Western diet induces colonic nitrergic myenteric neuropathy and dysmotility in mice via saturated fatty acid- and LPS-induced TLR4 signaling (original) (raw)

The Journal of Physiology, 2016

Abstract

Consumption of high-fat diets (HFD) is associated with myenteric neurodegeneration associated with delayed colonic transit and constipation. We examined the hypothesis that both HFD's inherent increase in plasma free fatty acids (FFA) and HFD-induced alteration in gut microbiota contribute to the pathophysiology of these disorders. C57BL/6 mice were fed a Western diet (WD, 35% kcal from fat- enriched in palmitate) or a purified regular diet (RD, 16.9% kcal from fat) for 3, 6, 9 and 12 weeks. Gut microbiota dysbiosis was investigated by fecal LPS measurement and metabolomics (LTQ-FTMS) analysis. Plasma FFA and LPS, colonic and ileal nitrergic myenteric neurons quantifications and motility were assessed. Compared to RD-fed control mice, WD-fed mice gained significantly more weight without blood glucose alteration. Dysbiosis was exhibited after 6 weeks of feeding as reflected by increased fecal LPS and bacterial metabolites and concomitant higher plasma FFA. Numbers of nitrergic myenteric neurons were reduced in the proximal colon after 9 and 12 weeks of WD and associated with delayed colonic transit. WD-fed TLR4(-/-) mice did not exhibit myenteric cell loss or dysmotility. Finally, LPS [0.5 to 2 ng/ml] and palmitate [20 and 30 μM] acted synergistically to induce neuronal cell death in vitro which was prevented by the NOS inhibitor L-NAME. In conclusion, WD-feeding results in increased levels of FFA and microbiota that, even in absence of hyperglycemia or overt endotoxemia, synergistically induce TLR4-mediated neurodegeneration and dysmotility. This article is protected by copyright. All rights reserved.

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