Lactobacillus johnsonii and 3-indolepropionic acid improve the depression-like behaviors via inhibiting neuroinflammation

Gut microbiota-derived metabolites play a crucial role in depression. This study aimed to elucidate the role of tryptophan metabolites herein. In a CSDS mouse model, we identified eight differential species, twelve altered neurotransmitters, and two up-regulated inflammatory factors (IL-6 and IL-1β). Notably, 3-indolepropionic acid (IPA) levels were consistently reduced in feces, colon, blood, and hippocampus of CSDS mice. The decreased abundance of Lactobacillus johnsonii (L. johnsonii) was correlated closely with depression-like behaviors (DLBs), reduced fecal IPA, and elevated IL-6 and IL-1β. Both L. johnsonii and IPA supplementation alleviated DLBs, along with up-regulated AhR and down-regulated NF-κB, NLRP3, IL-6, and IL-1β in hippocampus. Moreover, both treatments significantly elevated IPA levels in peripheral and central samples, and improved the mRNA levels of AhR and NF-κB p65 in hippocampus. Critically, the antidepressant effects of L. johnsonii and IPA were counteracted by AhR antagonist CH223191. Independent experimental results showed that CH223191 had no significant effects on behaviors of CSDS mice. To our knowledge, this was the first study to report reduced IPA levels in both peripheral and central samples of CSDS mice. We also provided the first demonstration that the antidepressant effects of L. johnsonii and IPA were mediated, at least in part, through the inhibition of neuroinflammation via AhR pathway, accompanied by the restoration of IPA levels in gut-brain axis. These findings positioned L. johnsonii and IPA as promising therapeutic candidates for depression.