Short-term exposure of HFD depresses intestinal cholinergic anti-inflammatory activity through hypothalamic inflammation in mice.

High-fat diet (HFD) exposure has been proven to impair vagus nerve function. However, it is not yet known whether the HFD challenge impacts vagal efferent-based intestinal cholinergic anti-inflammation activity. This investigation aims to evaluate the effect of HFD on intestinal cholinergic anti-inflammatory activity in mice. Mice with or without intracerebroventricular treatment with an antibody against toll-like receptor 4 (TLR4) were fed with HFD or standard chow for 2 weeks. Vagus nerve-based anti-inflammatory activity was analyzed by heart rate variability. Acetylcholine (ACh) content, nicotinic acetylcholine receptor α7 subtype (α7nAChR), and pro-inflammatory cytokines were analyzed by biochemical kits or qRT-PCR. HFD feeding mice exhibit a significant increase in high frequency (HF) and a decrease in the ratio of low frequency/HF, which were accompanied by lower ACh levels and α7nAChR mRNA expression in the intestinal segments. However, anti-TLR4 antibody-treated HFD mice showed normal ACh levels and α7nAChR mRNA expression in the intestinal segments. Moreover, TNF-α production in small intestine was significantly reduced in HFD + antibody group compared with HFD + vehicle group. Collectively, our present results reveal that HFD challenge depresses intestinal cholinergic anti-inflammatory activity, which is mediated by hypothalamic inflammation. Impairment of intestinal cholinergic anti-inflammatory pathway is the cause of intestinal low-grade inflammation by HFD consumption.