The findings, published in Science Immunology, suggest that gut Clostridia can be divided into two groups, with one group contributing to gut inflammation under certain conditions.

Scientists have known that Clostridia bacteria make proteins called flagellins, which build flagella. Flagellins can also interact with the immune system, with some triggering only weak immune responses and others causing inflammation. However, it’s unclear how differences in flagellin types affect their ability to stimulate the immune system and which flagellins promote or prevent inflammation in the gut.

To address this question, Lennard Duck at the University of Alabama at Birmingham and his colleagues set out to study more than 100,000 bacterial genomes from gut Clostridia.

Immune activation

The researchers found that the genes controlling flagella, called motility genes, are arranged differently across Clostridia bacteria, even among closely related families. Some bacteria, such as Lachnospiraceae, have multiple motility genes and more diverse flagellins, while others have fewer of these genes and less diversity. 

Based on flagellin diversity and motility gene organization, the team classified gut Clostridia into two groups, G1 and G2. Next, they tested these two groups of bacteria in germ-free mice to see how they affect the gut. 

Both groups could colonize the gut, boost protective immune cells, and stimulate the production of antibodies that help maintain normal gut balance. However, G2 bacteria triggered stronger responses in gut cells, including genes linked to inflammation and stress, while G1 bacteria mainly activated protective functions. 

Gut inflammation 

When the gut’s barrier was weakened, G2 bacteria—but not G1 bacteria—caused inflammation and tissue damage in the colon lining. The researchers found that flagellins differ between G1 and G2 gut bacteria: Most G1 bacteria produce flagellins at very low levels, while G2 bacteria produce flagellins that strongly activate the immune system. What’s more, G2 flagellins stimulate inflammatory signals, whereas G1 flagellins don’t. 

In people with Crohn’s disease, G1 bacteria are typically reduced, while G2 bacteria are more abundant in inflamed tissues, the researchers also found. This finding, they say, suggests that the balance between G1 and G2 bacteria and their flagellins may influence gut inflammation and disease. 

“This study identified key features of specific commensal bacteria that have colitogenic potential and revealed one mechanism whereby these organisms can potentially initiate intestinal inflammation,” the authors say.

The findings, published in Science Immunology, suggest that maintaining healthy T cells is key to preserving gut health and preventing chronic inflammation that drives aging-related diseases.

As we age, specific immune cells called CD4 T cells build up in the gut, altering immune responses. This causes the gut barrier to weaken, allowing harmful bacteria to trigger inflammation, which contributes to aging and related diseases. However, it’s still unclear how exactly CD4 T cells drive this process.

To address this question, Manuel Gómez de las Heras at the Universidad Autónoma de Madrid and his colleagues studied mice with defective CD4 T cells caused by a mitochondrial problem that mimics aging.

Increased inflammation

As mice with faulty CD4 T cells aged, their gut lining became damaged, leading to a “leaky gut” that let harmful bacteria and toxins enter the body. This weakening of the gut barrier was associated with changes in the gut microbiota. 

While the overall number of different microbial species stayed similar to that of healthy mice, harmful bacteria linked to inflammation grew more in mice with faulty T cells, and helpful bacteria that support gut health decreased. These changes influenced how the bacteria broke down nutrients and produced beneficial molecules such as short-chain fatty acids.

Mice with faulty T cells showed symptoms such as weight loss and diarrhea, with their guts becoming swollen and inflamed, before becoming sick and dying. The loss of gut barrier integrity played a key role in the animals’ health problems, the researchers found.

Gut barrier

In mice with faulty T cells, anti-inflammatory immune cells were reduced, while cells that promote inflammation increased. These changes disrupted normal immune responses and led to increased antibody production, causing damage to the gut. Although similar problems happen naturally during aging, they appeared earlier and were more severe in these mice, the researchers found. 

Transplanting healthy CD4 T cells into the mice restored gut immune balance, strengthened the gut barrier, reduced harmful bacteria, and lowered inflammation. This treatment also delayed signs of aging-related diseases. 

