Short-Chain Fatty Acids Manifest Stimulative and Protective Effects on Intestinal Barrier Function Through the Inhibition of NLRP3 Inflammasome and Autophagy

Abstract

Background/Aims: Short-chain fatty acids (SCFAs) are the major energy resources of intestinal epithelial cells. It has been reported that SCFAs can repair the dysfunction of intestinal barrier, however, the underlying mechanisms are still not fully understood. Here, we investigated the stimulative and protective effects of SCFAs on intestinal barrier function and the possible mechanisms. Methods: To investigate the effects of SCFAs on intestinal barrier function, the Caco-2 monolayers were exposed to acetate, propionate, butyrate respectively or simultaneously without or with lipopolysaccharide (LPS). Next, Caco-2 cells were treated with trichostatin A and etomoxir to identify whether SCFAs act as HDAC inhibitors or energy substances. To activate NLRP3 inflammasome and autophagy, Caco-2 cells were treated with LPS+ATP and rapamycin respectively without or with SCFAs. The transepithelial electrical resistance (TER) and paracellular permeability were respectively detected with a Millicell-ERS voltohmmeter and fluorescein isothiocyanate-labeled dextran. Immunoblotting and immunofluorescence were applied to analyze the expression and distribution of tight junction proteins, and the activation of NLRP3 inflammasome and autophagy. Results: Acetate (0.5mM), propionate(0.01mM) and butyrate (0.01mM) alone or in combination significantly increased TER, and stimulated the formation of tight junction. SCFAs also dramatically attenuated the LPS-induced TER reduction and paracellular permeability increase, accompanying significantly alleviated morphological disruption of ZO-1 and occludin. Meanwhile, the activation of NLRP3 inflammasome and autophagy induced by LPS were significantly inhibited by SCFAs. Trichostatin A imitated the inhibiting action of SCFAs on NLRP3 inflammasome, whereas etomoxir blocked the action of SCFAs on protecting intestinal barrier and inhibiting autophagy. In addition, the activation of autophagy and NLRP3 inflammasome by rapamycin and LPS+ATP resulted in TER reduction, paracellular permeability increase and morphological disruption of both ZO-1 and occludin, which was alleviated by SCFAs. Conclusion: It is suggested that SCFAs stimulate the formation of intestinal barrier, and protect the intestinal barrier from the disruption of LPS through inhibiting NLRP3 inflammasome and autophagy. In addition, SCFAs act as energy substances to protect intestinal barrier and inhibit autophagy, but act as HDAC inhibitors to suppress NLRP3 inflammasome. Furthermore, the mutual promoting action between NLRP3 inflammasome and autophagy would destroy intestinal barrier function, which could be alleviated by SCFAs.

Low Methoxyl Pectin Protects against Autoimmune Diabetes and Associated Caecal Dysfunction

“…The beneficial effects of dietary fiber on epithelial integrity and intestinal homeostasis are shaped by SCFAs‐NLRP3 inflammasome axis . Herein, we further determined the regulatory effects of LMP on NLRP3 inflammasome in caecum, and found that LMP suppressed NLRP3 inflammasome activation in mice.…”

The role of microbiome in the formation of child health (literature review)

“…Large intestine epithelial cells utilize SCFAs, especially butyrate, which supply them by 60-70% with energy and promote strengthening of the mucous membrane barrier [78]. SCFAs also regulate the metabolism of glucose and lipids and im mune functions [177].…”

“…Эпителиальные клетки толстой кишки используют КЦЖК, особенно бутират, кото рый на 60-70% обеспечивает их энергией, что способствует укреплению барьера слизистой оболочки [78]. КЦЖК также регулируют мета болизм глюкозы и липидов и иммунную функ цию [177].…”

Характеристика Состояния Кишечной Микрофлоры И Содержания Короткоцепочечных Жирных Кислот У Больных С Синдромом Раздраженного Кишечника

“…Butyrate also stabilizes the intestinal barrier function, in particular by influencing hypoxia-inducible factor [9]. In a Chinese study, Feng Y. et al (2018) found that SCFA stimulate the formation of the intestinal epithelial barrier and protect it against damage by lipopolysaccharides, in particular through inhibition of NLRP3 inflammasome and autophagy [10].…”