovered from COVID-19 but died from other causes were also sampled and analyzed. Results appeared on June 7, 2022, in Science Translational Medicine.

Both SARS-CoV-2 and influenza A infections were largely cleared within two weeks, similar to the course of recovery in humans. Following SARS-CoV-2 infection, however, animals showed much more extensive lung damage and slower recovery than those exposed to influenza A. Those exposed to SARS-CoV-2 also had more kidney damage.

When the scientists sampled different parts of hamster brains to analyze gene activity, they found that SARS-CoV-2 had unique effects on the hamster olfactory system—the parts of the nose and brain responsible for smell. The olfactory epithelium, the lining inside the nose, showed signs of extensive inflammation long after the virus could be detected. SARS-CoV-2 also caused high levels of inflammation in the olfactory bulb, a part of the brain involved in processing smell as well as in emotion and learning. Inflammation in these areas persisted long after the infection was cleared.

Interestingly, chronic inflammation in the olfactory system correlated with behavioral changes in the hamsters thought to reflect mood disorders like depression and anxiety. Although olfactory bulb tissue from people who recovered from COVID-19 and died of other causes is difficult to obtain, the few samples studied were comparable to that of the hamsters. This suggests that the inflammation seen in the hamsters may explain the mechanism responsible for symptoms of Long COVID in people. Further research is needed to fully understand the link between brain inflammation, brain activity, and behavioral changes.

“[T]his study suggests that the molecular mechanism behind many Long COVID-19 symptoms stems from this persistent inflammation while describing an animal model close enough to human biology to be useful in the design of future treatments,” tenOever says.

—by Larisa Gearhart-Serna, Ph.D.

Related Links

• T Cells Protect Against COVID-19 in Absence of Antibody Response
• Intranasal Proteins Could Protect Against COVID-19 Variants
• Antibodies Recognize New SARS-CoV-2 Omicron Variant After Booster
• COVID-19 Immune Response Improves for Months After Vaccination
• How COVID-19 Affects the Brain
• Long COVID or Post-COVID Conditions

References:  SARS-CoV-2 infection in hamsters and humans results in lasting and unique systemic perturbations post recovery . Frere JJ, Serafini RA, Pryce KD, Zazhytska M, Oishi K, Golynker I, Panis M, Zimering J, Horiuchi S, Hoagland DA, Møller R, Ruiz A, Kodra A, Overdevest JB, Canoll PD, Borczuk AC, Chandar V, Bram Y, Schwartz R, Lomvardas S, Zachariou V, tenOever BR. Science Translational Medicine . 2022 Jun 7:eabq3059.

Funding:  NIH’s National Institute of Neurological Disorders and Stroke (NINDS) and National Institute on Deafness and Other Communication Disorders (NIDCD); Zegar Family Foundation; New York Genome Center.

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Low-grade inflammation, diet composition and health: current research evidence and its translation

Anne m. minihane.

1 Department of Nutrition, Norwich Medical School, University of East Anglia, Norwich, NR4 7TJ, UK

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2 Mondelēz International – R&D, Nutrition Department, 91400, Saclay, France

Wendy R. Russell

3 Rowett Institute of Nutrition and Health, University of Aberdeen, Aberdeen, AB21 9SB, UK

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4 Formerly ILSI Europe a.i.s.b.l., Avenue E. Mounier 83, Box 6, B-1200, Brussels, Belgium

Helen M. Roche

5 Nutrigenomics Research Group, UCD Institute of Food and Health and UCD Conway Institute, Belfield, University College Dublin, Dublin 4, Republic of Ireland

Kieran M. Tuohy

6 Department of Food Quality and Nutrition, Research and Innovation Centre, Fondazione Edmund Mach, San Michele all'Adige, 38010, Trento, Italy

Jessica L. Teeling

7 Centre for Biological Sciences, Faculty of Natural and Environmental Sciences, University of Southampton, Southampton, SO16 6YD, UK

Ellen E. Blaak

8 Department of Human Biology, NUTRIM School for Nutrition, Toxicology and Metabolism, Maastricht University, Maastricht, The Netherlands

Michael Fenech

9 Nutrigenomics and Neurodegenerative Disease Prevention, Preventative Health Flagship, CSIRO, Animal, Food and Health Sciences, Adelaide, Australia

David Vauzour

Harry j. mcardle, bas h. a. kremer.

10 Microbiology and Systems Biology, TNO, Zeist, 3704, HE, The Netherlands

Luc Sterkman

11 Newtricious R&D B.V., Oirlo, 5808, AL, The Netherlands

Katerina Vafeiadou

12 School of Life and Medical Sciences, University of Hertfordshire, Hatfield, AL10 9AB, UK

Massimo Massi Benedetti

13 Department of Internal Medicine, University of Perugia, Perugia, Italy

Christine M. Williams

14 Hugh Sinclair Unit of Human Nutrition, Department of Food and Nutritional Sciences, University of Reading, Reading, RG6 6AP, UK

Philip C. Calder

Faculty of Medicine, University of Southampton, Southampton, SO16 6YD, UK

16 NIHR Southampton Biomedical Research Centre, Southampton University Hospital NHS Foundation Trust and University of Southampton, Southampton, SO16 6YD, UK

The importance of chronic low-grade inflammation in the pathology of numerous age-related chronic conditions is now clear. An unresolved inflammatory response is likely to be involved from the early stages of disease development. The present position paper is the most recent in a series produced by the International Life Sciences Institute's European Branch (ILSI Europe). It is co-authored by the speakers from a 2013 workshop led by the Obesity and Diabetes Task Force entitled ‘Low-grade inflammation, a high-grade challenge: biomarkers and modulation by dietary strategies’. The latest research in the areas of acute and chronic inflammation and cardiometabolic, gut and cognitive health is presented along with the cellular and molecular mechanisms underlying inflammation–health/disease associations. The evidence relating diet composition and early-life nutrition to inflammatory status is reviewed. Human epidemiological and intervention data are thus far heavily reliant on the measurement of inflammatory markers in the circulation, and in particular cytokines in the fasting state, which are recognised as an insensitive and highly variable index of tissue inflammation. Potential novel kinetic and integrated approaches to capture inflammatory status in humans are discussed. Such approaches are likely to provide a more discriminating means of quantifying inflammation–health/disease associations, and the ability of diet to positively modulate inflammation and provide the much needed evidence to develop research portfolios that will inform new product development and associated health claims.

Introduction and overview of the focus of the position paper

Inflammation is a central component of innate (non-specific) immunity. In generic terms, inflammation is a local response to cellular injury that is marked by increased blood flow, capillary dilatation, leucocyte infiltration, and the localised production of a host of chemical mediators, which serves to initiate the elimination of toxic agents and the repair of damaged tissue ( 1 ) . It is now clear that the termination (alternatively known as resolution) of inflammation is an active process involving cytokines and other anti-inflammatory mediators, particularly lipids, rather than simply being the switching off of pro-inflammatory pathways ( 2 , 3 ) .

Inflammation acts as both a ‘friend and foe’: it is an essential component of immunosurveillance and host defence, yet a chronic low-grade inflammatory state is a pathological feature of a wide range of chronic conditions, such as the metabolic syndrome (MetS), non-alcoholic fatty liver disease (NAFLD), type 2 diabetes mellitus (T2DM) and CVD ( 4 , 5 ) . Although the association between inflammation and chronic conditions is widely recognised, the issue of causality and the degree to which inflammation contributes and serves as a risk factor for the development of disease remain unresolved. As will be discussed, part of this uncertainty is due to a general lack of sensitive and specific biomarkers of low-grade chronic inflammation that can be used in human trials ( 1 ) .

The present article results from an International Life Sciences Institute (ILSI) Europe Workshop held in September 2013 in Granada, Spain entitled ‘Low-grade inflammation a high grade challenge: biomarkers and modulation by dietary strategies’, and aims to serve as an update to existing reviews in the area of inflammation and health and its assessment and modulation ( 1 , 6 , 7 ) . In particular, the present article will focus on the latest research findings in the areas of inflammation and cardiometabolic, cognitive and gut health, and how early-life nutrition and the macronutrient and plant bioactive composition of the adult diet influence inflammatory processes. It will discuss existing and emerging methods used to quantify inflammatory status in humans. Importantly, the article will identify knowledge gaps and methodological limitations that need to be addressed.

Exploring the role of inflammation in health and chronic diseases

Low-grade inflammation in cardiometabolic disease.

The role of inflammation in the early-stage pathophysiology of atherothrombotic events has been recognised for over 20 years. Leucocyte recruitment into the sub-endothelial compartment of damaged arteries initiates a cascade of events mediated by leucocyte-derived inflammatory mediators. In particular, chemokines and cytokines propagate atherosclerosis via (1) increased chemokine production and expression of endothelial adhesion molecules, stimulating further leucocyte recruitment, (2) promoting lipid-laden foam-cell formation, (3) initiating smooth muscle cell proliferation, and (4) inducing plaque instability and eventual rupture ( 8 , 9 ) . The ensuing thrombosis is also in large part dependent on the inflammatory status of the ruptured plaque.