The work, the authors say, “provides insights into the potential applications of T cell-based therapies to delay age-associated pathologies through the strengthening of intestinal barrier integrity.”

Writing in Gastroenterology, John Hawley at the Australian Catholic University in Melbourne and his colleagues reviewed evidence on how physical activity and muscle metabolism interact with other organs, especially the gut, and how exercise can impact the diversity of bacteria and microorganisms in the body. They also explored how exercise and the gut microbiota contribute to the prevention of gut-related diseases.

“Future efforts should concentrate on gaining a deeper understanding of the factors involved in exercise-gut interactions through the application of advanced techniques to measure both the microbiome and the systemic effects of exercise in a variety of diseased populations,” the authors say.

Gastrointestinal conditions

Regular physical activity can ameliorate health by improving cardiovascular fitness and promoting communication between organs through muscle-derived signals called myokines, which regulate metabolism and protect against diseases. Studies show that exercise diversifies the gut microbiota, increasing the levels of beneficial short-chain fatty acids. 

However, intense exercise can cause gastrointestinal symptoms, including nausea and diarrhea, which are common during activities such as prolonged running. Intense exercise can also disrupt the gut barrier, leading to inflammation and increased intestinal permeability. However, the severity of these symptoms varies based on exercise intensity, duration, fitness level and diet. 

Dietary interventions such as carbohydrate intake before exercise may help reduce gastrointestinal symptoms and intestinal damage, likely by supporting the gut microbiota. Probiotics have been tested to protect against exercise-induced gut damage, with mixed results. More research is needed to determine the most effective strains, dosages and mechanisms, the authors say.

Treating disease

Previous studies have shown that regular physical activity can alleviate symptoms of gastrointestinal conditions such as inflammatory bowel disease and irritable bowel syndrome. However, individual responses vary, and more research is needed to understand the mechanisms and optimal approaches for each condition.

Exercise also reduces the risk of various types of cancers, including colorectal cancer, by boosting immune function, activating immune cells and reducing inflammation. It influences the gut microbiota, promoting the production of butyrate and other short-chain fatty acids, which support gut health. Combining exercise with microbiota modulation could be a powerful strategy for cancer prevention and treatment, the authors say.

Finally, exercise prevents and treats many non-communicable diseases such as diabetes and obesity. Recent research suggests that fecal microbiota transfer from animals that exercise may improve metabolic health, highlighting the lasting impact of exercise on gut microbes and immunity. As research progresses, physical activity is expected to play a key role in treating several gastrointestinal diseases, the authors say.

The findings, published in Nature Biotechnology, suggest that bacteria-infecting viruses could be used as a drug delivery system for conditions such as inflammation and obesity.

Oral drug delivery is challenging because drugs must survive harsh stomach conditions and be absorbed in the gastrointestinal trait. Viruses that infect bacteria, called bacteriophages or phages, are abundant in the gut and can persist for long periods of time. 

Researchers led by Zachary Baker at Virginia Tech in Blacksburg hypothesized that genetically engineered phages could be used to deliver therapeutic proteins by infecting gut bacteria and releasing proteins upon breaking open bacterial cells.

Engineered phages

The phages were designed to express a fluorescent marker and released large amounts of it after infecting gut bacteria. In mice, the engineered phages successfully infected gut bacteria and produced fluorescent proteins in the gut, demonstrating the feasibility of using phages to deliver therapeutic proteins.

Next, the researchers engineered phages to produce an anti-inflammatory protein called Serpin, which inhibits a key driver of inflammation in colitis. In mice with the condition, phage-delivered Serpin promoted anti-inflammatory responses and improved disease symptoms.

The team also engineered phages to produce a protein that mimics a satiety hormone, and tested its effects in a mouse model of obesity. Obese mice colonized with the engineered phages gained less weight and ate less food, while also showing lower levels of inflammatory molecules associated with obesity. 

