Intestinal Dysbiosis Contributes to the Delayed Gastrointestinal Transit in High-Fat Diet Fed Mice

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• 作者：Mallappa Anitha¹ ; ^&lowast ; ; Franç ; ois Reichardt² ; ³ ; Sahar Tabatabavakili² ; ³ ; Behtash Ghazi Nezami² ; ³ ; Benoit Chassaing⁴ ; Simon Mwangi² ; ³ ; Matam Vijay-Kumar⁵ ; ^&Dagger ; ; Andrew Gewirtz⁴ ; Shanthi Srinivasan² ; ³ ; ^{ssrini2@emory.edu" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Myenteric Neurons ; Palmitate ; Gut Microbiota ; LPS ; TLR4 ; Colon Transit
• 刊名：CMGH Cellular and Molecular Gastroenterology and Hepatology
• 出版年：2016
• 出版时间：May 2016
• 年：2016
• 卷：2
• 期：3
• 页码：328-339
• 全文大小：2292 K

文摘

High-fat diet (HFD) feeding is associated with gastrointestinal motility disorders. We recently reported delayed colonic motility in mice fed a HFD for 11 weeks. In this study, we investigated the contributing role of gut microbiota in HFD-induced gut dysmotility.

Methods

Male C57BL/6 mice were fed a HFD (60% kcal fat) or a regular/control diet (RD) (18% kcal fat) for 13 weeks. Serum and fecal endotoxin levels were measured, and relative amounts of specific gut bacteria in the feces were assessed by real-time polymerase chain reaction. Intestinal transit was measured by fluorescent-labeled marker and a bead expulsion test. Enteric neurons were assessed by immunostaining. Oligofructose (OFS) supplementation with RD or HFD for 5 weeks also was studied. In vitro studies were performed using primary enteric neurons and an enteric neuronal cell line.

Results

HFD-fed mice had reduced numbers of enteric nitrergic neurons and showed delayed gastrointestinal transit compared with RD-fed mice. HFD-fed mice had higher fecal Firmicutes and Escherichia coli and lower Bacteroidetes compared with RD-fed mice. OFS supplementation protected against enteric nitrergic neuron loss in HFD-fed mice, and improved intestinal transit time. OFS supplementation resulted in a reduction in fecal Firmicutes and Escherichia coli and serum endotoxin levels. In vitro, palmitate activation of TLR4 induced enteric neuronal apoptosis in a Phospho–c-Jun N-terminal kinase–dependent pathway. This apoptosis was prevented by a c-Jun N-terminal kinase inhibitor and in neurons from TLR4^-/- mice.

Conclusions

Together our data suggest that intestinal dysbiosis in HFD-fed mice contribute to the delayed intestinal motility by inducing a TLR4-dependent neuronal loss. Manipulation of gut microbiota with OFS improved intestinal motility in HFD mice.