In addition to a direct role on events within the arterial wall, inflammation is an important determinant of the multi-organ cardiometabolic dysfunction, and the increased risk of T2DM, NAFLD and CVD associated with obesity ( 10 ) . Adipose tissue hypertrophy is associated with immune cell infiltration, in particular that of macrophages and T cells, and a local pro-inflammatory milieu wherein key cytokines including TNF-α, IL-6 and IL-1β impede the insulin signalling cascade to induce insulin resistance ( 11 , 12 ) . This ultimately leads to a dysregulation of glucose and lipid metabolism in adipose tissue, skeletal muscle and liver. However, up to 30 % of obese individuals are considered metabolically healthy (MHO) ( 13 ) , and there is evidence to suggest that a lack of the typical elevation in the inflammatory profile associated with obesity may underlie this ‘protected’ MHO phenotype. For example, in morbidly obese individuals, Barbarroja and co-workers observed mean homeostatic model assessment for insulin resistance (HOMA-IR) scores (insulin sensitivity index) of 3·31 and 11·48 in subjects with MHO (BMI 55 kg/m 2 ) or who were metabolically unhealthy obese (BMI 56 kg/m 2 ), respectively, which was associated with a 2- to 4-fold greater adipose expression of inflammatory cytokines (TNF-α, IL-1β and IL-6) between the two obese groups ( 14 ) .

Inflammation plays a direct role in the progression of NAFLD, the most common liver disorder in Western countries. NAFLD comprises a spectrum of conditions ranging from benign steatosis to non-alcoholic steatohepatitis characterised by hepatocyte injury (hepatocyte ballooning and Mallory bodies) and necroinflammation, and potentially to progressive fibrosis that can lead to cirrhosis ( 15 , 16 ) . The pathological progression of NAFLD is considered to have a two-hit basis ( Fig. 1 ). The first hit, hepatocyte accumulation of fat, is thought to arise due to an increased delivery of fatty acids to the hepatocyte, an increase in hepatocyte fatty acid and TAG synthesis, and decreased fatty acid oxidation. The resultant excess of fat may result in lipotoxicity and a pro-inflammatory and pro-oxidative state (the second hit), which ultimately induces cellular senescence, which, if unchecked, leads to fibrosis and cirrhosis. Hepatic inflammation is mediated via the activation of local macrophages called Kupffer cells. Currently, no medication or surgical procedure has been approved for treating NAFLD or non-alcoholic steatohepatitis with confidence. Considering the overall lack of success in curbing global trends in the prevalence of excess body weight, inflammatory processes are emerging as a strong therapeutic target to reduce the risk of T2DM, CVD and NAFLD in obese individuals.

Two-hit model of non-alcoholic fatty liver disease. (A colour version of this figure can be found online at http://www.journals.cambridge.org/bjn ).

Gut–systemic inflammatory associations

With recent significant advances in the ability to characterise the gut microbiota in increasing detail, comes the recognition of the importance of the microbiota not only in gastrointestinal health, but also in systemic metabolism and cardiometabolic health, with the immune system and inflammatory processes central to gut–systemic tissue ‘cross-talk’. The human intestine contains 1 × 10 13 to 1 × 10 14 bacterial cells, which outnumber human cells by a factor of 10 to 1 and contain approximately 150 times as many genes as the human genome ( 17 ) . Increasing evidence indicates that the microbiota is significantly altered through the ageing process ( 18 , 19 ) and in obesity ( 18 ) , with a deleterious decline in microbiota ‘richness’ and gene expression diversity evident in both situations ( 18 ) .

Gastrointestinal tract–microbiota interactions influence host health, and in particular immune function, by promoting the development and maintenance of the mucosal immune system, protecting against pathogen invasion and maintaining gastrointestinal tract barrier integrity ( 20 ) . Gut permeability to bacterial lipopolysaccharides (LPS), a potent inflammatory stimulant, appears to be an important trigger for low-grade systemic inflammation. LPS are found on the outer membrane of Gram-negative bacteria such as Proteobacteria (e.g. Escherichia coli ), and serve as an endotoxin. In the elderly, a higher count of LPS-producing bacteria in the colon, along with a lower abundance of bifidobacteria ( 21 , 22 ) , a combination which is thought to promote increased gut permeability ( 21 ) , is likely to lead to higher plasma levels of LPS (termed metabolic endotoxaemia). Through the interaction with Toll-like receptor 4 on mononuclear cells, microbiota-derived LPS may be an important trigger in the development of inflammation and metabolic diseases ( 23 ) . In a recent dietary intervention study in male C57Bl/6 mice, the alteration in microbiota profiles as a result of a high-fat diet was strongly associated with gut permeability, endotoxaemia and adipose tissue inflammation ( 24 ) .

In addition to its role in low-grade inflammatory cardiometabolic conditions, emerging evidence is suggesting that the gut microbiota can influence the risk of high-grade autoimmune inflammatory conditions such as type 1 diabetes mellitus, coeliac disease, inflammatory bowel disease and rheumatoid arthritis ( 25 – 27 ) , the incidence of which has risen dramatically since the 1940s. These conditions are now thought to affect 5–10 % of those in Western societies ( 28 ) . Certain members of the gut microbiota have been shown to induce mimics of human antigens and trigger the production of autoantibodies responsible for aberrant immune responses to normal human proteins and hormones including leptin, peptide YY and ghrelin ( 29 ) . It is not unreasonable to speculate that the adverse impact of the energy-dense, nutrient-poor Western-style diet on human gut microbiota and immune system, which have both been finely tuned and honed by high-fibre, high-polyphenol traditional diets over the millennia, may therefore be an important contributor to the environmental stimuli that trigger and progress autoimmune conditions ( 30 ) . A possible starting point when discussing the underlying mechanisms by which diets rich in whole plant foods or fermentable fibres can have an impact on immune function and tolerance may be the recent demonstration that butyrate, an important fermentation end product produced by the gut microbiota from fibre, controls human dendritic cell maturation, a key process in immune homeostasis, since dendritic cells are considered as ‘gate keepers’ of the immune system ( 31 , 32 ) . In addition, butyrate induces murine peripheral regulatory T-cell generation ( 33 ) , acetate affects neutrophil chemotaxis and oxidative burst, butyrate inhibits adipocyte–macrophage inflammatory interactions ( 34 ) , and propionate reduces the inflammatory output of adipose tissue ( 35 ) . Probiotic, fibre or polyphenol up-regulation of microbial activities that control both the quantity and profile of bile acids returning to the liver via the enterohepatic circulation with their subsequent regulation of farnesoid X receptor and TGR5 is also emerging as an important pathway linking the gut microbiota with extra-intestinal physiological/immune function ( 33 , 36 , 37 ) .

Low-grade systemic inflammation and neuroinflammation

Communication between the systemic immune system and the central nervous system (CNS) is a critical but often overlooked component of the inflammatory response to tissue injury, disease or infection. Activation of highly conserved neuronal and hormonal communication pathways in mammals drives diverse CNS-regulated components of the inflammatory response, including fever, neurogenic inflammation, descending anti-inflammatory mechanisms and a coordinated set of metabolic and behavioural changes, including fatigue, anhedonia, depression and mild cognitive impairment. These behavioural changes are collectively referred to as ‘sickness behaviour’ ( 38 – 40 ) . Experimental studies have provided evidence that activation of microglia, the macrophages of the CNS, as well as the cerebral vasculature, plays a key role in the development of these behavioural changes, by inducing pro-inflammatory mediators, such as IL-1β, TNF-α and PGE 2 in the CNS ( 38 , 41 , 42 ) .

Much of what we know is derived from studies using mimetics of bacterial and viral infection. Depending on the stimulus used, these mimetics induce a transient response in otherwise healthy subjects; for example, administration of LPS results in enhanced production of IL-6 (approximately 80-fold) and IL-1β (approximately 4-fold), peaking at 3 h after a challenge and returning to baseline at 24 h ( 32 ) . CNS responses to (patho)physiological stimuli, such as genuine infections or low-grade inflammation as a result of the MetS, are less well described.

