High‐fat diet–induced alterations to gut microbiota and gut‐derived lipoteichoic acid contributes to the development of enteric neuropathy

Abstract

BackgroundHigh‐fat diet, microbial alterations and lipopolysaccharide (LPS) are thought to cause enteric diabetic neuropathy and intestinal dysmotility. However, the role of the gut microbiota, lipoteichoic acid (LTA) from Gram‐positive bacteria and short‐chain fatty acids (SCFAs) in the development of diabetic enteric neuropathy and intestinal dysmotility is not well understood. Our aim was to examine the role of the gut microbiota, LTA and SCFAs in the development of diabetic enteric neuropathy and intestinal dysmotility.MethodsWe fed germ‐free (GF) and conventionally raised (CR) mice either a high‐fat (HFD) or standard chow diet (SCD) for 8 weeks. We analyzed the microbial community composition in CR mice using 16S rRNA sequencing and damage to myenteric neurons using immunohistochemistry. We also studied the effects of LPS, LTA, and SCFAs on duodenal muscularis externa contractions and myenteric neurons using cultured preparations.Key ResultsHigh‐fat diet ingestion reduced the total number and the number of nitrergic myenteric neurons per ganglion in the duodenum of CR but not in GF‐HFD mice. GF mice had fewer neurons per ganglion compared with CR mice. CR mice fed a HFD had increased abundance of Gram‐positive bacteria. LTA and LPS did not affect the frequency of duodenal muscularis contractions after 24 hours of cultured but reduced the density of nitrergic myenteric neurons and increased oxidative stress and TNFα production in myenteric ganglia. SCFAs did not affect muscularis contractions or injure myenteric neurons.Conclusions & InferencesGut microbial alterations induced increase in Gram‐positive bacterial LTA may contribute to enteric neuropathy.

Small intestine remodeling in male Goto–Kakizaki rats

“…In addition to obesity, other inflammatory conditions such as periodontal disease, obstructive pulmonary disease, arthritis, and muscular dystrophy are also associated with the development of IR and type 2 diabetes mellitus (T2DM; Demmer et al, 2008; McNeely & Boyko, 2004; Tiengo et al, 2008). Notably, most studies involving this T2DM and IR were performed using obese humans or animals fed a high‐calorie diet that resembles the western human diet (Lowette et al, 2016; Masi et al, 2017; Nyavor et al, 2020). However, not all patients with T2DM are obese.…”

Supernatants of intestinal luminal contents from mice fed high‐fat diet impair intestinal motility by injuring enteric neurons and smooth muscle cells

“…These abnormalities occur in prediabetes and diabetic patients, and disrupted mucosal barrier promotes an abnormal passage of luminal substances into the intestinal wall 43,44 . We recently reported that HFD‐induced changes to gut microbiota composition play a role in HFD‐induced neuropathy and dysmotility 45 . Additionally, changes to gut microbiota composition have been linked to the production of toxic molecules causing decreased colonic muscle contractility in irritable bowel disease, 46 and visceral hypersensitivity in colicky infants 47 .…”

“…43,44 We recently reported that HFD-induced changes to gut microbiota composition play a role in HFD-induced neuropathy and dysmotility. 45 Additionally, changes to gut microbiota composition have been linked to the production of toxic molecules causing decreased colonic muscle contractility in irritable bowel disease, 46 and visceral hypersensitivity in colicky infants. 47 Furthermore, there is an increasing number of studies providing evidence to link CNS neurologic diseases, notably autism spectrum disorder, Parkinson's disease, and Alzheimer's disease to altered gut microbiota and GI dysfunctions.…”

“…48,50,51 However, toxic molecules from the GI lumen are largely unknown. It is likely that neurotoxic and antimotility molecules in HFD-ICS and HFD-SPE1 are derived from altered gut microbial communities 45 and can cross the disrupted mucosal barrier and injure cells in the GI wall and other body organs. Whether this is the case in other GI disorders or CNS neurologic diseases remains to be determined.…”

Food-Induced Duodenal Obstruction Successfully Reopened by Endoscopic Treatment

“…Changes in the number of intestinal cells of Cajal and myenteric neurons due to impaired mucosal integrity and low baseline impedance in the duodenum which result in abnormal gastroduodenal motility, have been reported in patients with FD [ 15 , 16 ]. Alternatively, a high-fat diet and microbial alteration are thought to cause enteric diabetic neuropathy and intestinal dysmotility based on the reduction of nitrergic myenteric neurons per ganglion in the duodenum [ 17 ]. The median time of retention in the duodenum was reported to be longer in diabetic patients than in healthy volunteers (12.7 versus 8.1 minutes) [ 18 ].…”