Researchers Suspect Link Between Missing Gut Microbes, Ulcerative Colitis

Patients with ulcerative colitis (UC) are depleted of several types of microbes responsible for maintaining a healthy gut, according to a new study by researchers from Stanford. Patients with UC were also found to be deficient in a set of anti-inflammatory substances that the bacteria make.

"We hope it leads to our being able to treat it with a naturally produced metabolite that's already present in high amounts in a healthy gut," said lead researcher and associate professor of gastroenterology and hepatology, Aida Habtezion, MD, MSc, in a statement. A clinical trial to determine if these metabolites, called secondary bile acids (SBAs), are effective is currently underway at Stanford.

The study compared the stool samples of patients with UC with patients with familial adenomatous polyposis (FAP), a rare genetic condition where patients often have colectomies. Colectomies result in the lower end of the small intestine being reconfigured to form a J-shaped pouch which serves as a rectum. While both groups of patients may have to have all or part of their colon removed, individuals with UC can often experience pouchitis, a condition of returning inflammation symptoms after a colectomy. But patients with FAP do not suffer from the same inflammation.

About 1 in 5 patients with UC will progress to the point of requiring a total colectomy.

Using metabolomic, microbiome, metagenomic, and transcriptomic profiling, the researchers compared samples from the pouches of 17 patients with UC and 7 patients with FAP.

Stool samples showed that patients with UC had significantly lower levels of 2 prominent SBAs: deoxycholic acid (DCA) and lithocolic acid (LCA). SBAs are converted from primary bile acids (PBAs) when resistant bacteria in the digestive tracts perform enzymatic operations to break down fat molecules.

Patients with UC also had reduced expression of genes needed to convert PBAs to SBAs. Investigators also found that a single bacterial family, Ruminococcaceae, was underrepresented in patients with UC compared with patients with FAP. Ruminococcaceae is one of the few bacteria that carry genes that make enzymes responsible for converting PBAs to SBAs.

Testing on 3 mouse models with colitis showed that SBA supplementation with lithocholic acid and deoxycholic acid reduced markers of intestinal inflammation. In addition, classic symptoms of colitis, such as weight loss and signs of colon pathology, were reduced. Researchers said that the data suggests “that dysbiosis induces an SBA deficiency that promotes a pro-inflammatory state and that SBA restoration may treat intestinal inflammation” in humans.

UC is a chronic, relapsing inflammatory condition in which the immune system attacks tissue in the rectum or colon. Currently, there is no known cure and patients often suffer from heavy bleeding, diarrhea, weight loss, and life-threatening sepsis if the colon becomes sufficiently perforated.

Millions of patients worldwide are affected by UC, including about 1 million people in the United States. “Prevalence in Western countries exceeds 0.3% and incidence is rising in newly industrialized countries in Asia, Africa, and South America,” the researchers noted.

Researchers hope their results reveal that “SBAs may be important in maintaining immune homeostasis in the pouch.”

Researchers are hopeful that potential SBA supplementation treatment could also translate to patients with Crohn disease, a related condition to UC in which tissue-destroying inflammation can occur in both the colon and the small intestine.

Currently, there is an ongoing phase 2 trial testing on patients with UC aged 18 to 70 with post-colectomy pouches for an oral supplement with ursoldeoxycholic acid, a naturally occurring SBA that’s an FDA-approved treatment for primary biliary sclerosis and gallstone management.

Reference

Sinha SR, Haileselassie Y, Nguyen LP, et al. Stanford Medicine. Dysbiosis-induced secondary bile acid deficiency promotes intestinal inflammation [published online February 25, 2020].

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