All-trans retinoic acid protects piglets from TGEV-induced diarrhea and intestinal epithelial apoptosis by modulating redox status and endoplasmic reticulum stress pathways

Abstract Transmissible gastroenteritis virus (TGEV) is a significant pathogen responsible for diarrhea in piglets, with its pathogenesis intricately associated with apoptosis. As a bioactive vitamin A derivative, all-trans retinoic acid (ATRA) possesses antiviral, antioxidant and anti-apoptotic characteristics. This research aimed to explore whether ATRA could mitigate TGEV infection in piglets through inhibition of intestinal epithelial apoptosis. In a 19-day trial, 32 piglets were randomized into four treatments: non-challenged group (Control), TGEV-challenged group (TGEV), TGEV+ 5 mg/d ATRA group (TGEV+ATRA5) and TGEV+ 15 mg/d ATRA group (TGEV+ATRA15). On day 15, piglets except the control group were challenged with TGEV. Results demonstrated that piglets administered with ATRA effectively prevented growth inhibition, diarrhea and intestinal impairment caused by TGEV, as confirmed by increased average daily gain, reduced diarrhea rate and diarrhea score, and upregulated villus height and tight-junction protein level (ZO-1 and Occludin) (P < 0.05). ATRA also markedly decreased TGEV RNA copies in the jejunum of TGEV-infected piglets (P < 0.05). Meanwhile, ATRA inhibited TGEV-induced intestinal epithelial apoptosis through inhibition of apoptosis-related proteins expression (Bax, Fas, Caspase-9, -8 and -3) (P < 0.05). In addition, ATRA markedly attenuated TGEV-induced oxidative stress through reducing the production of hydrogen peroxide (H2O2) and malondialdehyde (MDA), while improving the activities of antioxidant enzymes (GSH-PX, SOD and CAT) (P < 0.05). Further research found that ATRA also down-regulated the phosphorylation levels of P38MAPK and JNK, as well as the levels of apoptosis pathway-related proteins (GRP78, p-PERK, ATF6 and CHOP) mediated by endoplasmic reticulum stress (ERS) in jejunal mucosa of TGEV-infected piglets (P < 0.05). Our research demonstrated that ATRA could mitigate TGEV-triggered diarrhea and intestinal impairment of piglets by suppressing TGEV replication and intestinal epithelial apoptosis. The underlying mechanism by which ATRA inhibits intestinal epithelial apoptosis may be related to the suppression of oxidative stress-mediated P38MAPK/JNK pathways and ERS-mediated PERK/ATF6-CHOP pathways.