Development of sickness behaviour in response to an infection is part of the normal response to fighting infection, and can occur during low-grade sub-pyrogenic inflammation ( 41 ) ; however, these adaptive responses are not always harmless. Microglia have a very low turnover, and it has been suggested that these long-lived cells have an innate memory, resulting in a prolonged and heightened response under neuroinflammatory conditions ( 43 ) . A normal part of the homeostatic signalling from the periphery to the brain, therefore, has the potential to have a profound impact on brain disease initiation or progression ( 44 , 45 ) . In a recent prospective clinical study, Alzheimer's disease patients were followed for 6 months and assessed for the presence of circulating cytokines, episodes of microbial infection and cognitive decline. Patients with both high levels of TNF-α (>4·2 pg/ml) at baseline and microbial infection during the assessment period showed a 4-fold greater cognitive decline, relative to patients with low levels of TNF-α ( < 2·4 ng/ml) at baseline and no infections ( 46 ) . Raised serum levels of TNF-α and IL-6, but not CRP, are also associated with increased frequency of other common neuropsychiatric symptoms observed in Alzheimer's disease patients, including apathy, anxiety, depression and agitation ( 47 ) .

Recently, the effects of LPS and a real infection ( Salmonella typhimurium ) on cerebral endothelial and microglial activation were compared. While LPS administration resulted in a robust but transient neuroinflammatory response, a genuine infection induced a prolonged pro-inflammatory cytokine response in the CNS, leading to microglial priming ( 48 ) .

A detailed consideration of the impact and mechanistic basis for the association between neuroinflammation and neuronal and overall CNS function, cognition and the risk of age-related cognitive decline and dementia is outside the scope of the present review, and has been the topic of many recent expert review articles ( 49 – 54 ) .

Collectively, these data highlight inflammatory pathways as important targets for strategies promoting healthy brain ageing and reducing the risk of age-related cognitive decline.

Dietary modulation of low-grade inflammation

There is a substantial amount of evidence to suggest that many foods, nutrients and non-nutrient food components modulate inflammation both acutely and chronically ( 1 , 6 ) . However, dietary studies have been typically limited to measuring a small number of blood markers of inflammation, often in the fasting state, and these may not necessarily reflect inflammation in tissue compartments or what happens in response to inflammatory challenges. This presents a significant limitation to our understanding of diet/nutrient–inflammation interactions. Previous ILSI Europe activities have dealt extensively with the food/nutrition–inflammation interaction ( 6 , 7 ) , and it is beyond the scope of the present review to provide a systematic or extensive coverage of this area. Instead, some specific examples will be discussed.

Dietary fats and inflammation

Dietary fatty acids may affect inflammatory processes through effects on body weight and adipose tissue mass and via an impact on membrane and lipid raft composition and function. Within the cell, membrane-derived fatty acids and their derivatives can influence inflammation by serving as modulators of NF-κB and PPAR-α/γ transcription factor pathways ( 55 ) , and as precursors for a host of eicosanoid and docosanoid oxidation products produced via the action of epoxygenases, lipoxygenases and cyclo-oxygenases ( 56 ) . Also, recent advances in the field have uncovered NLRP3 (NACHT, LRR and PYD domains-containing protein 3) inflammasome activation and IL-1β signalling as a key sensor of SFA-mediated metabolic stress in obesity and T2DM ( 57 ) and EPA- and DHA-derived resolvins and protectins that actively ameliorate a pro-inflammatory state ( 58 ) . Obesity significantly reduced DHA-derived 17-hydroxydocosahexaenoic acid, a resolvin D1 precursor, and protectin D1 in adipose tissue, which may in turn have pro-inflammatory consequences ( 59 ) . Also, dietary EPA/DHA supplementation within an obesogenic dietary challenge restored endogenous adipose resolvin and protectin biosynthesis, concomitant with attenuated adipose inflammation and insulin resistance ( 59 ) . An elegant human study showed that a relatively high dose of LC n -3 PUFA augmented anti-inflammatory eicosanoid secretion and attenuated inflammatory gene expression in the subcutaneous adipose tissue of severely obese non-diabetic patients ( 60 ) . Thus, there is much recent information on novel mechanisms of action by which dietary fatty acids of different classes influence inflammatory processes, some acting in pro-inflammatory and others in anti-inflammatory or inflammation-resolving ways.

There is some evidence, albeit not always consistent, for pro-inflammatory effects of dietary SFA ( 1 ) . Much of this evidence comes from either in vitro or cross-sectional studies, and there are limited randomised controlled trial (RCT) examining changes in SFA intake and inflammation in humans. The LIPGENE RCT investigated the effects of substituting dietary SFA with MUFA or as part of a low-fat diet, with or without LC n -3 PUFA supplementation, in subjects with the MetS ( 61 ) . While a low-fat n -3 PUFA-enriched diet significantly reduced the risk of the MetS ( 62 ) , modifying dietary fat had no significant effect on key biomarkers of cardiometabolic risk including insulin sensitivity and the plasma inflammatory markers assessed ( 63 ) . However, there was clear modulation of NF-κB-mediated inflammation and oxidative stress in the postprandial state according to lipid composition ( 64 , 65 ) . This lack of impact of LC n -3 PUFA on the fasting plasma inflammasome in humans ( 66 ) is in line with previous human studies ( 63 , 67 ) , but contradicts the effects observed in a wide variety of cell and animal models. However, as will be discussed in the section ‘Translating research into public health benefit and novel products’, it is difficult to know whether the output from these RCT truly demonstrates a lack of efficacy or reflects insufficient dose and/or duration or poor selection of fasting plasma biomarkers of inflammation, which are insensitive to physiologically meaningful changes occurring in key metabolic tissues such as the liver and adipose tissue.

As with other common phenotypes, there is evidence emerging that the associations between dietary fat composition and inflammation are influenced by common gene variants ( 68 ) . In the LIPGENE study, SNP in the genes encoding the anti-inflammatory peptide adiponectin (ADIPOQ) and its receptor (ADIPOR1) have been shown to interact with SFA to modulate the effect of dietary fat modification on insulin resistance ( 69 ) , and using a case–control approach, it was observed that a common SNP of the C3 gene was related to the risk of the MetS, but more importantly, the impact of this was greatly accentuated by high plasma levels of SFA ( 70 ) . Also, the combination of polymorphisms in genes encoding IL-6, lymphotoxin α (LTA) and TNF-α had an additive effect, which interacted with plasma fatty acid status to modulate the risk of the MetS ( 71 ) . Grimble et al. ( 72 ) demonstrated that the ability of LC n -3 PUFA to decrease TNF-α production is influenced by inherent TNF-α production and by polymorphisms in the TNF-α and LTA genes.

Inflammation in the postprandial state is likely to contribute to the pathological impact of exaggerated postprandial lipaemia ( 73 ) . Although there has been some investigation of the impact of meal fatty acid composition on non-fasting inflammatory biomarkers, the data thus far remain inconsistent ( 73 ) . It has been reported that in overweight men, plasma IL-6, TNF-α and soluble vascular adhesion molecule-1 concentrations decreased after an n -6 PUFA-rich meal, while markers were increased after a SFA-rich meal ( 74 ) . In contrast, Manning et al. ( 75 ) showed that high-fat meals increased IL-6, independent of the type of fatty acid, and had no impact on IL-8 and TNF-α concentrations.

Dietary carbohydrates and inflammation

Besides postprandial lipaemia, postprandial glucose is an independent predictor of diabetes and CVD, an effect which may be mediated through oxidative stress and inflammation ( 76 ) . Importantly, there appears to be no glycaemic threshold for reduction of either microvascular or macrovascular complications. The progressive relationship between plasma glucose and the risk of CVD extends well below the diabetic threshold ( 77 , 78 ) .

Acute glucose variations from peaks to nadirs include postprandial glucose excursions that can be described by two components. The first component, which is the duration of the postprandial glucose increment, is a major contributor to chronic sustained hyperglycaemia, while the second component, which is the magnitude of the postprandial rise, is more often a reflection of glucose variability. It is difficult to discriminate between the contributions of these two components of dysglycaemia. It seems that both contribute to the two main mechanisms that lead to diabetic and cardiovascular complications, namely excessive protein glycation and activation of oxidative stress and inflammation.

Although mechanistic evidence indicates a positive correlation between the glycaemic index and load of the diet and low-grade inflammation, intervention studies, to date, do not convincingly support this. Hu et al. ( 79 ) observed a stepwise relationship between dietary glycaemic index and oxidative stress markers in healthy adults. Furthermore, high-glycaemic index carbohydrates increase NF-κB activation and NF-κB binding in mononuclear cells of young, lean healthy subjects ( 80 ) . Diets low in glycaemic load and high in whole grains may have a protective effect against systemic inflammation in diabetic patients, as reviewed elsewhere ( 81 ) . Consistent with this, epidemiological studies have shown an inverse relationship between dietary fibre and CRP levels. Both the DASH diet (naturally high in fibre, i.e. 30 g fibre/d) and a fibre-supplemented usual diet (30 g psyllium fibre/d) decreased CRP concentrations in lean normotensive subjects ( 82 ) . In contrast, a high-carbohydrate, low-fat diet with a relatively high dietary fibre and complex carbohydrate content, within the context of a lifestyle intervention programme, has been shown to reduce diabetes incidence in the long term by 50 % ( 83 ) . The prominent role of the type of carbohydrate has also been illustrated in studies showing that dietary carbohydrate modification, i.e. an oat/wheat/potato diet, up-regulated sixty-two genes related to stress, cytokine–chemokine-mediated immunity and IL pathways compared with a rye–pasta diet ( 84 ) . These differences in the inflammatory response have been ascribed to differences in the early insulin response and the resultant late hypoglycaemia in the oat/wheat/potato group.