Drug delivery

The engineered phages did not alter the composition of the gut microbiota nor did they cause adverse effects, the researchers found. The findings suggest that engineered phages can deliver beneficial proteins in the mammalian gut by infecting bacteria naturally present there. 

The study also highlights the need for further research on factors such as diet, bacterial resistance and potential impacts on the gut microbiota. Future applications could involve using phages to produce different therapeutic proteins for treating complex diseases, the authors say. 

“Considering that these diseases are […] multifaceted, the in-situ production of other protein therapeutics to target other aspects of these diseases, whether together, at different stages, or alone, would be exciting future lines of investigation.”

What this research adds
Working in mice, researchers found that MAIT cells detect specific metabolites produced by bacteria. In an inflamed gut, microbes expand their production of riboflavin, which leads to an increase in riboflavin-derived metabolites. These metabolites activate MAIT cells, leading to anti-inflammatory responses. Mice lacking MAIT cells were more susceptible to gut inflammation and colorectal cancer.

Conclusions
The findings indicate that MAIT cells act as detectors of gut inflammation by interacting with the microbiota.

Gut inflammation alters the balance and function of gut microbes, but how the body senses and reacts to these microbiota changes is not yet fully understood. Now, working in mice, researchers have found that a specific type of immune cells called MAIT cells can detect molecules produced by microbes during intestinal inflammation. The resulting immune activation leads to anti-inflammatory responses in the gut.

The findings, published in Science Immunology, indicate that MAIT cells act as detectors of gut inflammation by interacting with the microbiota.

MAIT cells, or mucosal-associated invariant T cells, are a type of immune cells found in the liver and gut that are activated in conditions associated with gut dysbiosis, such as inflammatory bowel disease and colorectal cancer. However, how these cells interact with the microbiota is largely unknown.

So, researchers led by Yara El Morr at the Institut Curie in Paris set out to investigate the role of MAIT cells during gut inflammation in mice.

Activating immune responses

The researchers found that molecules able to activate MAIT cells, called MAIT ligands, are mostly produced by gut microbes such as Proteobacteria and Deferribacteres, which are adept at surviving in oxygen-rich environments. These bacteria bloom in the gut lumen during inflammation, the team also found.

In mice, gut inflammation brought immune cells into the gut lumen and increased the expression of genes linked to antibacterial defenses and riboflavin synthesis. In particular, the researchers found that Mucispirillum schaedleri is a major producer of MAIT ligands.

MAIT ligands produced in the gut quickly diffused through the gut wall to the lymph nodes and liver. Gut inflammation also increased the number of MAIT cells in the colon, leading to anti-inflammatory responses in the gut. Mice lacking MAIT cells were more susceptible to gut inflammation and colorectal cancer, the researchers found.

Gut surveillance

The results suggest that MAIT cells serve a surveillance role in the gut, the authors say. People with inflammatory bowel disease show activated MAIT cells that are recruited to inflamed sites and are linked with disease activity.

Other studies have shown that MAIT cells reduce gut damage and inflammation-associated tumors, promoting the integrity of the gut barrier. The current findings indicate that these cells play an important role in reducing gut inflammation and promoting tissue repair.

“We highlight a specific function of MAIT cells in the colon: monitoring the activity of a microbial metabolic pathway indicative of intestinal inflammation to provide anti-inflammatory and tissue-repair mediators in return,” the authors say.

During the 8th annual Microbiome Movement Drug Development Europe, held in Barcelona (Spain), Microbiomepost conducted an exclusive interview with Daniel Brownell, Senior Director of Research & Development at AOBiome Therapeutics, a life sciences company focused on transforming human health by developing microbiome-based therapies for local, nasal and systemic inflammatory conditions. The core of AOBiome Therapeutics technology is ammonia oxidizing bacteria, formulated as a topical suspension of bacteria applied topically to the skin to treat atopic dermatitis.

