Researchers have found three potential gut mechanisms linked to secondary bile acid (SBA) deficiencies implicated in intestinal inflammation in ulcerative colitis (UC), and reported that supplementation may aid in restoring bile acid levels and potentially treating intestinal inflammation, according to a study published in Cell Host & Microbe.
The study identified lower levels of the following gut components in SBA deficiency in colectomy patients with UC, compared with those with familial adenomatous polyposis (FAP): deoxycholic and lithocholic acids (DCA and LCA), the most abundant gut secondary bile acids (SBAs); expression of the genes needed to convert primary bile acids (PBAs) into SBAs; and the number of Ruminococcaceae, one of the few taxa that include bacteria that generate SBAs.
“Our findings confirm that significant changes in bacterial diversity and composition occur in UC versus FAP pouches,” wrote Sidhartha R. Sinha, MD, of Stanford (Calif.) University, and coauthors. “Notably, our finding of decreased Ruminococcaceae in UC, compared to FAP pouch stool, requires further exploration.” They added that this is the first study to identify Ruminococcaceae as a key contributor to the production of LCA or DCA from PBAs.
The study found average DCA counts of 60,957 in FAP versus 1,593 in UC (P = .002), and average LCA counts of 30,644 and 282.9, respectively (P = .001). The study profiled stools from ileal pouches in colectomy patients who had UC (17) or FAP (7), a noninflammatory disease. “Remarkably, our data identify LCA and DCA to be almost undetectable in UC pouch patients,” Dr. Sinha and coauthors wrote. “This striking finding in patients who underwent colectomy suggests that SBAs may play a role in dysregulated metabolism-induced intestinal inflammation.”
The study found that UC pouches demonstrated less bacterial diversity, or alpha-diversity, than FAP pouches, which is in line with previously reported findings (J Inflamm Res. 2017;10:63-73), and had significantly lower expression of bile-acid inducible genes that encode enzymes that transform PBA to SBA.
The researchers also demonstrated that LCA and DCA supplementation reduced intestinal inflammation in mice with UC.
“Our results show that LCA and DCA treatments caused a remarkable and significant decrease in multiple chemokines and cytokines associated with inflammation, including those often increased in intestinal inflammation,” Dr. Sinha and coauthors wrote. However, they found that LCA had no protective effect on dextran sodium sulfate–induced colitis in mice with TGR5-deficient immune cells. The TGR5 bile acid receptor influences the anti-inflammatory effect in SBA supplementation, the study reported.
The researchers have initiated a clinical study (NCT03724175) to investigate the role of SBAs in patients with pouchitis that doesn’t respond to antibiotic therapy. “Insights from this study will further inform our understanding of the role of SBAs in intestinal inflammation and hold promise to provide an effective treatment,” Dr. Sinha and coauthors wrote.
Christian Jobin, PhD, of the University of Florida, Gainesville, said in an interview these findings are consistent with a recent paper that found a correlation between production of SBAs such as DCA and disease remission (ISME J. 2020;14:702-13). Dr. Jobin coauthored a 2018 study that similarly found SBAs have a role in intestinal inflammation (Gastroenterology. 2018;154:1751-63).
“For a long time, secondary bile acid, especially DCA was linked to cell injury, toxicity and even cancer,” he said. “It’s time to rehabilitate this important signaling molecule and recognize its important role in regulating host homeostasis.” The 2018 paper he coauthored showed that injection of DCA into germ-free mice did not promote intestinal pathology. “Actually, DCA was critical in preventing Campylobacter jejune–induced colitis,” he added.
Dr. Sinha received funding from the Crohn’s & Colitis Foundation, Stanford Clinical and Translational Science Award, and Kenneth Rainin Foundation Synergy Award. Coauthors received funding from the National Institutes of Health, the Ann and Bill Swindells Charitable Trust, Leslie and Douglas Ballinger, and the Kenneth Rainin Foundation.
SOURCE: Sinha SR et al. Cell Host Microbe. 2020 Feb 25. doi: 10.1016/j.chom.2020.01.021.