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

Abstract

Background & AimsHigh-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.MethodsMale 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.ResultsHFD-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.ConclusionsTogether 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.

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

“…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. 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.…”

“…In addition to enteric neurons, glial cells act by integrating motility control and regulating intestinal barrier function and secretion, although their exact functions and mechanisms are still poorly understood. 4,17,18 Additionally, HFDs were reported to activate inflammatory processes by increasing the production of lipopolysaccharides (LPSs) by the microbiota and activate Toll-like receptors (TLRs). Previous studies reported that HFDs significantly altered the intestinal microbiota and increased intestinal permeability.…”

“…Previous studies reported that HFDs significantly altered the intestinal microbiota and increased intestinal permeability. 4,20,21 Saturated fatty acids (eg, palmitate) in the diet also directly activated TLR4 signaling and induced deleterious effects on enteric neurons, indicating that lipotoxicity was directly caused by the HFD. 19 Activation of the TLR4 signaling pathway by LPS in vitro resulted in neuronal death.…”

“…4,17,18 Additionally, HFDs were reported to activate inflammatory processes by increasing the production of lipopolysaccharides (LPSs) by the microbiota and activate Toll-like receptors (TLRs). 4,9,10,15,22 The inflammatory process and endotoxemia that are related to HFDs can be attenuated by prebiotic supplementation in the diet. 4,20,21 Saturated fatty acids (eg, palmitate) in the diet also directly activated TLR4 signaling and induced deleterious effects on enteric neurons, indicating that lipotoxicity was directly caused by the HFD.…”

“…19 Activation of the TLR4 signaling pathway by LPS in vitro resulted in neuronal death. 4,19 Prebiotics are non-digestible nutrients that stimulate the growth of specific groups of bacteria in the large intestine. 4,9,10,15,22 The inflammatory process and endotoxemia that are related to HFDs can be attenuated by prebiotic supplementation in the diet.…”