The findings, published in Cell Host & Microbe, suggest that HMGB1 protects intestinal cells and helps to maintain a healthy microbiota.

A protective mucus layer in the colon keeps gut microbes away from gut cells and helps prevent inflammation. HMGB1 typically helps gut cells cope with stress, but its role in normal mucus-based gut defense has been unclear.

So, Anne-Marie Overstreet at Cleveland Clinic in Ohio and her colleagues set out to investigate the role of HMGB1 in protecting the gut.

Keeping commensal bacteria

The researchers found that HMGB1, which is typically present in the cells lining the colon, is also present in the mucus layer that cover the colon in healthy people. In people with ulcerative colitis, HMGB1 was reduced or missing in the mucus, especially in areas with severe inflammation. 

Experiment in mice showed that HMGB1 is made by intestinal cells and released into colonic mucus in response to signals from gut bacteria. Mice lacking HMGB1 in gut cells had little to no HMGB1 in their mucus, and mice without gut bacteria had HMGB1 stuck inside their cells rather than released.

In mice lacking HMGB1 in gut cells, the researchers also found that bacteria moved closer to the gut lining and were more likely to invade it. HMGB1 appears to clump bacteria together and block their attachment to the gut lining, preventing invasion and epithelial cell damage. HMGB1 also suppresses bacterial virulence, keeping normally harmless gut microbes in a commensal state, the researchers found.

Antibacterial strategies 

In Escherichia coli, HMGB1 binds to the bacterial adhesin FimH—a protein used to stick to host cells. Further analyses revealed that HMGB1 binds to a specific part of FimH called ToH1, preventing E. coli from attaching to various types of cells, including gut cells. Mutating ToH1 reduced bacterial adhesion, and when HMGB1 was missing from intestinal cells, the gut lining was more vulnerable. 

In colon tissue from people with ulcerative colitis, the researchers found more bacteria expressing the adhesin FimH compared with tissue from healthy people. Computer modeling confirmed that as HMGB1 decreases, FimH-expressing bacteria increase. 

This result indicates that ulcerative colitis is associated with a failure of the HMGB1 defense system, allowing harmful bacteria to stick to and invade gut tissue, the authors say. Together, they add, the findings “suggest that ToH1 functions as a microbial virulence determinant and may serve as a target for developing antibacterial strategies that precisely target virulent bacteria.”

The findings, published in Nature Medicine, suggest that fecal transplants from healthy donors can boost the effectiveness of immunotherapy and protect against severe side effects by shaping a healthy, anti-inflammatory gut microbiota.

Previous research suggests that the gut microbiota influences both response to immunotherapy and toxicity. But while studies indicate that fecal transplants may reduce side effects and improve immunotherapy efficacy, their safety and benefits in kidney cancer remain unclear.

Ricardo Fernandes at Western University in London, Canada, and his colleagues tested whether giving people with kidney cancer a fecal transplant from a healthy donor alongside immune checkpoint therapy is safe and beneficial.

Transplant safety

From 2020 to 2023, the researchers gave 20 people with advanced kidney cancer one full and two half doses of oral fecal transplant capsules, followed by standard immunotherapy. 

The fecal transplant itself caused only a mild gut side effect in one participant, while most immune-related side effects came from the anti-cancer therapy. About 85% of patients experienced some immune-related side effects, and half had more serious effects such as colitis or diarrhea. 

Following fecal transplant and anti-cancer therapy, 18 patients were evaluated, and half showed tumor shrinkage, including two complete responses. Participants who responded to therapy generally had fewer severe side effects than those who did not respond. 

Boosting immunotherapy

The researchers found that specific bacterial species were linked to outcomes. For example, people with diverse, anti-inflammatory gut microbes, such as Faecalibacterium prausnitzii, were protected from severe immune-related toxicities and more likely to respond to therapy. In contrast, high levels of the inflammatory bacterium Segatella copri were linked to toxicity and poor response to immunotherapy.

Specific microbial enzymes linked to inflammation were passed from donors to patients who later developed severe side effects, whereas people receiving microbes lacking these enzymes did not present such toxicities. 

