Obeticholic acid reduces bacterial translocation and inhibits intestinal inflammation in cirrhotic rats

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• 作者：Mar&iacute ; a Ú ; beda¹ ; ² ; Margaret Lario¹ ; ² ; Leticia Muñ ; oz¹ ; ² ; Mar&iacute ; a-José ; Borrero¹ ; ² ; Macarena Rodr&iacute ; guez-Serrano³ ; Ana-Mar&iacute ; a Sá ; nchez-D&iacute ; az⁴ ; Rosa del Campo⁴ ; Lourdes Lledó ; ⁵ ; Ó ; scar Pastor⁶ ; Laura Garc&iacute ; a-Bermejo³ ; David D&iacute ; az¹ ; ² ; ⁷ ; Melchor Á ; lvarez-Mon¹ ; ² ; ⁷ ; ^&dagger ; ; Agust&iacute ; n Albillos¹ ; ² ; ⁸ ; ^&dagger ; ; ^{agustin.albillos@uah.es" class="auth_mail" title="E-mail the corresponding author}
• 关键词：GBT ; gut bacterial translocation ; TJ ; tight junction ; ZO-1 ; zonula occludens-1 ; FXR ; farnesoid X receptor ; MLN ; mesenteric lymph nodes ; OCA ; obeticholic acid ; SHP ; small heterodimer partner ; OTU ; operational taxonomic units ; TNF ; tumor necrosis factor ; IL ; interleukin
• 刊名：Journal of Hepatology
• 出版年：2016
• 出版时间：May 2016
• 年：2016
• 卷：64
• 期：5
• 页码：1049-1057
• 全文大小：994 K

文摘

In advanced cirrhosis, gut bacterial translocation is the consequence of intestinal barrier disruption and leads to bacterial infection. Bile acid abnormalities in cirrhosis could play a role in the integrity of the intestinal barrier and the control of microbiota, mainly through the farnesoid X receptor. We investigated the long-term effects of the farnesoid X receptor agonist, obeticholic acid, on gut bacterial translocation, intestinal microbiota composition, barrier integrity and inflammation in rats with CCl₄-induced cirrhosis with ascites.

Methods

Cirrhotic rats received a 2-week course of obeticholic acid or vehicle starting once ascites developed. We then determined: bacterial translocation by mesenteric lymph node culture, ileum expression of antimicrobial peptides and tight junction proteins by qPCR, fecal albumin loss, enteric bacterial load and microbiota composition by qPCR and pyrosequencing of ileum mucosa-attached contents, and intestinal inflammation by cytometry of the inflammatory infiltrate.

Results

Obeticholic acid reduced bacterial translocation from 78.3% to 33.3% (p <0.01) and upregulated the expression of the farnesoid X receptor-associated gene small heterodimer partner. Treatment improved ileum expression of antimicrobial peptides, angiogenin-1 and alpha-5-defensin, tight junction proteins zonulin-1 and occludin, and reduced fecal albumin loss and liver fibrosis. Enteric bacterial load normalized, and the distinctive mucosal microbiota of cirrhosis was reduced. Gut immune cell infiltration was reduced and inflammatory cytokine and Toll-like receptor 4 expression normalized.

Conclusions

In ascitic cirrhotic rats, obeticholic acid reduces gut bacterial translocation via several complementary mechanisms at the intestinal level. This agent could be used as an alternative to antibiotics to prevent bacterial infection in cirrhosis.