Diet‐induced dysmotility and neuropathy in the gut precedes endotoxaemia and metabolic syndrome: the chicken and the egg revisited

Abstract

Neuropathy of the enteric nervous system (ENS) is one of the major underlying causes of debilitating gastrointestinal (GI) motility disorders in diabetic patients. Recent studies suggest that diet–microbiome–host interactions – in particular, excess dietary calories, microbial metabolites, lipopolysaccharide (LPS) and disrupted mucosal barrier – play a fundamental role in the pathobiology of obesity and type II diabetes (Boulangé et al. 2016). Furthermore, the composition of the GI microbiome influences ENS physiology, neurochemistry and nerve cell health, as well as GI motility patterns, and vice versa (Kashyap et al. 2013). However, links between such interactions and the mechanisms underlying this neuropathy are not fully understood. In this issue of The Journal of Physiology, Reichardt et al. (2017) address the question of whether ingesting a Western diet (WD) rich in saturated fatty acids and the associated alteration to the gut microbiome disrupts motility, and induces loss of nitrergic myenteric neurons (NMNs), the phenotype that is commonly damaged in diabetic neuropathy (Yarandi & Srinivasan, 2014). The rationale is that most studies have used a high fat diet (HFD; 60–72% kcal from fat), leading to little understanding of how a normal WD affects GI motility, the ENS and their role in the pathobiology of the metabolic syndrome and diabetes. The authors used C57BL/6 mice fed WD (35% kcal from fat, enriched in palmitate) or a regular diet (RD, 16.9% kcal from fat, 4× less palmitate) for 3, 6, 9 and 12 weeks, and TLR4 and germ free mice fed WD and RD diets for 6 weeks. Gastrointestinal motility was measured, and damage to myenteric neurons and NMNs was studied in the ileum and proximal colon. Palmitateand LPS-induced damage to NMNs and the role of nitric oxide synthase (nNOS) in such injury were determined in vitro using immortalized myenteric neurons. Faecal metabolites, systemic and visceral fat and mucosal inflammation were analysed. After ingesting WD for 6 weeks, mice were ‘overweight’, developed gut microbiota dysbiosis, altered faecal metabolites, increased intraluminal LPS and increased plasma free fatty acid (FFA) levels. Interestingly, unlike HFD, WD did not elicit hyperglycaemia, endotoxaemia and inflammation, suggesting the need to define key differences between the effect of HFD and WD on gut microbiome and metabolic profiles. Another important observation was that WD caused GI dysmotility before