This suggests that the functional traits of donor microbes, not just the presence of certain species, play a key role in how well people tolerate therapy and respond to treatment, the authors say. However, they add, “validation in larger, multicenter trials is necessary to refine donor selection, clarify microbiome−immunity mechanisms and confirm these exploratory findings.”

The findings, published in Cell Metabolism, suggest that restoring R. gnavus or supplementing isovaleric acid could be a promising microbiota–based strategy to prevent or treat atrial fibrillation. 

Atrial fibrillation has been linked to alterations of the gut microbiota, which produces compounds that affect inflammation and metabolism. However, it’s unclear which specific microbes or metabolites influence atrial fibrillation. 

Researchers led by Ning Ding at Xi’an Jiaotong University in Xi’an, China, set out to study the gut bacteria and blood metabolites of people with atrial fibrillation.

Protective effect

Compared with healthy people, those with atrial fibrillation had reduced levels of R. gnavus, which normally helps produce beneficial compounds such as short-chain fatty acids (SCFAs). 

One SCFA called isovaleric acid was also lower in people with atrial fibrillation, and lower levels of isovaleric acid were associated with higher inflammation, larger heart size, and greater risk of recurrence of atrial fibrillation after treatment. 

Next, the team tested how gut bacteria affect atrial fibrillation using mice grown without microbes, which naturally have higher risk of heart problems. When the gut bacteria of these animals were restored, the heart problems improved. Supplementing mice with R. gnavus reduced atrial fibrillation events, heart tissue scarring, and inflammation.

Preventing atrial fibrillation

Further experiments showed that R. gnavus produces isovaleric acid from the amino acid leucine through a bacterial enzyme called vorC. Isovaleric acid binds to a receptor on heart cells called GPR109A, suppressing a signaling pathway that drives inflammatory cell death. 

Giving mice isovaleric acid reduced heart problems and inflammation, the researchers found. In humans, a signaling pathway that triggers inflammatory cell death contributes to atrial fibrillation, and isovaleric acid could suppress this pathway.

Although the study mainly focused on short-chain fatty acids, other metabolites may also be involved in protecting against atrial fibrillation, the authors say. Regardless, they add, “these results reveal that the microbial metabolismof dietary leucine and the production of [isovaleric acid] play pivotal roles in preventing [atrial fibrillation] onset and progression.”

The findings, published in Cell Metabolism, suggest a gut microbiota-mediated mechanism by which a ketogenic diet can protect the lungs during sepsis.

Gut damage during sepsis allows bacteria and their by-products to reach the lungs, creating a “gut-lung connection” that may worsen injury. A ketogenic diet may help in sepsis by altering energy metabolism and gut bacteria, but it remains unclear which effects are most important for protecting the lungs.

Researchers led by Mingyuan Wei at South China Normal University in Guangzhou, China, tested the effects of a ketogenic diet on sepsis-related lung injury in mice by feeding the animals either a very high fat, no carbs diet or a standard high-carb diet for two weeks, then inducing sepsis.

Protecting the lungs

Mice on a ketogenic diet had lower death rates and less lung damage compared with mice on a standard diet. However, the benefits disappeared in mice without gut bacteria or after antibiotics. Transferring gut bacteria from mice on a ketogenic diet to other mice reduced lung injury and mortality.

The ketogenic diet changed the gut microbiota of mice by increasing the levels of specific gut bacteria, Limosilactobacillus reuteri and Lactiplantibacillus plantarum, while decreasing others such as Lactobacillus johnsonii and Lactobacillus murinus. Similar shifts were observed in people after two weeks on a ketogenic diet.

The ketogenic diet also increased the levels of a specific metabolite in the gut, blood, and lungs of mice. This metabolite, called azelaic acid, reduced death and lung injury, the researchers found.

Dietary interventions 

The production of azelaic acid depended on gut bacteria, in particular Limosilactobacillus reuteri and Lactiplantibacillus plantarum, which use an enzyme called FMO to convert dietary fat into azelaic acid. 

Further experiments indicated that azelaic acid travels from the gut to the lungs, where it activates immune cells to reduce inflammation and protect the lungs. The researchers also found that higher levels of azelaic acid in the lungs of people with sepsis were linked to better recovery.