What this research adds
Researchers analyzed stool samples from 219 healthy adults and 221 people with rheumatoid arthritis, psoriatic arthritis or ankylosing spondylitis, and found that people with those inflammatory conditions showed alterations to their gut microbiotas. In particular, patients with more severe symptoms had increased levels of Ruminococcus gnavus and other pro-inflammatory bacteria compared with those with milder symptoms. In people with rheumatoid arthritis and linked conditions, the researchers also identified microbiota-driven pathways associated with inflammatory disease.

Conclusions
The findings may help identify targets for the prevention or treatment of rheumatoid arthritis and other inflammatory conditions.

Chronic inflammatory conditions affect nearly 20% of the global population, but not much is known about whether — and how — shifts in the gut microbiota are involved in some of these disorders. Now, researchers have found that specific changes in the microbial communities inhabiting the gut correlate with the severity of rheumatoid arthritis, a chronic inflammatory disorder affecting the joints, and related conditions.

The findings, published in Science Translational Medicine, may help identify targets for the prevention or treatment of these disorders. “Our study contributes to the growing body of evidence that the gut microbiome and inflammation throughout the body are tightly coupled,” the authors say.

Abnormal immune responses are responsible for many subtypes of arthritis, including rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis. These immune responses can be triggered or sustained by interactions with gut microbial populations. But although conditions such as inflammatory bowel disease have been linked to changes in gut bacteria, it’s unclear whether these links extend to inflammatory arthritis.

To address this question, Kelsey Thompson at Harvard University in Boston, Massachusetts, and her colleagues analyzed stool samples from 219 healthy adults and 221 people with rheumatoid arthritis, psoriatic arthritis or ankylosing spondylitis.

Microbial shifts

From June 2015 to March 2020, the researchers recruited participants aged 20-93 from clinical centers across the United Kingdom. Compared with controls, people with inflammatory arthritis had an altered gut microbiota composition characterized by lower levels of beneficial bacteria such as Faecalibacterium prausnitzii and Roseburia intestinalis, and higher levels of Escherichia coli, Ruminococcus gnavus and other pro-inflammatory bacteria.

Patients with more severe symptoms had increased levels of Ruminococcus gnavus and other pro-inflammatory bacteria compared with those with milder symptoms, the researchers found.

Microbe types that were substantially more common in people with arthritis included Streptococcus species, which are normally found in the oral cavity but not in the gut. “Previous studies have found that the patients with [rheumatoid arthritis] were four times as likely to have poor dental health,” the researchers say. 

Disease pathways

Next, the researchers examined the functional implications of the microbiota alterations observed in people with arthritis. They identified several microbiota-driven pathways associated with inflammatory disease.

Some of these pathways impacted the gut’s ability to sequester iron and harvest vitamin B from food — changes that could have implications for disease. “Some of these alterations, such as those for B vitamin metabolism, could represent mechanisms for long-term prevention, risk reduction or treatment, as could microbial iron sequestration during arthritis-linked anemia,” the researchers say. 

Although it’s unclear whether the changes in gut bacteria are a cause or a consequence of alterations to the immune system, the findings may help inform future microbiota-based interventions, the authors say.

What this research adds
Working in mice, researchers found that pregnancy causes changes in the microbiota composition. Reduced levels of Parabacteroides merdae during pregnancy leads to decreased formononetin (FMN), a potent anti-inflammatory agent. These alterations accelerate immune dysfunction associated with sepsis in pregnant animals. However, treating mice with P. merdae or FMN reduces sepsis-associated inflammation.

Conclusions
The findings reveal a microbe-immune axis that is disrupted in pregnant animals, suggesting potential therapeutic approaches for pregnancy-associated sepsis.

Sepsis — the body’s extreme response to an infection — can lead to serious complications during pregnancy, and is one of the main causes of maternal mortality in the United Kingdom. Now, a study done in mice reveals that pregnancy alters the gut microbiota in ways that accelerate immune dysfunction associated with sepsis.

The findings, published in Immunity, suggest potential therapeutic approaches for pregnancy-associated sepsis.

Scientists have known that pregnancy can predispose women to sepsis, but the mechanisms leading to the immune perturbations behind this phenomenon remain unclear. What’s more, the gut microbiota is known to modulate susceptibility to multiple organ failure — the hallmark of sepsis. 

