Fructose consumption impairs serotonergic signaling in the murine enteric nervous system

Abstract

The intake of free fructose has increased substantially since the development of high-fructose corn syrup. This has not only been associated with metabolic disorders but recent evidence also indicates that chronic fructose consumption can affect neuronal and cognitive function. In this study we investigated the effects of fructose consumption on serotonergic signaling and neuronal activity in the mouse submucous plexus. Male mice were put on a control or fructose (23% solution) diet for 6 weeks or were assigned to a recovery group that received normal water (2 weeks) after 4 weeks of fructose. At the end of the diet, gene expressions and enteric neuronal activity, after depolarization with high K(+) and 5-HT, were measured using Ca(2+) imaging and RT-qPCR, respectively. Even in the lack of gain weight and the absence of changes in duodenal permeability, the total number of 5-HT-responding neurons and the depolarization and 5-HT-evoked Ca(2+) amplitudes were significantly lower after fructose consumption. Expression of synaptobrevin CaV 2.1 and CaV 2.2 mRNA did not differ after fructose intake; however, CaV 2.1 mRNA levels were significantly higher in the recovery animals. SERT mRNA concentration, isolated from submucosal plexus containing mucosal epithelium, was significantly decreased after fructose consumption. Chronic fructose consumption impairs serotonergic signaling in the mouse submucous plexus, prior to weight gain and detectable intestinal permeability problems.

Intestinal Permeability, Inflammation and the Role of Nutrients

“…Increased dietary fructose in mice for 6 weeks did not modify body weight but induced downregulation at the mRNA level of tight junction proteins of the leak pathway occludin and ZO-1 in the small intestinal. Nevertheless, the intestinal permeability to ions assessed by TEER measurements remained intact [40]. A longer fructose administration for 12 weeks showed similar results, with no changes in body weight but an increased permeability to PEG and dextran (4 KDa each), which was associated with the downregulation of occludin and ZO-1 at mRNA levels.…”

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.…”

Finding the Sweet Spot: Parsing Tissue-Specific Contributions of Fructose Metabolism

“…Fructose consumption reduces ENS serotonin levels in mice by interfering with L-tryptophan metabolism (Janssen et al, 2011). Interestingly, blocking serotonergic signaling through the 5-HT3 receptor with Ondansetron increased consumption of a mixed-meal liquid at maximal satiation in people (Lowette et al, 2016), suggesting reduced serotonin may contribute to a feedforward loop to consume more fructose.…”