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Author Notes:

Corresponding Author Shanthi Srinivasan, M.D. Associate Professor of Medicine Division of Digestive Diseases Whitehead Biomedical Research Building, Suite 201A 615 Michael Street, Atlanta, GA, 30322 Tel: 404-727-5298, Fax: 404-727-5767; Email: ssrini2@emory.edu

All authors contributed to the final version of the manuscript.

MA, ST, FR, BC, AG and SS designed the experiments, analyzed and interpreted the data; MA, ST and BC collected and analyzed the data; MA, FR and SS wrote the article; BC, BGN, SM, MVK and AG revised the article critically for important intellectual content.

All authors approved the final version of the manuscript.

The authors would like to acknowledge the animal facility in Emory University.

Subjects:

Research Funding:

This research was funded by the NIH grant number NIH-RO1-DK080684 and VA-Merit Award.

Keywords:

  • LPS
  • Myenteric neurons
  • TLR4
  • colon transit
  • gut microbiota
  • palmitate

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

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Journal Title:

Cellular and Molecular Gastroenterology and Hepatology

Volume:

Volume 2, Number 3

Publisher:

, Pages 328-339

Type of Work:

Article | Final Publisher PDF

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.

Copyright information:

© 2016 The Authors.

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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