Properties of myenteric neurones and mucosal functions in the distal colon of diet‐induced obese mice

Abstract

Key points• We investigated altered colonic functions in high fat diet-induced obesity in pre-diabetic mice.• After feeding an adipogenic diet for 12 weeks, accelerated colonic transit was associated with upregulation and enhanced signalling of acetylcholine and serotonin, two key mediators in the enteric nervous system (ENS). Importantly, these changes occurred without signs of impaired mucosal integrity or immune cell infiltration in the gut wall. Neuronal sensitization was not observed in obese mice fed for 4 weeks.• Weight gain correlated positively with the level of adipocyte markers and the degree of neuronal sensitization.• We conclude that enhanced neural excitation in the colon by acetylcholine and serotonin is a key feature of a later phase of obesity and is involved in altered ENS functions and abnormal colonic transit.• Furthermore, the results suggest that the occurrence of altered gut functions in obesity is independent of inflammation in the gut wall.Abstract Colonic transit and mucosal integrity are believed to be impaired in obesity. However, a comprehensive assessment of altered colonic functions, inflammatory changes and neuronal signalling of obese animals is missing. In mice, we studied the impact of diet-induced obesity (DIO) on: (i) in vivo colonic transit; (ii) signalling in the myenteric plexus by recording responses to nicotine and 2-methyl-5-hydroxytryptamine (2-methyl-5-HT), together with the expression of tryptophan hydroxylase (TPH) 1 and 2, serotonin reuptake transporter, choline acetyltransferase and the paired box gene 4; and (iii) expression of proinflammatory cytokines, epithelial permeability and density of macrophages, mast cells and enterochromaffin cells. Compared with controls, colon transit and neuronal sensitivity to nicotine and 2-methyl-5-HT were enhanced in DIO mice fed for 12 weeks. This was associated with increased tissue acetylcholine and 5-hydroxytryptamine (5-HT) content, and increased expression of TPH1 and TPH2. In DIO mice, upregulation of proinflammatory cytokines was found in fat tissue, but not in the gut wall. Accordingly, mucosal permeability or integrity was unaltered without signs of immune cell infiltration in the gut wall. Body weight showed positive correlations with adipocyte markers, tissue levels of 5-HT and acetylcholine, and the degree of neuronal sensitization. DIO mice fed for 4 weeks showed no neuronal sensitization, had no signs of gut wall inflammation and showed a smaller increase in leptin, interleukin-6 and monocyte chemoattractant protein 1 expression in fat tissue. DIO is associated with faster colonic transit and impacts on acetylcholine and 5-HT metabolism with enhanced responsiveness of enteric neurones to both mediators after 12 weeks of feeding. Our study demonstrates neuronal plasticity in DIO prior to the development of a pathological histology or abnormal mucosal functions. This questions the common assumption that increased mucosal inflammation and permeability initiate functional disorders in obesity.

Poststroke emotional disturbances and a tryptophan hydroxylase 2 gene polymorphism

“…Elevation of glucocorticoid creates a vulnerability to emotional disturbance (Mak, Tang, Chan, Cheak, & Ho, ); and elevation of corticosterone is associated with increased TPH2 expression (Donner, Montoya, Lukkes, & Lowry, ). Increased TPH2 expression was associated with an increase in leptin and interleukin‐6 (IL‐6) (Reichardt et al., ) and a decrease in GABA (Waider et al., ); which play a key role in the pathogenesis of emotional disturbance (Liu, Ho, & Mak, ; Yang, De Xiang Liu, Pan, Ho, & Ho, ; Lu et al., ).…”

The Enteric Nervous System

“…Most recently, Reichardt et al ( 2013 ) used mice fed a Western diet to examine changes in myenteric neuron excitability in the mouse distal colon. A fast voltagesensitive dye (di-8-ANEPPS acquired at 1000 Hz) enabled exploration of changes in response to microejection of the neurotransmitter analogues nicotine and 2-methyl 5-HT that activate receptors that normally mediate enteric fast EPSPs.…”

Excitability and Synaptic Transmission in the Enteric Nervous System: Does Diet Play a Role?

“…Most recently, Reichardt et al (2013) used mice fed a Western diet to examine changes in myenteric neuron excitability in the mouse distal colon. A fast voltage-sensitive dye (di-8-ANEPPS acquired at 1000Hz) enabled exploration of changes in response to microejection of the neurotransmitters analogues nicotine and 2-methyl 5-HT that activate receptors that normally mediate enteric fast EPSPs.…”