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Impact of Gut Microbiota on Intestinal and Hepatic Levels of Phase 2 Xenobiotic-Metabolizing Enzymes in the Rat

Departments of Nutritional Toxicology (W.M., H.G.), Gastrointestinal Microbiology (S.S., M.B.), and Biochemistry of Micronutrients (R.B.-F.), German Institute of Human Nutrition Potsdam-Rehbrücke, Nuthetal, Germany

Using immunoblotting, we compared levels of phase 2 enzymes in liver, small intestine, cecum, and colon of germ-free and control rats (reassociated with rat intestinal microbiota). In addition, colonic levels were studied after association with human intestinal microbiota. The glutathione transferases (GSTs) studied, gastrointestinal glutathione peroxidase (GPX2), both epoxide hydrolases (EPHXs), and N-acetyltransferase (NAT) 1, were detected in all tissues. GPX2 and GSTP1 were highest in large bowel; the other enzymes of this group were highest in liver. NAT2 was found in the large bowel but not in the liver or small bowel. Sulfotransferases (SULTs) were detected in liver but were absent in small intestine; two forms were present at moderate levels in the large intestine. Strong gender-dependent differences were observed for several enzymes in liver but not in gut. Colonic levels in germ-free animals differed from those in control animals (* indicates statistical significance) for GSTA1/2 (4.0*- and 5.0*-fold in males and females, respectively), GSTA4 (1.5*/1.9*-fold), GSTM1 (1.1/1.5*-fold), EPHX1 (3.5*/2.4*-fold), EPHX2 (1.4/2.1*-fold), SULT1B1 (0.4*/0.6*-fold), SULT1C2 (1.3/1.6*-fold), and NAT2 (1.4/1.5*-fold). Smaller effects were observed when rats were colonized with human, compared with rat, intestinal bacteria. Cecal enzyme levels in germ-free rats were changed similarly to those in colon. No effects were seen in small intestine. In liver, SULT1A1, SULT1C1, and SULT1C2 were elevated in germ-free animals of both genders (1.5- to 2.6-fold); hepatic EPHX2 was elevated 1.6-fold in females. In conclusion, intestinal microbiota can affect levels of xenobiotic-metabolizing enzymes in large intestine and liver, but the effects observed were moderate compared with tissue-dependent expression differences.