Antidepressant Effects of 3-Indolepropionic Acid by Regulating Inflammation Level via Short-Chain Fatty Acids

3-indolepropionic acid (IPA) is an important gut microbiota-derived metabolite and has anti-inflammatory properties. We have observed the potential antidepressant effects of IPA, and therefore conducted this study to further detect its potential antidepressant effects and search for the possible action mechanisms.

Chronic restraint stress (CRS) was used to induce depression-like behaviors (DLBs) in mice, and then IPA was administered to mice with DLBs (double-blind manner, 20 mg/kg, once daily for 10 consecutive days, intraperitoneal injection, ten days). The feces and hippocampus samples were collected to detect gut microbiota compositions, short-chain fatty acids (SCFAs), G protein-coupled receptor 43 (GPR43), and inflammation-related factors.

Disordered gut microbiota, decreased SCFA levels, decreased GPR43 (SCFA receptors), and increased inflammation levels were observed in CRS-induced depressed mice. After IPA treatment, DLBs in CRS mice were significantly improved, along with the improved gut microbiota and increased SCFA levels, especially acetic acid, propanoic acid, and valeric acid. Meanwhile, we found that IPA could increase the level of GPR43 and decrease the levels of inflammation-related factors in the hippocampus of CRS mice. In addition, close relationships among SCFAs, GPR43, and inflammation-related factors were observed.

These results suggested that IPA might exert antidepressant effects through gut microbiota modulation, which elevated SCFA levels and subsequently alleviated brain inflammation.