Taken together, studies have suggested that healthy eating patterns characterised by reduced postprandial glycaemia and lipaemia are associated with reduced concentrations of markers of low-grade inflammation.

Plant bioactive compounds and inflammation

Recent prospective cohort data suggest that improved cognitive function and a reduced risk of age-related neurodegenerative diseases, associated with increased fruit and vegetable intake ( 85 – 87 ) , may be in large part attributable to intake of specific flavonoids ( 87 ) , and may involve an effect on inflammatory processes ( Table 1 ). In particular, increased consumption of total flavonoids was positively associated with episodic memory in middle-aged adults ( 88 ) and with a reduced rate of cognitive decline in adults aged 70 years and over ( 89 ) . The anthocyanin group of flavonoids, with certain soft fruits providing the most significant dietary source, has emerged as being particularly potent. In the Nurses' Health Cohort, greater intakes of blueberries and strawberries were associated with slower rates of cognitive decline, with a high intake of soft fruits estimated to delay cognitive ageing by up to 2·5 years ( 90 ) . Furthermore, a large cross-sectional study has also indicated that total flavonoid intake is inversely correlated with serum CRP concentrations ( 91 ) . In support of this association, a number of dietary intervention studies have provided evidence that dietary flavonoids are capable of modulating inflammatory cytokines (e.g. TNF-α) and CRP production ( 91 – 94 ) . However, there are relatively few human RCT investigating the anti-inflammatory and cognitive effects of flavonoids ( Table 1 ).

Dietary flavonoids and inflammation: evidence from epidemiological and intervention studies

CRP, C-reactive protein; TNF-R2, TNF receptor 2; IFN-α, interferon-α; RANTES, regulated on activation, normal T-cell expressed and secreted; 8-OHdG, 8-hydroxydeoxyguanosine.

Although the effects of flavonoids were originally ascribed to an antioxidant action, it is now clear that levels achieved in biological tissues may not be sufficient to act in this way. Evidence indicates that flavonoids are capable of acting in a number of other ways that may result in their targeting of inflammation, including (1) the modulation of intracellular signalling cascades that control neuronal survival, death and differentiation; (2) an impact on gene expression and (3) interacting with the mitochondria ( 95 – 98 ) . In particular, emerging evidence suggests that dietary flavonoids may exert neuroprotective effects by suppressing the activation of microglia, which mediate inflammatory processes in the CNS (see the earlier section). Although rather complex, the main anti-inflammatory properties of flavonoids include (1) an inhibitory role in the release of cytokines, such as IL-1β and TNF-α, from activated microglia; (2) an inhibitory action against inducible NO synthase induction and subsequent NO production in response to glial activation; (3) an ability to inhibit the activation of NADPH oxidase and subsequent generation of reactive oxygen species in activated glia; and (4) a capacity to down-regulate the activity of pro-inflammatory transcription factors, such as NF-κB, through their influences on a number of glial and neuronal signalling pathways ( 99 , 100 ) . However, almost all mechanistic studies have been carried out in vitro at rather supraphysiological concentrations, with limited research on animal models and scarce data from human RCT.

Early-life nutrition and inflammation

During development, the human embryo and fetus undergo an enormously complex series of changes in both cell type and cell number. Each of these changes takes place in a strictly choreographed series, and disruption of the process can lead to dramatic and long-lasting consequences. There are many recent summaries of the processes involved ( 101 ) . In humans, this was most clearly demonstrated in the Second World War, when Dutch women were placed under famine conditions following a railway workers' strike (the Dutch Hunger Winter) ( 102 , 103 ) . Studies on the offspring of women who were pregnant at this time have shown clearly that women who were pregnant in the first trimester gave birth to babies who would go on to develop a much wider spectrum of health problems than babies born to women who were in the second or third trimester, though these offspring still would continue to show health problems ( 104 ) .

Factors other than undernutrition can also have both short- and long-term consequences. Of particular relevance, obese women give birth to babies with a higher risk of both small for gestational age and large for gestational age, of complications at birth and of developing the MetS ( 105 , 106 ) . All these cannot be explained by postnatal events, and are at least partly explained by the phenomenon known as ‘fetal programming’ or ‘developmental programming’ ( 107 , 108 ) . This hypothesis states that nutrition-related exposures in utero ‘programme’ the baby to expect a postnatal nutritional environment, and if a different one is experienced, then there is a risk of the development of metabolic complications. There have been refinements to the basic hypothesis and to our understanding of the mechanisms involved ( 109 – 112 ) ; however, the fundamental observations remain unchanged and unchallenged. How these associations are mediated is not yet clearly demonstrated, but several hypotheses are being tested. There is substantial support for nutrition altering the epigenetic profile of the offspring, including hypermethylation of cytokine receptors. Evidence indicates that low Fe status at birth, which is associated with impaired lung function in children, can result in reduced nephron number and decreased levels of cell-cycle enzymes ( 113 ) , suggesting that nutritional deficiency during a critical phase of development can inhibit organ growth. This fits with data showing that thymus growth is reduced, and that this leads to changes in the cytokine profile.

Maternal obesity also has dramatic effects on pregnancy outcome. Again, there are many detailed reviews dealing with this topic ( 107 ) . The mechanisms seem to involve inflammatory responses, and increased cytokine levels have been reported in the placenta and cord blood of babies born to obese mothers. Whether, in humans, the placenta alone is responsible is not clear, and it is quite likely that adipose tissue itself, which becomes infiltrated with macrophages, will produce increased amounts of pro-inflammatory cytokines ( 114 ) . The situation becomes more complex in obesity, because in addition to the cytokines, or possibly because of the cytokines, inflammation results in changes in Fe metabolism ( 115 ) , and there is abundant evidence to show that decreased Fe status during pregnancy has adverse effects on the offspring ( 116 – 119 ) . Obesity results in increased hepcidin production ( 120 , 121 ) . Hepcidin is a negative regulator of Fe absorption ( 122 ) , and lower Fe status in the mother before birth is associated with an increased risk of wheezing in the children (W Bright, G Devereux, HJ McArdle, unpublished results). Thus, decreased Fe status may be an additional risk factor in obese mothers.

Translating research into public health benefit and novel products

Biomarkers of inflammation in human nutrition studies.

As explained previously, inflammation is a normal process, and there are a large number of cells and mediators involved; measurement of these is often used as a ‘biomarker’ of inflammation, i.e. an indicator that inflammation is occurring. These cells and mediators are largely involved in, or are produced as a result of, the inflammatory process, irrespective of the trigger or its location in the body, and are common to all inflammatory situations ( 1 ) . To monitor inflammation in a meaningful way, the markers used must be valid: they must reflect the inflammatory process under study and must be predictive of future health status. The range of potential biomarkers of inflammation was considered by an Expert Group of ILSI Europe, with the aim of identifying robust and predictive markers, or patterns or clusters of markers, which can be used to assess inflammation in human nutrition studies in the general population; markers indicative of a specific inflammatory pathology (e.g. rheumatoid arthritis) and/or in less accessible tissue sites (e.g. in lung lavage fluid or in intestinal biopsy material) were not considered to be relevant to more healthy populations ( 7 ) . Currently, there is no consensus as to which markers best represent low-grade inflammation ( 6 ) , or differentiate between acute and chronic inflammation or between the various phases of inflammatory responses ( 7 ) . Therefore, a range of blood cellular markers (e.g. total leucocytes, granulocytes and activated monocytes) and soluble mediators (cytokines and chemokines (TNF, IL-1, IL-6, IL-8, CC chemokine ligand 2 (CCL2), CCL3, CCL5), adhesion molecules (vascular cell adhesion molecule-1, intercellular adhesion molecule-1, E-selectin), adipokines (adiponectin) and acute-phase proteins (CRP, serum amyloid A, fibrinogen)) are frequently measured. Some of these are associated with future risk of CVD and with cardiometabolic health ( 1 , 6 , 7 ) . However, there are several key issues concerning the use of these markers as determinants of low-grade inflammation. First, they are non-specific acute-phase response and pro-inflammatory response markers, and, by themselves, do not represent metabolic low-grade inflammation. Second, even in healthy individuals, there is wide variation in the measurements made. This is because there are a number of modifying factors that affect the concentration of an inflammatory marker at a given time. These modifying factors include age, diet, body fatness, physical fitness and genetics, among others ( 1 ) .

