Short-Chain Fatty Acids Regulate the Enteric Neurons and Control Gastrointestinal Motility in Rats

Background & Aims

Little is known about the environmental and nutritional regulation of the enteric nervous system (ENS), which controls gastrointestinal motility. Short-chain fatty acids (SCFAs) such as butyrate regulate colonic mucosa homeostasis and can modulate neuronal excitability. We investigated their effects on the ENS and colonic motility.

Methods

Effects of butyrate on the ENS were studied in colons of rats given a resistant starch diet (RSD) or intracecal perfusion of SCFAs. Effects of butyrate were also studied in primary cultures of ENS. The neurochemical phenotype of the ENS was analyzed with antibodies against Hu, choline acetyltransferase (ChAT), and neuronal nitric oxide synthase (nNOS) and by quantitative polymerase chain reaction. Signaling pathways involved were analyzed by pharmacologic and molecular biology methods. Colonic motility was assessed in vivo and ex vivo.

Results

In vivo and in vitro, RSD and butyrate significantly increased the proportion of ChAT- but not nNOS-immunoreactive myenteric neurons. Acetate and propionate did not reproduce the effects of butyrate. Enteric neurons expressed monocarboxylate transporter 2 (MCT2). Small interfering RNAs silenced MCT2 and prevented the increase in the proportion of ChAT- immunoreactive neurons induced by butyrate. Butyrate and trichostatin A increased histone H3 acetylation in enteric neurons. Effects of butyrate were prevented by inhibitors of the Src signaling pathway. RSD increased colonic transit, and butyrate increased the cholinergic-mediated colonic circular muscle contractile response ex vivo.

Conclusion

Butyrate or histone deacetylase inhibitors might be used, along with nutritional approaches, to treat various gastrointestinal motility disorders associated with inhibition of colonic transit.

Keywords: Butyrate, Neuron, Colon, Monocarboxylate Transporters

Abbreviations used in this paper: ANOVA, analysis of variance, AUC, area under the curve, ChAT, choline acetyltransferase, EFS, electrical field stimulation, ENS, enteric nervous system, GI, gastrointestinal, H3K9, histone H3 lysine 9, HDAC, histone deacetylase, Hu, hydroxyurea, IR, immunoreactive, L-NAME, nitro-l-arginine methyl ester, MCT, monocarboxylate transporter, nNOS, nitric oxide synthase, RSD, resistant starch diet, RT-PCR, reverse transcribed polymerase chain reaction, SCFA, short-chain fatty acid, SD, standard diet, SEM, standard error of the mean, siRNA, small interfering RNA, TSA, trichostatin A