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Background:This study investigated the protective effects of L. reuteri ZJ617 on intestinal and liver injury and the underlying mechanisms in modulating inflammatory, autophagy, and apoptosis signaling pathways in a piglet challenged with lipopolysaccharide (LPS). Methods:Duroc × Landrace × Large White piglets were assigned to 3 groups (n=6/group):control (CON) and LPS groups received oral phosphate-buffered saline for 2 weeks before intraperitoneal injection (i.p.) of physiological saline or LPS (25μg/kg body weight), respectively, while the ZJ617+LPS group was orally inoculated with ZJ617 for 2 weeks before i.p. of LPS. Piglets were sacrificed 4 h after LPS injection to determine intestinal integrity, serum biochemical parameters, inflammatory signaling involved in molecular and liver injury pathways. Results:Compared with controls, LPS stimulation significantly increased intestinal phosphorylated-p38 MAPK, phosphorylated-ERK and JNK protein levels and decreased IκBαprotein expression, while serum LPS, TNF-α, and IL-6 concentrations (P<0.05) increased. ZJ617 pretreatment significantly countered the effects induced by LPS alone, with the exception of p-JNK protein levels. Compared with controls, LPS stimulation significantly increased LC3, Atg5, and Beclin-1 protein expression (P<0.05) but decreased ZO-1, claudin-3, and occludin protein expression (P<0.05) and increased serum DAO and D-xylose levels, effects that were all countered by ZJ617 pretreatment. LPS induced significantly higher hepatic LC3, Atg5, Beclin-1, SOD-2, and Bax protein expression (P<0.05) and lower hepatic total bile acid (TBA) levels (P<0.05) compared with controls. ZJ617 pretreatment significantly decreased hepatic Beclin-1, SOD2, and Bax protein expression (P<0.05) and showed a tendency to decrease hepatic TBA (P=0.0743) induced by LPS treatment. Pretreatment of ZJ617 before LPS injection induced the production of 5 significant metabolites in the intestinal contents:capric acid, isoleucine 1TMS, glycerol-1-phosphate byproduct, linoleic acid, alanine-alanine (P<0.05). Conclusions:These results demonstrated that ZJ617 pretreatment alleviated LPS-induced intestinal tight junction protein destruction, and intestinal and hepatic inflammatory and autophagy signal activation in the piglets.