One can question whether static measurements of single or complex biomarkers are truly informative about health status, reasoning from the concept that health is defined by the ability to adequately adapt to everyday challenges ( 123 ) . Measuring the concentration of inflammatory markers in the bloodstream under basal conditions is probably less informative and relatively insensitive compared with measurements of the concentration change in response to a challenge. A number of inflammatory challenges have been described. These include an oral glucose load ( 80 ) , an oral fat load ( 124 , 125 ) , acute exercise, administration of bacterial LPS ( 126 ) , exposure to UV irradiation ( 127 , 128 ) and vaccination. Although each of these challenges has been used in nutritional studies, many are poorly standardised, limiting the comparisons that can be made. Most often, the markers measured in response to challenges are those mentioned earlier in the context of static basal measurements. Currently, a number of large European consortia, i.e. PhenFlex ( http://www.nugo.org/everyone/42 701/7/0/30 ), NutriTech ( http://www.nugo.org/nutritech ) and BioClaims ( http://bioclaims.uib.es ), are developing and validating the metabolic challenge test concept for application in the assessment of health status, including the study of inflammatory process markers ( 129 ) .

The past decade has seen huge growth in innovation in ‘omics’ technologies that provide enormous opportunities for high-throughput biological sample characterisation, with patterns and clusters of markers (signatures or fingerprints) emerging as robust biomarkers of inflammation ( 89 , 130 ) . The enormous challenge in this era of big data is making biological sense of different levels of data, including the transcriptome, proteome, metabolome and clinical chemistry data. Novel data analysis methodologies, such as machine learning, offer large potential for identifying relevant data for specific biological outcomes based on complex multidimensional datasets ( 131 ) . In addition, bioinformatic tools have been developed to interpret these complex data in the context of existing biological knowledge in the literature and databases, also termed network biology ( 132 , 133 ) . These technologies will be instrumental to the discovery of relevant biomarker signatures that reflect ‘low-grade inflammation’ based on inflammatory response networks connected to organ-specific metabolic derailment.

With the coming of age of the ‘omics’ technologies and bioinformatic tools, a large increase in the number, specificity and sensitivity of candidate biomarkers of inflammation can be expected in the next decade ( 134 ) . A screening of the ‘Thomson Reuters Integrity SM Biomarker Database’ reveals that as of May 2014, 945 candidate biomarkers of inflammation have been described, of which only seventeen, including CRP, TNF-α, serotransferrin and erythrocyte sedimentation rate, have been developed into biomarker assays approved and recommended by regulatory bodies for use in clinical studies. This represents the classical biomarker gap: many candidate biomarkers are identified based on preclinical and clinical studies; however, due to relatively limited efforts in validation and assay development, these are subsequently not further developed ( 135 ) . To accelerate biomarker development, a paradigm shift in this area is needed; instead of single companies developing a single biomarker assay, pre-competitive collaborations between different industrial, academic, and research and technology organisations have the advantage of a more efficient development process time- and cost-wise, by combining a wide diversity of expertise, in the development of a harmonised, standardised and accepted assay. In these consortia, ideally, companies from nutrition, pharma and diagnostics join forces in a pre-competitive way.

A major concerted effort should comprise (1) the discovery of context-based biomarker signatures for the assessment of the status of low-grade inflammation, (2) the development of challenge tests that determine the inflammatory response functionality in the context of metabolic stress-induced low-grade inflammation, and (3) the development of the identified biomarkers towards application in a clinically accepted assay, with normative data.

Low-grade inflammation and health claims

The European Food Safety Authority (EFSA) guidance document on scientific requirements for health claims related to gut and immune function ( 136 ) specifically states that chronic inflammation is associated with the development of a number of diseases, and that ‘altering levels of markers of inflammation might indicate a beneficial effect in the context of “a reduction of disease risk claim”, if it can be demonstrated that altering the levels of inflammatory markers is accompanied by a reduced incidence of a disease for a specific dietary intervention’. No additional specificity is added for chronic low-grade inflammation. At present, the European Union health claim register ( http://ec.europa.eu/nuhclaims ) does not contain any authorised or non-authorised health claims that specifically address the health benefit area of suppression or control of low-grade inflammation.

To build strong health claims on nutrition for improving inflammation control in the future, one of the key focus areas should be the need for clinically relevant prognostic marker(s) or marker signatures that reflect the inflammatory state in a context-specific manner, which have been well validated and for which a robust standardised assay is available. The lack of health claims is probably attributable to the fact that, although numerous biologically plausible mechanisms have been established to explain inflammation–disease associations, no single biomarker or cluster of biomarkers of inflammation has yet been robustly demonstrated to be sufficiently predictive of future disease. Based on the EFSA guidance on this topic ( 136 ) and the classification of candidate biomarkers as described by the expert group of ILSI Europe ( 137 ) , the suggested strategy for building a EFSA health claim dossier ( Fig. 2 ) comprises (1) a definition of the composition of the product; (2) a well-founded selection of the target population; (3) the selection of a clinically relevant composite biomarker panel representing inflammation as well as the selected health benefit (or disease risk) endpoints; and (4) a number of sufficiently powered and well-controlled human studies assessing the effect of the test material (nutrient, food, product) on the relevant biomarkers in the relevant target population.

Schematic of topics to be addressed when building a dossier for a European Food Safety Authority (EFSA) health claim on control of chronic low-grade inflammation. The blue boxes indicate the main topics to be addressed; the white boxes state the actual content topics. Building a strong EFSA health claim dossier requires (1) a definition of the composition of the nutritional component including manufacturing procedures in scope and out of scope for the claim, (2) a clear definition of the target population, being the general population or a specific subpopulations at risk, including the defining parameters, (3) a definition of biomarkers measured to assess the health effects of the nutritional component, including a description of the proof of clinical relevance, or the clinical validity of the combination of inflammation biomarkers and related clinically relevant biomarkers for health benefit endpoints associated with the health claim, and (4) a full description of clinical study design for all studies included in the dossier, including statistical power analysis and safety evaluation. The red arrow indicates the primary hurdle for functional health claims in the area of chronic low-grade inflammation, which is the lack of (combinations of) inflammation biomarkers with established and therefore accepted clinical relevance. This is primarily the consequence of inflammatory responses being non-specific normal physiological responses to tissue damage, and discrimination between normal and abnormal levels or combinations has not been well established in relation to chronic low-grade inflammation. The description of the classification of clinical relevance of biomarkers (categories A–D) was adapted from Albers et al. ( 137 ) . RCT, randomised controlled trial. (A colour version of this figure can be found online at http://www.journals.cambridge.org/bjn ).

Summary and suggestions for the way forward

Inflammation is a normal component of host defence; however, elevated unresolved chronic inflammation is a core perturbation in a range of chronic diseases and is an important determinant of the pathological impact of excess adiposity. Cell, animal and human epidemiological studies have identified a number of potential diet derived anti- and pro-inflammatory components, some of which have been discussed here; this topic has been dealt with more extensively elsewhere ( 1 , 6 , 7 ) . Available human RCT evidence is more limited and sometimes conflicting or inconsistent, in part attributable to under-powered studies where inflammation was not specified as a primary study outcome. Furthermore, research tends to take a reductionist approach and examine the impact of individual dietary components in isolation, despite the identification of numerous potential diet-derived anti-inflammatory and inflammation-resolving bioactive compounds, with likely additive or synergistic effects. There is a need to take a more holistic approach and consider the impact of combinations of components of foods and dietary patterns, with a likely greater overall benefit than each single component might have on its own. Moreover, although it is evident that the inflammatory response is highly variable, a full understanding of the source of heterogeneity is distinctly lacking. More extensive profiling of participants in human studies and consideration of potential key variables such as age, sex, genotype and lifestyle factors in statistical models is needed in order to help understand the aetiology of the variation in both inflammation itself and in its response to dietary change. This approach will also allow for the identification of population subgroups that may particularly benefit from interventions that target inflammation.

Establishing and quantifying reliable, precise diet–inflammation–health associations is reliant on the availability of approved, standardised biomarkers with normative data for use in human observation studies and RCT. Biomarker research is a highly active area with significant advances to be expected in the coming years ( 138 ) . Rather than rely on a limited number of generic markers common to both acute and low-grade chronic inflammation, future inflammation ‘testing’ is likely to involve quantifying clusters or signatures of markers with some tissue specificity. Such biomarkers should generally be measured in the challenged state ( 1 ) , with the choice of the physiological stressor dependent on the tissue, and research question of interest. The biomarkers assessed are likely to include those already typically measured (cytokines, chemokines, soluble adhesion molecules, etc.), but are also likely to include tissue-specific markers and fingerprints based on gene expression profiles (e.g. in blood mononuclear cells), cell or plasma proteomics, and microRNA.

