242 Box 2. Miscellaneous component pairs from sparse-CCA analysis. The microbial part of the fifth pair of components (component pair 5, P=2.87x10-8, FDR<0.05) was formed by Christensenellaceae, Ruminococcaceae, Lachnospiraceae (NK4A136 group), Coriobacteria and the genera Coprococcus and Ruminoclostridium, which are all inversely associated with pathways representing SLC-mediated transmembrane transport (e.g. transport of bile acids and organic acids, metal ions and amine compounds) as well as biological oxidation and fat metabolism pathways including arachidonic acid metabolism and (glycero)phospholipid biosynthesis (Supplementary Tables S15-S16). In the sixth pair of components (component pair 9, P=9.65x10-7, FDR<0.05), the microbial component was primarily composed of bifidobacteria (i.e. order Bifidobacteriales, family Bifidobacteriaceae and genus Bifidobacterium), which were inversely associated with pathways representing phospholipid synthesis (e.g. phosphatidic acid synthesis) and NR1H2/NR1H3 or liver X receptor (LXR)-mediated signaling (Supplementary Tables S17-S18). NR1H3 (LXR-α) and NR1H2 (LXR-β) are ligand-activated transcription factors stimulated by endogenously produced oxysterols, which are in turn produced by oxidation of cholesterol, enzymatic reactions or alimentary processes.1 Under physiological conditions, oxysterols are formed proportional to the cellular cholesterol content and thereby stimulate LXRs (acting as cholesterol sensors) to alter gene expression and activate protective mechanisms to prevent cholesterol overload in the cell. This occurs via inhibition of intestinal cholesterol absorption, activation of cholesterol efflux from cells to HDL (via ABCA1 and ABCG1 transporters) and activation of the hepatic conversion of cholesterol to bile acids and stimulation of biliary cholesterol and bile acid excretion. In addition, LXR-agonists enhance de novo synthesis of fatty acids by stimulating the expression of the lipogenic transcription factor SREBP-1c, which may result in elevated plasma triglycerides and hepatic steatosis. LXRs are also involved in modulation of innate and adaptive immune responses and regulate diverse aspects of inflammatory gene expression in macrophages. The ability of LXRs to coordinate metabolic and immune response constitutes an attractive therapeutic target for treatment of IBD. Jakobsson T, Treuter E, Gustafsson JA, Steffensen KR. Liver X receptor biology and pharmacology: new pathways, challenges and opportunities. Trends Pharmacol Sci 2012;33(7):394-404. doi: 10.1016/j. tips.2012.03.013. 1 Chapter 6
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