Colonic neuronal loss and delayed motility induced by high‐fat diet occur independently of changes in the major groups of microbiota in Swiss mice

Abstract

The prevalence of obesity is a public health concern, and evidence links obesity to the development of chronic diseases, such as diabetes, cancer, and diseases of the cardiovascular and nervous systems. 1 Obesity has also been associated with gastrointestinal motility disorders 2 ; constipation and longer colonic transit times are frequently observed in animal models of excessive fat intake in the diet. 3,4 Normal intestinal motility involves the coordinated function of extrinsic innervation of the intestine and the enteric nervous Abstract Background: Obesity has been linked to gastrointestinal disorders, and the loss of myenteric neurons in the intestine caused by high-fat diets (HFD) has been attributed to changes in microbiota and lipotoxicity. We investigated whether the prebiotic inulin modulates bacterial populations and alleviates neuronal loss in mice fed HFD. Methods: Swiss mice were fed purified rodent diet or HFD (59% kcal fat), or both diets supplemented with inulin for 17 weeks. Intestinal motility was assessed and a metagenome analysis of the colonic microbiota was performed. The gene expression of inflammatory markers was evaluated, and immunofluorescence was performed for different types of myenteric neurons and glial cells in the distal colon. Key Results: The HFD caused obesity and delayed colonic motility. The loss of myenteric neurons and glial cells in obese mice affected all of the studied neuronal populations, including neurons positive for myosin-V, neuronal nitric oxide synthase, vasoactive intestinal peptide, and calretinin. Although obese mice supplementedwith inulin exhibited improvements in colonic motility, neuronal, and glial cell loss persisted. The HFD did not altered the expression levels of inflammatory cytokines in the intestine or the prevalence of the major groups in microbiota, but inulin increased the proportion of the genus Akkermansia in the obese mice. Conclusions and Inferences:In Swiss mice, the HFD-induced neuronal loss but did not change the major groups in microbiota. This suggests that, despite the increase in the beneficial bacteria, other factors that are directly linked to excess dietary lipid intake affect the enteric nervous system.

High‐fat diets on the enteric nervous system: Possible interactions and mechanisms underlying dysmotility

“…HFD‐induced neuroplasticity also seems to be characterized by specific enteric neuron subpopulations being targeted. Previous studies have shown a decrease in the density of nitrergic, cholinergic, and vasoactive intestinal peptide (VIP)‐ergic neurons 14,19,32,36,39,40 . These findings may help to explain the mechanisms involved in the impaired motility observed in this model with excitatory and inhibitory motoneurons with acetylcholine, and VIP and NO as primary neurotransmitters, respectively 44 .…”

“…Myenteric neurons directly control motility and are among the most affected enteric neural cells in the HFD model (Table 1). Increasing data suggest that different HFD interventions, independent of percentages and duration, can promote changes that may result in myenteric neuronal loss 32–34,36,39–41 …”

“…Thus, the HFD model may induce pathological enteric plasticity. Furthermore, HFD‐induced enteric neuroplasticity and dysmotility are suggested to occur earlier than traditional metabolic obesity outcomes 10,19,28,32–36 …”

Association of Dietary Energy Intake With Constipation Among Men and Women: Results From the National Health and Nutrition Examination Survey

“…However, to our knowledge, minimal studies have evaluated the impact of dietary intake on constipation from the perspective of its integrated effects, such as total energy loads, which were mainly supplied by the metabolism of protein, carbohydrate, and fat ingested by us every day. A few pieces of literature have shown that inappropriate intake of macronutrients like a high-fat diet may disturb gastrointestinal motility, suggesting that high energy intake may do as well ( 10 – 13 ). Therefore, we hypothesize that high energy intake may correlate with a higher risk of chronic constipation.…”

"Differential Effects of Unsaturated Fatty Acids and Saturated Fatty Acids on Lipotoxicity and Neutral Lipid Accumulation in Neuro-2a Cells"

“…While neurons are not energy-storing cells and their use of fatty acids as an energy source is minimal, they do contain LD [20]. High fat diet causes obesity and loss of myenteric neurons in Swiss mice [21].…”