The research focus on the establishment of a robust diet–inflammation–health association is justifiable, considering the substantial role of low-grade inflammation in the pathology of numerous chronic diseases, thereby making it a key future preventative and therapeutic target.

Acknowledgements

The present review results from a workshop organised by the European Branch of ILSI Europe. This publication was coordinated by Dr Peter Putz, Scientific Project Manager at ILSI Europe. The workshop was funded by the ILSI Europe Obesity and Diabetes Task Force, the ILSI Europe Metabolic Imprinting Task Force, ILSI Brazil, ILSI North America and ILSI Southeast Asia Region. Industry members of the task forces are listed on the ILSI Europe website at http://www.ilsi.eu . For further information about ILSI Europe, please email [email protected] or call +32 2 771 00 14. The opinions expressed herein and the conclusions of this publication are those of the authors and do not necessarily represent the views of ILSI Europe nor those of its member companies.

The authors thank the members of the Organising Committee: Professor Jean-Louis Bresson and Professor Ascension Marcos for their invaluable contribution to this work through their enthusiastic and generous participation. The authors are also grateful to Ms Belinda Antonio, Ms Toula Aslanidis, Ms Ruth Marquet, Mr Pierre Mouelhi and Mr Alex Rankin for their administrative support. The authors thank Dr Lorraine Gambling, Dr Helen Hayes and Ms Val Stevens for technical assistance.

The authors' contributions are as follows: A. M. M. and P. C. C. had responsibility for producing the final version of the manuscript. All authors contributed to the discussion and had input into the writing of the manuscript.

L. S. is an employee of Newtricious and S. V. is an employee of Mondelēz International. A. B. was an employee of ILSI Europe. The remaining authors have no conflicts of interest.

Abbreviations: CNS, central nervous system; ILSI, International Life Sciences Institute; LPS, lipopolysaccharide; MetS, metabolic syndrome; NAFLD, non-alcoholic fatty liver disease; RCT, randomised controlled trial; T2DM, type 2 diabetes mellitus

How the inflamed brain becomes disconnected after a stroke

Whether reeling from a sudden stroke or buckling under the sustained assault of Alzheimer’s, the brain becomes inflamed, leading to cognitive problems and even death.

Scientists have known for many years that severe inflammation can kill the brain’s neurons. Now, researchers at UC San Francisco have discovered that even subtle inflammation damages the brain. Instead of killing neurons outright, however, relatively mild inflammation only destroys the arm-like projections, called neurites, that wire neurons together. These connections are vital for everything the brain does, including learning and memory.

The findings,  published last month  in Cell Reports, describe in detail a new degenerative pathway that scientists can now try to disrupt. This could help stem the damage from common neurological diseases. “There are several exciting drugs now entering clinical use that interrupt these inflammatory processes, and now we know to look at their effects on neurites,” said  Raymond Swanson , M.D., senior author on the paper and a professor of neurology with joint appointments at UCSF and the  San Francisco Veterans Affairs Medical Center . “Not too far off, this could have a big impact on helping our patients.”

Friendly fire from the immune system

Inflammation is the body’s first line of defense when something goes wrong. It rushes blood to an injured area, bathing it with immune cells that release chemicals to kill pathogens.

The brain’s neurons (yellow) connect with one another using a vast network of neural wires, called neurites.

The strategy works well against bacteria, but it’s brutal on the brain’s delicate neural networks. Swanson’s team wanted to know how this inflammatory process was damaging the brain. They were particularly interested in molecular aggregates, called cofilactin rods (CARs), that appear after a stroke. CARs form when two proteins, called cofilin and actin, that normally maintain neurites, break loose, forming messy clumps. CARs are known to form in response to a chemical called superoxide, which immune cells release when the brain is inflamed.

Connecting the dots from inflammation to dysfunction

To get a closer look at this process, the researchers stimulated inflammation in a part of the mouse brain that controls movement. They expected that neurons would die and the mice would have trouble moving.

Ray Swanson’s team discovered that inflammation — a consequence of diseases like Alzheimer's and stroke — destroys these wires but spares the neurons.

The mice did struggle to move, but when the researchers looked at their brain tissue under a microscope, they were surprised to see that only the neurites had withered away, leaving the neurons isolated like stars in the night sky. The loss of these connections was enough to rob the mice of some of their motor coordination. The scientists then tried reducing the amount of either superoxide or cofilin, and treated the brain with the same inflammatory substance. Under these conditions, fewer CARs formed, and the neurites survived. The mice also retained their coordination. They had discovered a new pathway: inflammation caused immune cells to release superoxide, pulling cofilin and actin out of neurites and making CARs. Neurites died, and the disconnected brain malfunctioned.

A new target for treating neurodegeneration

Many neurological diseases involve inflammation, including multiple sclerosis, traumatic brain injury, and amyotrophic lateral sclerosis (ALS). Now that scientists understand it better, they can design therapies to interrupt this inflammatory pathway. Stroke patients, for example, could be treated early on with anti-inflammatory agents to shield neurites from damage and preserve cognition. “Particularly in the aging brain, inflammation can be harmful,” Swanson said. “By homing in on how neurites are so vulnerable to inflammation, we may be able to finally gain the upper hand against some of the most common neurological diseases.”

In laboratory animals treated with increasing doses of the inflammatory molecule, S100β, the healthy web of neurites slowly deteriorates, leaving the neurons disconnected.

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Study of cancer-induced liver inflammation finds a promising therapeutic target

by Perelman School of Medicine at the University of Pennsylvania

Liver inflammation, a common side-effect of cancers elsewhere in the body, has long been associated with worse cancer outcomes and more recently associated with poor response to immunotherapy. Now, a team led by researchers from the Abramson Cancer Center and Perelman School of Medicine at the University of Pennsylvania has found a big reason why.

In their study, published today in Nature Immunology , the researchers discovered that cancer-induced liver inflammation causes liver cells to secrete proteins called serum amyloid A (SAA) proteins, which circulate through the body and hinder the ability of T cells—major anticancer weapons of the immune system—to infiltrate and attack tumors elsewhere.

"We want to better understand what causes cancer to resist or respond to immunotherapy to help design more effective strategies for patients," said senior author Gregory Beatty, MD, Ph.D., an associate professor of Hematology-Oncology and the director of Clinical and Translational Research for the Penn Pancreatic Cancer Research Center.

"Our findings show that liver cells—with their release of SAA proteins—effectively serve as an immune checkpoint regulating anti-cancer immunity, making them a promising therapeutic target."

The study builds on previous research from the team, including co-lead authors Meredith Stone, Ph.D., a research associate, and Jesse Lee, a graduate student, into liver inflammation in cancer: In a 2019 study , they showed how it promotes pancreatic tumor metastasis to that organ.

In 2021 , researchers from the Beatty Laboratory observed that systemic inflammation, involving many of the same molecules implicated in liver metastasis, is associated with worse responses to immunotherapies in pancreatic cancer patients. The latest study was designed to investigate in more detail how liver inflammation may block the effects of these immune-boosting therapies.

First, they looked at mouse models of pancreatic cancer, measuring the amount of T-cell infiltration in pancreatic tumors—a basic indicator of anti-tumor immune activity. They found that mice with less T cell infiltration in their tumors tended to have more liver inflammation. These mice also showed stronger signs of an inflammatory signaling pathway called the IL-6/JAK/STAT3 pathway—the same one the team had implicated in liver metastasis in their 2019 study.

The researchers next showed that STAT3 activation in liver cells is associated with the reduced production of immune cells called dendritic cells , which are critical for normal T cell responses. When the scientists deleted STAT3 from liver cells, dendritic cell production and T cell activity picked up, and tumors that previously had only low T cell-infiltration developed high T cell-infiltration.

Ultimately the team found that STAT3 activation in liver cells has its dendritic cell- and T cell-suppressing effect by inducing the production of SAA proteins, which target receptors on immune cells. Deleting the SAA proteins had the same immune-restoring effect as deleting STAT3, and increased survival times and the likelihood of cures in mice that had pancreatic tumors surgically removed.

To get a sense whether the mouse model findings would translate to humans, the researchers measured SAA levels in tissue samples from patients whose pancreatic tumors had been surgically removed and found that those with low SAA levels at surgery went on to have significantly longer survival times afterward.

"The translational findings in human patients highlight the likely clinical relevance of our discoveries in the mice," Beatty said. "Now that we've shown how liver inflammation puts up a roadblock to immunotherapy, our next step is to see if the same pathway can be targeted to reverse inflammation in patients who already have liver metastasis."