“These findings highlight the therapeutic potential of a combined dietary-probiotic strategy for sepsis,” the authors say, “and they suggest that dissecting the mechanisms underlying [ketogenic diet] may pave the way for targeted dietary interventions that optimize both efficacy and safety in the emerging era of personalized nutrition.”

The findings, published in Nature, suggest that early social interactions, especially among nursery peers, help to build and diversify the infant gut microbiota.

Previous studies showed that microbes are shared between peers, suggesting that nurseries may shape infant microbiotas through baby-to-baby transfer. However, not much is known about how babies’ microbiotas change once they begin interacting with other children.

Liviana Ricci at the University of Trento in Italy and her colleagues followed 43 babies during their first year of nursery and tracked how their gut microbiotas changed over time.

Similar microbiotas

The researchers collected and analyzed more than 1,000 stool samples from babies, family members, caregivers, and household pets. The team confirmed expected differences between adult and baby microbiotas, and showed that babies’ microbial diversity increased over time, especially as they attended nursery. 

Babies shared many microbial strains with their mothers at the start of the study, and people living in the same family also shared more strains with each other than with unrelated individuals. 

Babies with siblings tended to have more diverse microbiotas, and factors such as birth method or antibiotics at birth no longer had a strong effect on gut microbes by about 10 months of age. As babies spent time together in nurseries, their microbiotas became more similar to each other, the researchers found.

Building microbiotas

Using genetic tracking, the researchers were able to reconstruct bacterial strains passing from a baby to another baby in the nursery and then spreading to that child’s parents at home. They also found a few examples of microbes being shared between babies and pets.

Within a few months, bacteria acquired from nursery peers made up a larger share of babies’ microbiotas than those from family members. Even after long breaks, such as summer vacation, babies continued to share more microbes with former nursery peers than with children from other nurseries, the researchers found.

“Overall, our results reveal the centrality of social factors in shaping the infant microbiome via inter-individual microbial transmission, thus rebalancing social interactions as key to building a healthy microbiome,” they say.

The findings, published in Science Immunology, suggest that these intestinal cells, rather than immune cells, are the key sensors of beneficial microbes, helping maintain gut health and prevent inflammation.

Scientists have known that macrophages depend on signals from gut microbes to develop properly, and when this process fails, chronic diseases such as inflammatory bowel disease can occur. Although sensors called Toll-like receptors on the surface of immune cells help detect microbes, what guides macrophage recruitment is unclear.

So, researchers led by Ming-Ting Tsai at Baylor College of Medicine in Houston, Texas, set out to investigate how epithelial cells in the gut communicate with the immune system.

Activating immunity

The researchers found that colonizing mice with a specific strain of the commensal bacterium Escherichia coli, called 541-15, restored macrophages after antibiotic treatment. Mice with E. coli 541-15 were also protected against chemically induced colitis, showing less inflammation, longer colons, and lower disease markers than mice without the bacterium. 

E. coli 541-15, through its flagellin protein—which makes up the tail-like flagellum that the bacteria use to move, is sensed by a specific Toll-like receptor called TLR5 on epithelial cells that act like stem cells in the gut. These cells secrete molecules that attract immune cells, including macrophages. 

Using lab-grown “mini-colons” that mimic human intestinal tissue, the team discovered that mature colon cells did not respond to the bacteria, while the stem-like cells strongly activated genes involved in immune recruitment without causing inflammation. 

Microbial sensing 

Further experiments showed that E. coli 541-15 helps the colon recruit key immune cells that can develop into macrophages, leading to more mature, protective macrophages and fewer immature ones. 

This effect depended on a chemical signal called CCL2. When CCL2 was blocked or genetically removed from epithelial cells, mice were no longer protected against colitis, and fewer immune cells were recruited to the gut lining. E. coli strains with active flagellin activated TLR5 on epithelial cells, while strains without active flagellin didn’t.

It’s still unclear how these findings apply to humans, and whether other microbial signals help recruit immune cells to the gut, the authors say. However, they add, “our study demonstrates a role for intestinal epithelial stem cells in microbial sensing, which promotes intestinal macrophage replenishment and maturation and supports intestinal barrier function.”

