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Ursodeoxycholic acid and lithocholic acid exert anti-inflammatory actions in the colon Inflammatory bowel disease

Ursodeoxycholic acid and lithocholic acid exert anti-inflammatory actions in the colon

Inflammatory bowel disease (IBD), includes basically ulcerative colitis and Crohn’s disease, that are involved in inflammatory disorders of gastrointestinal tract which are known to be chronic. IBD pathogenesis mainly involves epithelial cells that line the colonic lumen. The main feature of IBD is epithelial barrier dysfunction that is associated with increased permeability and induction of cytokine release. Many components of endogenous and exogenous origin include cell wall components, viral RNA, and bile acids, bacterial toxins alter the gut inflammation, that have the capacity to cytokine release. CDCA ,the 1? bile acids by bacterial action in colon produces UDCA a naturally occurring bile acid. The bile acid UDCA plays a immunomodulatory role to halt the cytokine levels. For UDCA to be functional it has to be metabolized by microbiota which is explained by this paper.

The effects of UDCA on release of cytokines i.e., proinflammatory cytokines were studied on T84 colonic epithelial cells. Poly(I:C) specific ligand for TLR-3 was used to assess cytokine release which was analysed by multiplex arrays. The UDCA used at a concentration of 200┬ÁM significantly attenuated the pro-inflammatory cytokine TNF-? secretion and also other cytokines IL-6, IL-1? levels were inhibited. But UDCA did not change the level of IFN-? released. Later on the effects of UDCA in DSS mouse model was studied. DSS at 2.5% in drinking water was given to C57BL/6 mice which led to reduced in body weight and disease activity index was increased in 5-day experimental time period. The effects of which were subsided by UDCA treatment. The DSS treated mice had shorter colons and lack stool pellet formation compared to the mice treated with UDCA which restored stool pellet formation colon length was not shortened in this mice. Haematoxyllin-eosin staining of tissue cross section was done which revealed that bile acid, UDCA prevented damage to colonic epithelium and inflammation score was reduced and also cell infiltration was reduced. In invivo DSS induced mouse model also UDCA drastically reduced pro-inflammatory cytokine levels TNF-?,IL-1?, IL-6 but IFN-? levels were not reduced by it. The bacterial metabolism of UDCA to form LCA in colon was studied by considering cecal contents of mice and bile acid concentration in cecum by HPLC-tandem Mass spectrometry analysis. 6-MUDCA a nonmetabolizable bile acid was used to check its anti-inflammatory action on pro-inflammatory cytokines released. It was observed that 6-MUDCA was able to reduce the pro-inflammatory cytokine levels in T84 cells. 6-MUDCA was unable to act as anti-inflammatory bile acid in DSS treated mice which was measured by disease activity index. This was basically due to unmetabolizable nature of 6-MUDCA on bacteria to further enhace its full expression as protective bile acid invivo.
The bacterial action on UDCA was important for its full expression to produce its major product LCA in regulating chronic inflammation invitro as well as invivo. The effects of LCA on cytokine release was studied by treating the cells with poly(I:C) and then checking the pro-inflammatory cytokines levels by cytokine analysis in T84 cells. It was found that LCA was significantly able to prevent the cytokine secretion i.e., TNF-?, IL-6, IL-1?. It was also observed that IFN-? levels were also significantly decreased compared to UDCA. It was noted that for poly(I:C) receptor i.e., TLR3 LCA was not specific and inhibited IL-8 secretion along with pro-inflammatory cytokine,TNF-?. The Acid phosphatase activity was assasyed which dictates the no. of cells present which were reduced due to increased bile acid activity.
Then LCA action on colonic inflammation was studied invivo on DSS treated mice were LCA levels were increased in cecum and there was significant loss of body weight by 5th day and there was complete prevention of inflammation on disease activity index observed. LCA led to colon shortening compared to control and prevented further shortening in mice treated with DSS. The immunohistology of colonic epithelial cell revealed that LCA totally changed the epithelial lining by preventing inflammation induced by DSS and further enhanced inflammation score. Then LCA action on pro-inflammatory cytokine was studied invivo were the results revealed that LCA was more potent bile acid than UDCA in decreasing the levels of TNF-?. IL-6, IL-1? cytokines invivo and has marked decreased production of IFN-? production.