The research team is now working to set up further preclinical and eventually clinical studies of STAT3- and/or SAA-inhibiting agents as potential add-on therapies in combination with immunotherapy—for example, prior to surgery—that could improve cancer patient outcomes.

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New Research Shows How Brain Inflammation in Children May Cause Neurological Disorders Such as Autism or Schizophrenia

October 12, 2023 | Heide Aungst

Findings Show Inflammation Stops Some Neurons from Maturing in the Developing Brain, Which Could Open the Door to New Treatments

Severe   inflammation in   early   childhood is a clinically known risk factor for developing autism and schizophrenia. Now, for the first time, scientists from the University of Maryland School of Medicine (UMSOM) have discovered that inflammation alters the development of   vulnerable brain cells, and this could have mechanistic links to neurodevelopmental disorders. This finding could lead to treatments for many different childhood-onset neurodevelopmental disorders.

Using single-cell genomics to study the brains of children who died from inflammatory conditions—such as a bacterial or viral infections or asthma—along with those who died from a sudden accident, researchers from the University of Maryland School of Medicine (UMSOM) led a study that found inflammation in early childhood prevents specific neurons in the cerebellum from maturing completely. The cerebellum is a brain region responsible for motor control and higher cognitive functions used in language, social skills, and emotional regulation.

Previous research has shown that babies born with abnormalities of the cerebellum frequently go on to experience neurodevelopmental disorders, and animal models exposed to inflammation before birth also develop these conditions.

“We looked at the cerebellum because it is one of the first brain regions to begin developing and one of the last to reach its maturity, but it remains understudied,” said Seth Ament, PhD , IGS scientist and Associate Professor in the Department of Psychiatry at UMSOM who co-led the research with Margaret McCarthy, PhD , the James and Carolyn Frenkil Dean’s Professor and Chair in Pharmacology and Director of UM-MIND. “With the fairly new technology of single nucleus RNA sequencing we could look at the cell level to see changes in the brains.”

The researchers examined donated post-mortem brain tissues of 17 children who died when they were one to five years old, eight from conditions that involved inflammation and nine from accidents. None of the donors had been diagnosed with a neurological disorder prior to death. The two groups were similar in age, gender, race/ethnicity, and time since death. These unique brain tissue specimens had been collected over many years by UMSOM researchers at the   University of Maryland Brain and Tissue Bank , a tissue repository of the NIH NeuroBioBank, as well as the Maryland Brain Collection of the Maryland Psychiatric Research Center .

The study found that two specific, yet rare types of cerebellar neurons were most vulnerable to brain inflammation—the Golgi and Purkinje neurons. At the single-cell level, these two types of neurons showed premature disruption of their maturation.

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“Although rare, Purkinje and Golgi neurons have critical functions,” Dr Ament said. “During development, Purkinje neurons form synapses connecting the cerebellum to other brain regions involved in cognition or emotional control, while Golgi neurons coordinate communication between cells within the cerebellum.  Disruption of either of these developmental processes could explain how inflammation contributes to conditions like autism spectrum disorders and schizophrenia.”

As with many diseases, both genetics and the environment—in this case, inflammation—likely contribute to the risk of developing these disorders. That’s why it is crucial to understand the roles of specific cells within the brain regions—as well as how they interact with genes to influence brain function—to find treatments for brain disorders, like ASD and schizophrenia, as well as others including dementia, Parkinson’s disease, or substance use disorders.

The data from this study—along with all of the BRAIN Initiative papers—has been deposited in the Neuroscience Multi-Omic Archive (NeMO Archive)— a curated genomic data repository—housed at the Institute for Genome Sciences at UMSOM. Neuroscience researchers can access the archive’s data through a user-friendly portal to transform their understanding of the complex workings of the brain.

About the Institute for Genome Sciences : The Institute for Genome Sciences (IGS) at the University of Maryland School of Medicine has revolutionized genomic discoveries in medicine, agriculture, environmental science, and biodefense since its founding in 2007. IGS investigators research areas of genomics and the microbiome to better understand health and disease, including treatments, cures, and prevention. IGS investigators also lead the development of the new field of microbial forensics. IGS is a leading center for major biological initiatives currently underway including the NIH-funded  Human Microbiome Project  (HMP) and the NIAID-sponsored  Genomic Sequencing Center for Infectious Diseases  (GSCID). Follow us on X @GenomeScience and @MDGenomics.

About UM-MIND : The newly founded University of Maryland – Medicine Institute for Neuroscience Discovery ( UM-MIND ) focuses on foundational and translational research in the areas of brain development, neuropsychiatric disorders, traumatic brain injury, brain cancers, aging and neurodegenerative disorders.  State-of-the-art facilities in microscopy and CRISPR-Cas9 technology provide researchers with the tools they need to unravel the many remaining mysteries of brain function in both health and disease. Follow us on X @um_mind.

About the University of Maryland School of Medicine

Now in its third century, the University of Maryland School of Medicine was chartered in 1807 as the first public medical school in the United States. It continues today as one of the fastest growing, top-tier biomedical research enterprises in the world -- with 46 academic departments, centers, institutes, and programs, and a faculty of more than 3,000 physicians, scientists, and allied health professionals, including members of the National Academy of Medicine and the National Academy of Sciences, and a distinguished two-time winner of the Albert E. Lasker Award in Medical Research. With an operating budget of more than $1.2 billion, the School of Medicine works closely in partnership with the University of Maryland Medical Center and Medical System to provide research-intensive, academic, and clinically based care for nearly 2 million patients each year. The School of Medicine has more than $500 million in extramural funding, with most of its academic departments highly ranked among all medical schools in the nation in research funding. As one of the seven professional schools that make up the University of Maryland, Baltimore campus, the School of Medicine has a total population of nearly 9,000 faculty and staff, including 2,500 students, trainees, residents, and fellows. The School of Medicine, which ranks as the  8th highest  among public medical schools in research productivity (according to the Association of American Medical Colleges profile) is an innovator in translational medicine, with 606 active patents and 52 start-up companies. In the latest  U.S. News & World Report  ranking of the Best Medical Schools, published in 2023, the UM School of Medicine is  ranked #10 among the 92 public medical schools  in the U.S., and in the top 16 percent  (#32) of all 192 public and private  U.S. medical schools. The School of Medicine works locally, nationally, and globally, with research and treatment facilities in 36 countries around the world. Visit  medschool.umaryland.edu

Heide Aungst [email protected] 216-970-5773 (cell)

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Acute inflammation articles from across Nature Portfolio

Acute inflammation is a short-term process occurring in response to tissue injury, usually appearing within minutes or hours. It is characterized by five cardinal signs: pain, redness, immobility (loss of function), swelling and heat.

Maternal rhythms suppress neonatal inflammation

Maternal circadian rhythms influence the health of infants. Cui, Xu and colleagues find that disruption of maternal rhythms impairs neonatal immune cell function and aggravates neonatal inflammatory disorders, which can be rescued by the administration of docosahexaenoic acid (a metabolite found in breast milk).

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Preparation of AIEgen-based near-infrared afterglow luminescence nanoprobes for tumor imaging and image-guided tumor resection

This protocol describes the preparation of long-lasting aggregation-induced emission-based, near-infrared afterglow luminescence nanoprobes. Their enhanced afterglow intensity results in improved imaging sensitivity and depth in vivo.

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Intranasal administration of ceramide liposome suppresses allergic rhinitis by targeting CD300f in murine models

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A rare case of spontaneous giant pneumorrachis presenting with cauda equina syndrome: a case report

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A distinct subtype of stromal cell orchestrates the inflammatory response to tissue injury

After acute injury to skeletal muscle, an ‘early responder’ subtype of stromal cells rapidly produces an array of inflammatory mediators. Disruption of this response causes abnormal accumulation of several adaptive lymphocyte populations, a prolongation of inflammation, and an effect on tissue regeneration.

Inflammaging aggravates stroke pathology

In mice and humans, changes in neutrophil phenotypes and functionality during aging aggravate thromboinflammation in ischemic brain injury and determine the pathology associated with strokes. In mice, inhibition of CXCL3 signaling and rejuvenation of bone marrow offer ways of restricting brain injury and improving stroke outcomes.

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ERADication of STING limits inflammation

The cGAS–STING cytosolic double-stranded-DNA-sensing pathway provides protection against infection but also contributes to inflammatory pathology and thus must be tightly regulated. In this issue, Jie et al. find that endoplasmic-reticulum-associated degradation of the adaptor STING by SEL1L–HRD1 controls steady-state STING levels to limit STING-driven inflammation.

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Therapeutic Treatment Long COVID leads to inflammatory markers in the blood

People with long COVID have distinct patterns of inflammation detectable in the blood, which could potentially be targeted with immune therapies.

Findings from the largest UK study of patients hospitalised with SARS-CoV-2 infection show that long COVID leads to ongoing inflammation which can be detected in the blood.