Because gut microbiota composition is reshaped during pregnancy, researchers led by Shenhai Gong at Southern Medical University set out to investigate the role of gut microbes in immune dysfunction in pregnant mice. To do so, they used a mouse model of sepsis, which consists in perforating the cecum to trigger the release of fecal material into the peritoneal cavity. This generates an infection that results in an exacerbated immune response.

Microbial shift

After cecum perforation, pregnant mice had a higher mortality rate than non-pregnant animals, and they were more susceptible to pneumonia induced by Pseudomonas aeruginosa.

However, compared with non-pregnant mice that received gut bacteria from non-pregnant donors, those that received gut bacteria from pregnant mice developed more severe organ injury in response to sepsis.

In both mice and women, pregnancy caused a shift in the gut microbiota composition as well as changes in microbial metabolites, the researchers found. In particular, the levels of Parabacteroides merdae and formononetin (FMN), a potent anti-inflammatory agent, were decreased in pregnant individuals. 

Immune dysfunction

Further analyses showed that decreased P. merdae abundance resulted in lower FMN levels, indicating that the microbe may be involved in the progression of sepsis during pregnancy. Indeed, treating mice with P. merdae or FMN reduced sepsis-associated inflammation.

In septic mice, FMN inhibited the death of macrophages, a type of immune cell that kills pathogens and stimulates the activity of other immune cells. FMN also boosted the macrophages’ ability to surround and kill microorganisms.
Although the mechanisms responsible for pregnancy-associated reduction of P. merdae remain unknown, the results reveal a microbe-immune axis that may be leveraged to prevent or treat sepsis during pregnancy. “Our findings illustrate the cross talk between gut microbiota dysbiosis and immune dysfunction in [pregnant] septic hosts,” the researchers say.

What this research adds
Researchers have found that, compared with controls, mice born from mothers that lack a type of immune cells known as γδ T cells show increased lung inflammation following the “first breath response,” an immune reaction that results in lung tissue remodeling when the lungs are filled with gas after birth. Upon infection, these mice have a heightened inflammatory response. They also harbor a different gut microbiota from control mice and have reduced levels of beneficial short-chain fatty acids (SCFAs) in their guts. Supplementing mice with SCFAs reduces inflammation after both infection and first breath response.

Conclusions
The findings suggest that a newborn’s lung immunity is influenced by the interplay between maternal γδ T cells, the gut microbiota and microbial-derived SCFAs.

The development of a child’s immune system is influenced by several maternal factors, but how specific components of a mother’s immune system influence a newborn’s immune status remains a mystery. Working in mice, researchers have now found that maternal γδ T cells, a type of immune cells, are involved in the development of lung immunity in the offspring. The cells appear to exert an effect on the pups’ gut bacteria and on short-chain fatty acids (SCFAs), a type of microbial metabolites that have been shown to promote health.

The findings, published in Cell Reports, suggest that a newborn’s lung immunity is influenced by the interplay between maternal γδ T cells, the gut microbiota and microbial-derived SCFAs.

The transfer of antibodies from the mother is known to influence the development of the offspring’s immune system. However, it’s unclear how other components of the maternal immune system affect a newborn’s immune status. For example, the γδ T cells are a type of white blood cells that reside in the female reproductive tract, the skin and the mammary glands. These cells are known to control antibody production and participate in a cross-talk with the microbiota, but their role in the development of the newborn’s immune system is unknown. 

To fill this knowledge gap, researchers led by Pedro Papotto at the University of Manchester and Bruno Silva-Santos at the University of Lisbon set out to investigate how maternal γδ T cells influence the maturation of the immune system of newborn mice.

Immune development

In the first breath after birth, the liquid that fills the lungs is replaced by gas. This causes an immune reaction called “first breath response,” which results in lung tissue remodeling. Compared with controls, mice born from mothers lacking γδ T cells showed increased lung inflammation following the first breath response, the researchers found.

