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

• Type of Material: Article
• Authors: Mallappa Anitha, Pennsylvania State University; François Reichardt, Emory University; Sahar Tabatabavakili, Emory University; Behtash Ghazi Nezami, Emory University; Benoit Chassaing, Georgia State University; Simon Mwangi, Emory University; Matam Vijay-Kumar, Pennsylvania State University; Andrew Gewirtz, Emory University; Shanthi Srinivasan, Emory University
• Language: English
• Date: 2016-05-01
• Publisher: Elsevier
• Publication Version: Final Published Version
• Copyright Statement: © 2016 The Authors.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.jcmgh.2015.12.008
• Title of Journal or Parent Work: Cellular and Molecular Gastroenterology and Hepatology
• ISSN: 2352-345X
• Volume: 2
• Issue: 3
• Start Page: 328
• End Page: 339
• Grant/Funding Information: This research was funded by the NIH grant number NIH-RO1-DK080684 and VA-Merit Award.
• Keywords: TLR4; Myenteric neurons; LPS; colon transit; palmitate; gut microbiota
• Research Categories: Engineering, Biomedical; Health Sciences, Health Care Management; Health Sciences, General

Abstract

Background & Aims: 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.