In an analysis of more than 650 people who had been hospitalised with severe COVID-19, patients with prolonged symptoms showed evidence of immune system activation.

The exact pattern of this activation varied depending on the sort of symptoms that they predominantly had – for example, mainly fatigue or cognitive impairment.

The research, led by Imperial College London with infrastructure support from NIHR Imperial BRC, suggests that existing drugs which modulate the body’s immune system could be helpful in treating long COVID and should be investigated in future clinical trials

The study , published in the journal  Nature Immunology , is the latest research from two collaborative UK-wide consortia, PHOSP-COVID and ISARIC-4C.

These involve scientists and clinicians from Imperial alongside collaborators from the Universities of Leicester, Edinburgh and Liverpool among others and core funded by UK Research and Innovation (UKRI) and the NIHR.

Professor Peter Openshaw , from Imperial’s National Heart & Lung Institute and an ISARIC-4C lead investigator, said: “With one in ten SARS-CoV-2 infections leading to long COVID and an estimated 65 million people around the world suffering from ongoing symptoms, we urgently need more research to understand this condition. At the moment, it’s very hard to diagnose and treat.

“This study, which includes detailed clinical data on symptoms and a raft of inflammatory blood plasma markers, is an important step forward and provides crucial insights into what causes long COVID.”

Runaway inflammation

In the latest study, researchers included a total of 426 people who were experiencing symptoms consistent with long COVID – having been admitted to hospital with COVID-19 infection at least six months prior to the study.

They were compared with 233 people who were also hospitalised for COVID-19 but who had fully recovered. The researchers took samples of blood plasma and measured a total of 368 proteins known to be involved in inflammation and immune system modulation.

They found that, relative to patients who had fully recovered, those with long COVID showed a pattern of immune system activation indicating inflammation of myeloid cells and activation of a family of immune system proteins called the complement system.

Myeloid cells are formed in the bone marrow and produce various types of white blood cells that circulate in the blood and migrate into organs and tissues where they respond to damage and infection.

The complement system consists of a cascade of linked proteins that are activated in response to infection or tissue damage. Notably, overactivation of the complement system is known to be associated with many autoimmune and inflammatory conditions.

Dr Felicity Liew, from Imperial’s National Heart & Lung Institute, said: “Our findings indicate that complement activation and myeloid inflammation could be a common feature of long COVID after hospitalisation, regardless of symptom type.

“It is unusual to find evidence of ongoing complement activation several months after acute infection has resolved, suggesting that long COVID symptoms are a result of active inflammation.

“However, we can’t be sure that this is applicable to all types of long COVID, especially if symptoms occur after non-hospitalised infection.”

Sub-types of long COVID

The researchers were also able to obtain comprehensive information about the range of symptoms that patients were experiencing, and which ones were most common.

They found that certain groups of symptoms appeared to be associated with specific proteins. For example, people with gastrointestinal symptoms had increased levels of a marker called SCG3, which has previously been linked to impaired communication between the gut and the brain.

Overall, there were five overlapping subtypes of long COVID with different immune signatures, despite some commonalities, namely: fatigue; cognitive impairment; anxiety and depression; cardiorespiratory; and gastrointestinal.

The researchers stress, however, that these groups are not mutually exclusive, and people can fall between groups depending on their symptoms.

Nevertheless, these long COVID subtypes seem to represent clear biological mechanisms of disease and highlight that different symptoms may have different underlying causes. The researchers suggest this could be useful in designing clinical trials, especially for treatments that target immune responses and inflammation.

One such treatment could include drugs called IL-1 antagonists, such as anakinra, which is commonly used to treat rheumatoid arthritis, as well as another drug class called JAK inhibitors, used to treat some types of cancers and severe forms of rheumatoid arthritis. Both drug types work by targeting components of the immune system that might be activated in long COVID.

The researchers highlight that one limitation of their study was that it only included people who had severe SARS-CoV-2 infections and who were hospitalised as a result. Yet a sizeable proportion of people who develop long COVID in the wider population only report mild initial SARS-CoV-2 infection and it’s unclear if the same immune mechanisms are at work.

Professor Openshaw concludes: “This work provides strong evidence that long COVID is caused by post-viral inflammation but shows layers of complexity.

“We hope that our work opens the way to the development of specific tests and treatments for the various types of long COVID and believe that a ‘one size fits all’ approach to treatment may not work.

“COVID-19 will continue to have far reaching effects long after the initial infection has passed, impacting many lives. Understanding what’s happening in the body, and how the immune system responds, is key to helping those affected.”

The PHOSP-COVD and ISARIC4C are both funded by UK Research and Innovation (UKRI) and the National Institute for Health and Care Research (NIHR) and both include partner institutions from all four nations of the UK.

More stories from COVID-19, Infection & Antimicrobial Resistance

Award Imperial NHS Trust becomes the first in the UK to receive BSAC Antimicrobial Stewardship accreditation

Partnership New global research consortium established to optimise antimicrobial use

Award UKRI funds three projects to tackle future disease threats

Event BRC London Human Challenge Meeting

Award Three Imperial researchers awarded Academy of Medical Sciences Fellowships

New Inflammatory Bowel Disease testing protocol could speed up diagnosis

Serial home tests would reduce unnecessary colonoscopy testing.

Patients with suspected inflammatory bowel disease (IBD) could benefit from better testing protocols that would reduce the need and lengthy wait for potentially unnecessary colonoscopies, a new study has found.

In a paper published in Frontline Gastroenterology , researchers from the Birmingham NIHR Biomedical Research Centre (BRC) at the University of Birmingham tested a new protocol to improve IBD diagnosis combining clinical history with multiple home stool tests.

In the two-year study involving 767 participants, patients were triaged and had repeated faecal calprotectin (FCP) tests and the research team found that the use of serial FCP tests were able to strongly predict possible IBD as well as Crohn's Disease and Ulcerative Colitis.

The team observed that a second FCP test was a strong indicator of a potential need for further investigation including colonoscopy; although the researchers observed that only 20% of patients had two samples submitted prior to referral to secondary care.

Dr Peter Rimmer from the Birmingham NIHR Biomedical Research Centre at the University of Birmingham and corresponding author of the study said:

"Patients who experience symptoms associated with inflammatory bowel diseases often have a long wait until getting a diagnosis, and current testing is under immense strain.

"Using a comprehensive 13-point symptom checker and multiple FCP tests, we have been able to identify much more accurately patients who had IBD and other diseases. The rollout of this protocol could reduce the time taken to get a diagnosis and start treatment for IBDs as much more of the screening and testing can be done through primary care. The sensitivity of multiple FCP tests can be used to flag those patients who urgently need referral into secondary care."

Dr Rachel Cooney, Consultant Gastroenterologist at University Hospitals Birmingham NHS Foundation Trust, researcher at the NIHR Birmingham BRC and co-author of the study, added:

"In its simplest form, this study may help improve referral triage for IBD patients. But as we plan new care pathways, it could open up new exciting possibilities: with the growing availability of home FCP testing, these tests' results combined with simple symptom questionnaires could feed into algorithms that allow patients to self-refer to secondary care services, reducing strain on primary care. This is something we're going to explore in a large follow-up study we're currently initiating."

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Story Source:

Materials provided by University of Birmingham . Note: Content may be edited for style and length.

Journal Reference :

• Peter Rimmer, Jonathan Cheesbrough, Jane Harris, Melanie Love, Samantha Tull, Asif Iqbal, Daniel Regan-Komito, Rachel Cooney, Karl Hazel, Naveen Sharma, Thomas Dietrich, Iain Chapple, Mohammad Nabil Quraishi, Tariq H Iqbal. Optimising triage of urgent referrals for suspected IBD: results from the Birmingham IBD inception study . Frontline Gastroenterology , 2024; flgastro-2023-102523 DOI: 10.1136/flgastro-2023-102523

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Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration

Vaccines are a public health success story, as they have prevented or lessened the effects of many infectious diseases. To address concerns around potential vaccine injuries, the Health Resources and Services Administration (HRSA) administers the Vaccine Injury Compensation Program (VICP) and the Countermeasures Injury Compensation Program (CICP), which provide compensation to those who assert that they were injured by routine vaccines or medical countermeasures, respectively. The National Academies of Sciences, Engineering, and Medicine have contributed to the scientific basis for VICP compensation decisions for decades.

HRSA asked the National Academies to convene an expert committee to review the epidemiological, clinical, and biological evidence about the relationship between COVID-19 vaccines and specific adverse events, as well as intramuscular administration of vaccines and shoulder injuries. This report outlines the committee findings and conclusions.

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• Digital Resource: Evidence Review of the Adverse Effects of COVID-19 Vaccination
• Digital Resource: Evidence Review of Shoulder Injuries from Intramuscular Administration of Vaccines
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