Potential Effects of Indole-3-Lactic Acid, a Metabolite of Human Bifidobacteria, on NGF-Induced Neurite Outgrowth in PC12 Cells

Gut microbiota-derived tryptophan metabolites such as indole derivatives are an integral part of host metabolome that could mediate gut-brain communication and contribute to host homeostasis. We previously reported that infant-type Human-Residential Bifidobacteria (HRB) produced higher levels of indole-3-lactic acid (ILA), suggesting the former might play a specific role in microbiota-host crosstalk by producing ILA in human infants. Nonetheless, the biological meaning of bifidobacteria-derived ILA in infant health development remains obscure. Here, we sought to explore the potential role of ILA in neuronal differentiation. We examined the neurite outgrowth and acetylcholinesterase (AchE) activity of PC12 cells following exposure to ILA and NGF induction. We found that ILA substantially enhanced NGF-induced neurite outgrowth of PC12 cells in a dose-dependent manner, and had the most prominent effect at 100 nM. Significant increases in the expression of TrkA receptor, ERK1/2 and CREB were observed in ILA-treated PC12 cells, suggesting ILA potentiated NGF-induced neurite outgrowth through the Ras/ERK pathway. Additionally, ILA was found to act as the aryl hydrocarbon receptor (AhR) agonist and evoked NGF-induced neurite outgrowth in an AhR-mediated manner. These new findings provide clues into the potential involvement of ILA as the mediator in bifidobacterial host-microbiota crosstalk and neuronal developmental processes.