Trehalose supplementation ameliorates heat stress-induced intestinal barrier dysfunction by suppressing endoplasmic reticulum stress and modulating gut microbiota in mice

Abstract

Heat stress (HS) compromises intestinal barrier integrity and microbiota homeostasis. Trehalose, a nonreducing disaccharide, is well known as a molecular chaperone to prevent protein misfolding under stress. However, whether trehalose supplementation can affect intestinal barrier integrity and microbiota under HS remains unknown. Male C57BL/6 mice (6-week-old) were randomly divided into 3 groups (7 mice/group): a normal control group (CON, 23℃), a heat stress group (HS, 42℃) and heat stress + trehalose group (HT, received 2.0% trehalose in drinking water under HS condition). Trehalose supplementation decreased rectal temperature and body weight loss in heat-stressed mice. HS-induced intestinal permeability characterized by increased d-lactate was inhibited by upregulating protein expression of tight junction proteins including occludin and Zo1 in mice administrated by trehalose. Supplementary trehalose significantly ameliorated HS-induced oxidative stress by elevating activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX) as well as protein expression of catalase (CAT). Trehalose intervention reversed the up-regulation of endoplasmic reticulum (ER) stress proteins glucose-regulated protein 78 (GRP78), growth arrest and DNA damage-inducible protein 34 (GADD34), phosphorylated eukaryotic initiation factor 2α (p-eif2α), activating transcription factor 4 (ATF4), and C/EBP homologous protein (CHOP) as well as proapoptotic proteins BAX, Cytc, and active-caspase3 in heat-stressed mice. Trehalose supplementation evidently elevated the abundance of beneficial bacteria Lachnospiraceae_NK4A136_group while reducing that of harmful bacteria Bacteroidetes in heat-stressed mice. Taken together, these results revealed that supplementary trehalose could attenuate HS-induced intestinal barrier dysfunction via reducing oxidative stress, reversing ER stress induced apoptosis and gut microbial dysbiosis, suggesting trehalose as a promising dietary additive to counteract the intestinal injury induced by HS in mice.