Stanford scientists link ulcerative colitis to missing gut …

Prior research has suggested, without much elaboration or follow-up, that secondary bile acids are depleted in ulcerative colitis patients and in those with a related condition, Crohns disease, in which tissue-destroying inflammation can occur in both the colon and the small intestine.

The researchers confirmed that levels of the two most prominent secondary bile acids, deoxycholic acid and lithocholic acid, were much lower in stool specimens taken from the ulcerative colitis pouch patients than from FAP pouch patients. Clearly, the surgical procedure hadnt caused the depletion.

These findings were mirrored by the scientists observation that microbial diversity in the specimens from ulcerative colitis pouch patients was diminished. Moreover, the investigators showed that a single bacterial family Ruminococcaceae was markedly underrepresented in ulcerative colitis pouch patients compared with FAP pouch patients. A genomic analysis of all the gut bacteria in the participants showed that the genes for making enzymes that convert primary bile acids to secondary bile acids were underrepresented, too. Ruminococcaceae, but few other gut bacteria, carry those genes.

All healthy people have Ruminococcaceae in their intestines, Habtezion said. But in the UC pouch patients, members of this family were significantly depleted.

Incubating primary bile acids with stool samples from FAP pouch patients, but not from ulcerative colitis pouch patients, resulted in those substances effective conversion to secondary bile acids.

In three different mouse models of colitis, supplementation with lithocholic acid and deoxycholic acid reduced infiltration by inflammatory immune cells and levels of several inflammatory signaling proteins and chemicals in the mices intestines, the researchers showed. The supplements also mitigated the classic symptoms of colitis in the mice, such as weight loss or signs of colon pathology.

All three mouse models are considered representative of not just ulcerative colitis but inflammatory bowel disease in general, a category that also includes Crohns disease. So the findings may apply to Crohns disease patients, as well, Habtezion said.

In an ongoing Phase 2 trial at Stanford, Sinha, Habtezion and their colleagues are investigating the anti-inflammatory effects, in 18- to 70-year-old ulcerative colitis pouch patients, of oral supplementation with ursodeoxycholic acid, a naturally occurring secondary bile acid approved by the Food and Drug Administration for treatment of primary biliary sclerosis and for management of gall stones. Information about the trial, which is still recruiting people, is available at https://clinicaltrials.gov/ct2/show/NCT03724175.

Habtezion is associate dean for academic affairs in the School of Medicine, a faculty fellow of Stanford ChEM-H and a member of Stanford Bio-X, the Stanford Cancer Institute, the Stanford Pancreas Cancer Research Groupand the Wu Tsai Neurosciences Institute at Stanford.

Other Stanford co-authors of the study are postdoctoral scholars Min Wang, PhD, Estelle Spear, PhD, Gulshan Singh, PhD, and Hong Namkoong, PhD; former research scientist Linh Nguyen, PhD; former postdoctoral scholar Carolina Tropini, PhD; former gastroenterology medical fellow Davis Sim, MD; research assistant Karolin Jarr; Laren Becker, MD, instructor of gastroenterology and hepatology; Michael Fischbach, PhD, associate professor of bioengineering; and Justin Sonnenburg, PhD, associate professor of microbiology and immunology.

Researchers from the Childrens Hospital of Philadelphia also contributed to the work.

The work was funded by the National Institutes of Health (grants R01DK101119, KL2TR001083 and UL1TR001085), the Ann and Bill Swindells Charitable Trust, the Kenneth Rainin Foundation, and Leslie and Douglas Ballinger.

Stanfords Department of Medicine also supported the work.

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Stanford scientists link ulcerative colitis to missing gut ...