The human gut is home to trillions of bacteria that play vital roles in digestion, immunity, and overall health. Disruption of the interaction between the gut microbiome and the host can contribute to the development of chronic diseases such as ulcerative colitis (UC), an inflammatory condition of the large intestine.
One of the hallmarks of UC is a deficiency in certain bile acids (BAs), molecules that help digest fats and regulate gut health. These molecules are produced by the liver, and then further processed by gut bacteria into forms that support intestinal healing. UC patients often show lower levels of specific bile acids, suggesting that their restoration could promote recovery.
Research teams led by Kristina Schoonjans, PhD, and Rizlan Bernier-Latmani, PhD, at Ecole Polytechnique Fédérale de Lausanne (EPFL), have now identified Clostridium scindens, a bacterium that converts primary bile acids into 7α-dehydroxylated bile acids, as a key player in gut healing. Their study in experimental mice with induced colitis found that supplementing the gut with this bacterium could improve recovery from colonic injury, offering a new potential therapy for UC and related disorders.
The researchers, including collaborators at the University of Bern and the University of Lausanne, reported their findings in EMBO Molecular Medicine, in a paper titled “Bile acid 7α-dehydroxylating bacteria accelerate injury-induced mucosal healing in the colon.”
“Inflammatory bowel diseases (IBD) are chronic and debilitating gastrointestinal disorders, and their prevalence is rising exponentially, constituting a substantial societal burden,” the authors wrote. Crohn’s disease and UC are forms of IBD, but for some patients with UC current treatments offer limited relief or carry significant risks, including immune suppression. Researchers are exploring alternative ways to restore gut health, focusing on the microbiome’s ability to heal the intestinal lining.
The exact etiology of inflammatory bowel diseases isn’t completely understood, the authors noted, although prevailing theories indicate that environmental factors and genetic predisposition have a significant impact. “Within this framework, the intestinal microbiome emerges as a key actor,” the team continued. “Dysbiosis, characterized by a significant change in the microbial composition and associated alterations in bacterial metabolites, is increasingly recognized as a key characteristic of IBD.”
Microbiome dysbiosis can lead to altered production of bacterial metabolites, and previous studies have shown that dysbiotic UC patients have lower levels of 7α-dehydroxylated BAs compared with healthy individuals. “7α-dehydroxylated bile acids are notably diminished in inflammatory bowel disease patients,” the investigators wrote.
For their newly reported study, the researchers investigated in mice whether restoration of 7α-dehydroxylated bile acid levels by the bacterium Clostridium scindens, a human-derived 7α-dehydroxylating bacterium, could improve healing following colon injury. To do this they studied mice with experimentally induced colitis, a disease model that mimics UC.
The team introduced C. scindens into some of the colitis-model mice, while leaving others untreated. The animals’ recovery was monitored by measuring weight loss, colon inflammation, and markers of intestinal healing.
The results showed that when compared with the control animals, those mice that had received C. scindens recovered more quickly, demonstrated less inflammation, and enhanced regeneration of the gut lining. “In this study, we demonstrated that colonizing various mouse models with the human-derived 7α-dehydroxylating bacterium C. scindens improves the outcomes of experimental colitis,” the scientists stated. “Colonization enhanced the production of 7α-dehydroxylated bile acids and conferred prophylactic and therapeutic protection against colon injury through epithelial regeneration and specification.”
The researchers found that these effects were dependent on TGR5, a receptor that responds to 7α-dehydroxylated bile acids, which stimulates the proliferation and differentiation of intestinal stem cells. When they tested the therapy in mice lacking this receptor, the benefits disappeared, confirming that bile acid metabolism is essential for healing. The collective findings from their studies, they noted, “… imply that introduction of C. scindens in the distal gut fosters intestinal epithelial cell (IEC) regeneration and reestablishes homeostasis through TGR5 activation.”
To further validate their findings, the investigators also analyzed patient data to determine whether similar mechanisms were at play in humans. They found that in UC patients, the lower levels of 7α-dehydroxylated bile acids strongly correlated with impaired intestinal cell renewal. “… our results obtained from publicly available omics datasets of UC and healthy individuals … support the notion that restoring the balance between primary BAs and secondary 7α-dehydroxylated BAs could stimulate regeneration in UC patients,” they wrote.
The study results reinforce the link between bile acid metabolism and intestinal healing. “Our findings highlight the potential of microbiome-targeted strategies to modulate bile acid metabolism and promote gut healing,” said first author Antoine Jalil, PhD. Unlike conventional treatments that focus on suppressing inflammation, this approach targets the underlying issue, being the impaired ability of the gut to heal itself. By restoring natural bile acid balance through beneficial bacteria, this strategy could provide an alternative and more sustainable treatment option for UC patients.
The authors, in addition, pointed out that further research will be needed to explore clinical applications. “Further investigations are necessary to validate these promising findings in other experimental colitis models and explore their potential therapeutic applications for UC patients.”