Enteric dysbiosis associated with a mouse model of alcoholic liver disease.
The translocation of bacteria and bacterial products into the circulation contributes to alcoholic liver disease. Intestinal bacterial overgrowth is common in patients with alcoholic liver disease. The aims of our study were to investigate bacterial translocation, changes in the enteric microbiome, and its regulation by mucosal antimicrobial proteins in alcoholic liver disease. We used a mouse model of continuous intragastric feeding of alcohol or an isocaloric diet. Bacterial translocation occurred prior to changes observed in the microbiome. Quantitative changes in the intestinal microflora of these animals were assessed first using conventional culture techniques in the small and large intestine. Although we found no difference after 1 day or 1 week, intestinal bacterial overgrowth was observed in the gastrointestinal tract of mice fed alcohol for 3 weeks compared with control mice fed an isocaloric liquid diet. Because <20% of all gastrointestinal bacteria can be cultured using conventional methodologies, we performed massively parallel pyrosequencing to further assess the qualitative changes in the intestinal microbiome following alcohol exposure. Sequencing of 16S ribosomal RNA genes revealed a relative abundance of Bacteroidetes and Verrucomicrobia bacteria in mice fed alcohol compared with a relative predominance of Firmicutes bacteria in control mice. With respect to the host's transcriptome, alcohol feeding was associated with down-regulation in gene and protein expression of bactericidal c-type lectins Reg3b and Reg3g in the small intestine. Treatment with prebiotics partially restored Reg3g protein levels, reduced bacterial overgrowth, and lessened alcoholic steatohepatitis.


CONCLUSIONS
Alcohol feeding is associated with intestinal bacterial overgrowth and enteric dysbiosis. Intestinal antimicrobial molecules are dysregulated following chronic alcohol feeding contributing to changes in the enteric microbiome and to alcoholic steatohepatitis.
Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA.
Arthur W
AW
Yan
Derrick E
DE
Fouts
Johannes
J
Brandl
Peter
P
Stärkel
Manolito
M
Torralba
Eckart
E
Schott
Hide
H
Tsukamoto
Karen E
KE
Nelson
David A
DA
Brenner
Bernd
B
Schnabl
D000818:Animals; D018988:Bacterial Translocation / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D005235:Fatty Liver, Alcoholic / Q000378:metabolism; D007421:Intestine, Small / Q000382:microbiology; D007422:Intestines / Q000382:microbiology*; D008108:Liver Diseases, Alcoholic / Q000382:microbiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D000073718:Pancreatitis-Associated Proteins; D011506:Proteins / Q000235:genetics; D012336:RNA, Ribosomal, 16S / Q000235:genetics
D000073718:Pancreatitis-Associated Proteins; D011506:Proteins; D012336:RNA, Ribosomal, 16S; C490253:Reg3b protein, mouse; C490255:Reg3g protein, mouse
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