The findings, published in Cell Reports, point to new avenues for preventing and treating the condition.

Although genetics play a role, obesity is mainly driven by lifestyle changes, including reduced physical activity and diets rich in highly processed foods. The gut microbiota is known to influence obesity, and emerging evidence suggests that people with obesity have less diverse and more inflammatory oral bacteria. But it is unclear whether and how oral bacteria may affect whole-body metabolism.

So, Ahmed Shibl at New York University Abu Dhabi in the United Arab Emirates and his colleagues analyzed data from the UAE Healthy Future Study, a project designed to understand factors that contribute to heart and metabolic diseases among Emirati adults.

Microbiota differences

The researchers analyzed data from 669 participants aged 18 to 43, collecting mouthwash samples, health measurements such as body weight, blood pressure, and cholesterol, and detailed lifestyle information, including smoking and exercise habits. 

By analyzing mouth bacteria, the team found that obesity was associated with distinct bacterial communities, lower microbial diversity, and increased levels of microbes linked to inflammation.

The researchers also found that many microbial pathways involved in breaking down sugars and generating obesity-related compounds were more active in obese people than in healthy-weight people.

Therapeutic strategies 

Compared to healthy-weight individuals, those with obesity had higher levels of molecules that are known to promote inflammation, interfere with insulin signaling, increase hunger, and raise the risk of diabetes and fatty liver disease. At the same time, people with obesity showed reduced microbial pathways responsible for making essential B vitamins, which are important for healthy energy use.

Computer models combining oral bacteria, their metabolic functions, and saliva chemicals could better distinguish obese from healthy individuals compared with clinical measurements alone. 

These results indicate a potential role of mouth bacteria in obesity-related diseases, the authors say. The findings, they add, “also suggest opportunities for microbiome-based prevention and therapeutic strategies against obesity and underscore the importance of investigating the oral microbiome’s contributions to other complex diseases.”

The findings, published in Stem Cell Reports, suggest that argeting the gut microbiota could help improve gut repair in aging or disease.

Intestinal stem cells produce new cells that eventually become the various specialized cells of the gut. Aging not only reduces the function of these stem cells, it also alters the intestinal microbiota, which can contribute to digestive problems and other conditions. However, the exact interactions between gut microbes and stem cell aging are not yet fully understood.

To address this question, researchers led by Kodandaramireddy Nalapareddy at the University of Cincinnati in Ohio altered the microbiota of mice using antibiotics and fecal transplants between young and aged animals.

Boosting regeneration

Gut microbes are known to control a key signaling system called Wnt, which helps intestinal stem cells maintain and repair the gut lining. When mice were treated with antibiotics or raised without any gut microbes, Wnt signaling decreased. 

Transferring gut microbes from young mice into older animals boosted Wnt signaling and improved the function of intestinal stem cells. When aged mice received fecal transplants from young mice, their stem cells showed stronger activity, more cell division, and better regeneration after damage.

Instead, transferring gut microbes from old mice into younger animals had only a small effect on signaling and regeneration, the researchers found. 

Rejuvenating cells

In mice, certain microbes that become more common in aged intestines, such as Akkermansia muciniphila, were able to reduce Wnt signaling in intestinal stem cells and impair their regenerative function. This effect also involved changes in other microbial species that interact with A. muciniphila. 

The findings indicate that a youthful microbiota can boost the regenerative function of aged stem cells, but the exact interactions between microbes and intestinal stem cells need more research, the authors say.

“Our data imply potential therapeutic approaches via modulation of the composition of microbiota for aging-associated changes in the function of [intestinal stem cells].”

The findings, published in Nature Medicine, suggest that the therapy is safe and effective at reducing recurrence of C. difficile infection.

Previous studies using fecal microbiota transplants and microbiota-based therapies suggest that restoring gut bacteria could prevent recurrent C. difficile infection. In particular, VOS—an FDA-approved oral microbiota therapy, made of purified Firmicutes spores from healthy donors—has been shown to reduce infection risk compared to traditional fecal transplants. 

