Lactobacillus reuteri or Lactobacillus rhamnosus GG intervention facilitates gut barrier function, decreases corticosterone and ameliorates social behavior in LPS-exposed offspring

Abstract

Probiotic therapy with Lactobacillus reuteri and Lactobacillus rhamnosus (LGG) demonstrates potential as an adjunctive treatment for autism spectrum disorder (ASD). In a rat model of ASD induced by lipopolysaccharide (LPS) injection during pregnancy, we evaluated the effects of these probiotics on offspring. Administration of L. reuteri or LGG for three weeks post-birth improved social deficits and reduced anxiety in LPS-exposed rats. Additionally, probiotics significantly modified short-chain fatty acid profiles, increasing butyric acid levels and decreasing propionic acid levels. They also enhanced colonic barrier integrity by upregulating tight junction proteins, including ZO-1, Occludin, and Claudin4. RNA sequencing identified differential gene expression in pathways related to inflammation, the HPA axis, and reactive oxygen species metabolism, with NADPH oxidase 1 (NOX1) emerging as a crucial gene. Validation studies confirmed that Lactobacillus strains reduced inflammatory cytokines, inhibited corticosterone secretion, increased antioxidant levels, and suppressed the NF-κB/NOX1 pathway. In an H₂O₂-induced oxidative stress model using Caco-2 cells, pre-treatment with L. reuteri, LGG, or NF-κB inhibitors enhanced cellular antioxidants, inhibited NF-κB/NOX1 activation, and improved barrier function. Overall, L. reuteri and LGG administration improved social behavior, bolstered colonic barrier function, and mitigated HPA axis overactivation in LPS-exposed rats, while also alleviating oxidative stress in the colon and Caco-2 cells. These findings suggest that L. reuteri and LGG have substantial clinical potential for ASD treatment by targeting multiple pathophysiological mechanisms, including inflammation, HPA axis dysregulation, and oxidative stress, thereby presenting a promising adjunctive therapeutic strategy for enhancing social behavior and gut health in ASD.

Keywords: Colonic barrier function; HPA axis; Lactobacillus reuteri; Lactobacillus rhamnosus GG; NF-κB/NOX1 pathway; Social behavior.