The pups’ lungs were enriched in immune cells and molecules associated with a type of immune response that drives tissue inflammation and causes tissue changes such as swelling, itching and pain. Pups born from mothers lacking γδ T cells that were treated with antibiotics had similar lung levels of immune molecules to controls. 

Pups born from mothers with γδ T cells had increased abundances of Rikenellaceae, Muribaculaceae and Lachnospiraceae, whereas those born from mothers lacking γδ T cells showed higher levels of Lachnoclostridium. Compared to controls, these pups also showed reduced levels of short-chain fatty acids (SCFAs), a class of microbial metabolites that have been shown to promote health.

Preventing inflammation

When infected with a parasite that affects the lungs, pups born from mothers without γδ T cells showed increased lung damage compared with controls. However, supplementing mice with SCFAs reduced inflammation after infection, the researchers found.

Microbial-derived SCFAs also prevent exacerbated lung inflammation after immune activation induced by the first breath response. 

The findings, the researchers say, “suggest that maternal γδ T cells regulate postnatal microbial colonization and microbial-derived metabolite availability in the offspring, ultimately impacting the pulmonary immune system development.” However, they note, more work is needed to identify the mechanism by which these cells change microbiota composition.

What this research adds
Researchers analyzed 40 of the most common flagellin types within a database of human gut metagenomes. They found that these flagellins bind to specific immune receptors, but they do not cause a strong activation of the receptors. That’s because ‘silent’ flagellins lack a specific domain that binds a secondary site of the immune receptors that triggers immune responses. Silent flagellins are more common in the gut microbiota of non-industrialized populations compared with that of industrialized populations.

Conclusions
The findings provide a mechanism that explains how the immune system tolerates flagellins of commensal bacteria while mounting an immune response against flagellins produced by pathogens.

Our immune system can mount powerful responses against pathogens, but it usually doesn’t react to commensal bacteria. New research has revealed that some gut microbes can avoid immune surveillance thanks to the structure of their flagellin proteins — key components of the hair-like filament that allows bacteria to move around.

The findings, published in Science Immunology, provide a mechanism that explains how the immune system tolerates flagellins from commensal bacteria while mounting an immune response against flagellins produced by pathogens.

Flagellins are one of the immune system’s main targets, as the proteins are found in both harmful and beneficial gut microbes. These proteins are recognized by an immune receptor called Toll-like receptor 5 (TLR5). When TLR5 binds flagellin, it triggers a cascade of cellular processed, including the production of inflammatory molecules. However, how commensal bacteria that produce flagellins avoid immune surveillance remains poorly understood.

To address this question, Ruth Ley at the Max Planck Institute for Biology and her colleagues analyzed 40 of the most common flagellin types within a database of human gut metagenomes.

Silent flagellins

More than 5,000 proteins encoded by the human gut microbiota were classified as flagellins, and most were produced by Lachnospiraceae, a common type of gut bacteria that includes beneficial microbes such as Roseburia and Eubacterium, the researchers found.

Flagellins produced by gut bacteria were able to bind TLR5, but they stimulated only weakly the receptor. The team dubbed these proteins ‘silent’ flagellins, in reference to their inability to activate TLR5 despite binding it.

Further experiments showed that silent flagellins lack a specific domain that binds a secondary site of TLR5 that triggers immune responses. This allows the immune system to tolerate silent flagellins from commensals yet remain responsive to flagellins from pathogens, the researchers say.

Population differences

Next, the researchers assessed how common silent flagellins are in the human microbiota. Metagenomes from non-industrialized populations had a greater proportion of silent flagellins compared with metagenomes from industrialized populations, the team found.

“The decrease in flagellin abundance with industrialization was most pronounced for the silent flagellins,” they say. “Reduced flagellin diversity may reflect shifts in host-microbiome interactions associated with industrialization.”

The findings shed light onto the flagellin-TLR5 interaction, which has been implicated in several conditions, including bacterial infections and inflammatory bowel diseases.