However, it’s unclear which specific bacterial species or metabolites are most important, and how VOS prevents recurrent C. difficile infection at a mechanistic level. So, Jessica Bryant at Seres Therapeutics in Cambridge, Massachusetts, and her colleagues conducted a clinical trial testing VOS in people with recurrent C. difficile infection.

Restoring the microbiota

The researchers gave either VOS bacteria or a placebo to 182 people who had recently taken the antibiotic vancomycin and had at least three C. difficile infection. Stool samples were collected before and after treatment to track how VOS bacteria colonized the gut.

Compared with people receiving the placebo, those who received VOS had more beneficial bacterial species appear in their guts, with more protective Firmicutes and fewer Proteobacteria and other disease-associated species. These bacteria stayed in the participants’ guts for at least 24 weeks, the researchers found.

In contrast, people on the placebo had slower and incomplete microbiota recovery, with fewer beneficial bacteria and more harmful species persisting in their guts. Participants who received VOS did not report significant side effects compared to those receiving the placebo.

Preventing recurrence

Before VOS treatment, participants had high levels of primary bile acids and low levels of protective secondary bile acids, a pattern that favors C. difficile growth. After VOS treatment, secondary bile acids and beneficial fatty acids increased rapidly, while primary bile acids decreased. 

Laboratory tests confirmed that these fatty acids can slow or stop C. difficile growth. Similar changes were also produced by VOS bacterial spores outside the body, suggesting that the treatment restores gut metabolites that help block infection, the authors say.“These data support a potential role for VOS, after antibiotic therapy, to restore the microbe-associated metabolic functions needed to prevent [C. difficile infection] recurrence.”

Now, in a Commentary published in Med, Emily Hoedt and Nicholas Talley at the University of Newcastle in Callaghan, Australia, argue that effective treatment of IBD requires an approach combining tailored donors, microbiota analysis, and diet. “To move forward, we must embrace a more nuanced, personalized approach,” they say.

Because disruptions to gut microbes are common in conditions such as IBD, including ulcerative colitis and Crohn’s disease, therapies aimed at restoring the microbiota have gained increasing attention. Fecal microbiota transplants have shown promise, particularly in ulcerative colitis, but responses remain variable, and success appears to depend on donor characteristics. 

Diet, especially fiber intake, is thought to support microbial recovery, yet clinical results are inconsistent. While certain fibers can promote beneficial bacteria such as Faecalibacterium prausnitzii, many patients do not to improve or even experience worse symptoms. 

These mixed outcomes suggest that microbial presence alone may not be sufficient for treating disease, and that the functional capacity of the gut microbiota—such as the ability to degrade dietary fiber—may be critical, the authors say. However, they add, “mechanistic understandings of how food components influence disease activity are limited.”

Microbial function

Recent studies suggest that successful microbiota-based therapies depend not only on introducing beneficial microbes, but also on restoring microbial function. Fiber supplements, rather than improving outcomes for all patients, may have counterproductive effects if the recipient’s microbiota lacks the enzymes needed to degrade it or converts it into inflammatory metabolites.

The authors emphasize that beneficial clinical effects arise when engrafted microbes actively produce protective metabolites—such as short-chain fatty acids—and interact appropriately with the host’s immune system. This suggests that matching donors and recipients is important.

Beyond bacteria, also fungi and viruses may influence outcomes, indicating that microbial composition alone is less important than microbial functionality and host-microbe interactions for therapeutic success.

Lasting remission 

Supporting beneficial microbes while limiting inflammation can improve the effectiveness of microbiota-based therapies, the authors say. In the future, they add, larger studies will be essential to identify responders and guide precision nutrition.

Hoedt and Talley conclude that microbiota-based therapies such as fecal microbiota transplants cannot be optimized through a one-size-fits-all approach. Long-term remission in IBD and related conditions likely relies on personalized strategies combining donor selection, microbiota profiling, and tailored diet, the authors say.

“This will require interdisciplinary collaboration across microbiology, nutrition, immunology, and clinical medicine,” they add. “Only then can we unlock the full potential of microbiome-based therapies and achieve lasting remission for patients with chronic gastrointestinal diseases.”