Enteric glial cells respond to a dietary change in the lamina propria in a MyD88-dependent manner

Abstract

Immune and nervous system sensing are two important ways of detecting inner and outer environmental changes. Immune cell activation in the gut can promote metabolic disorders. However, whether enteric nervous system sensing and activities are also important in metabolic syndromes is not clear. Enteric glial cells (EGCs) are thought to have sensing ability, but little is known about the potential connections between EGC and metabolic disorders. Consuming a modern Western-type high-fat low-fiber diet increases the risk of obesity. Here, we reported that dietary shift from a normal chow diet to a high-fat diet in wild-type (WT) C57BL/6 mice induced a transient emergence of glial fibrillary acidic protein (GFAP)-positive EGC network in the ileal lamina propria, accompanied by an increase of glial-derived neurotrophic factors production. Inhibition of EGC metabolic activity via gliotoxin fluorocitrate or glial-intrinsic deletion of myeloid differentiation factor 88 (Myd88) in mice blocked this dietary change-induced activity. Furthermore, we found a different role of MYD88 in glial cells versus adipocyte in diet-induced obesity. The glial Myd88 knockout mice gained less body weight after HFD feeding compared to the littermate controls. In contrast, adipocyte deletion of Myd88 in mice had no impact on the weight gain but had exacerbated glucose metabolic disorders. Pharmacological interventions of glial activities by fluorocitrate prevented body weight gain in a dietary type- and glial MYD88-independent manner. Collectively, our data reveal a previously unappreciated function of EGC in sensing a dietary shift-induced perturbation and glial activities as a whole may play roles in diet-induced obesity.New & NoteworthyIt is known that obesity and its related metabolic syndrome can damage the neuronal system. However, whether the neuronal system also participates in the development of obesity is unclear. Diet is an important contributing factor to obesity. Our study reveals that consuming a high-fat diet can induce a transient enteric glial cell response via its intrinsic sensing molecule(s). Inhibiting overall glial cell activities may have an impact on the development of the metabolic syndrome.

Enteric glia in homeostasis and disease: From fundamental biology to human pathology

“…Type 2 ILCs also express RET, but its role in these cells is yet undetermined. Enteric glial MYD88 has also been shown in a recent preprint manuscript to modulate the response to a high-fat diet (Liu et al, 2020), a condition known to alter the gut microbiome (Hildebrandt et al, 2009). EGCs of mice fed a high-fat diet assumed a reactive phenotype and increased production of S100B and GFLs, including GDNF and ARTN.…”

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

“…In the gut, ILC‐3 function is under the direct enteric glial influence through GDNF signaling in a Myd88 dependent manner 115 . Remarkably, EGCs in the lamina propria respond to HFD in a Myd88 dependent manner 116 . When Myd88 signaling is defective in EGCs, both glial activation associated with GDNF release and IL‐22 release by ILC‐3 are blocked 115,116 .…”

“…116 When Myd88 signaling is defective in EGCs, both glial activation associated with GDNF release and IL-22 release by ILC-3 are blocked. 115,116 This signaling shows that EGCs are sensitive to dietary changes involving a signaling axis related to immune modulation, which can underlie gut dysfunction. 10,117 The EGCs and intestinal epithelium are also in close proximity to the mesenteric adipose tissue.…”

“…Remarkably, EGCs in the lamina propria respond to HFD in a Myd88 dependent manner 116 . When Myd88 signaling is defective in EGCs, both glial activation associated with GDNF release and IL‐22 release by ILC‐3 are blocked 115,116 . This signaling shows that EGCs are sensitive to dietary changes involving a signaling axis related to immune modulation, which can underlie gut dysfunction 10,117 …”