Abstract
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.
Highlights
The human gastrointestinal tract harbors a diverse and dynamic microbial community called the gut microbiota, that plays a vital role in human biology and health, including metabolic and nutritional homeostasis, immune system maturation and stimulation and even brain activity [1,2]
We previously found that indole-3-lactic acid (ILA) was the only tryptophan metabolite produced in bifidobacteria culture supernatants, and its level was substantially higher in bifidobacterial species naturally inhabiting the infant intestines
The present study revealed that tryptophan-derived ILA potentiated nerve growth factor (NGF)-induced neurite outgrowth in PC12 cells through the Ras/ERK signaling pathway
Summary
The human gastrointestinal tract harbors a diverse and dynamic microbial community called the gut microbiota, that plays a vital role in human biology and health, including metabolic and nutritional homeostasis, immune system maturation and stimulation and even brain activity [1,2]. Tryptophan is an essential amino acid bearing an indole ring, derived from dietary proteins [5]. It is mainly digested and absorbed in the small intestine, but significant amounts of tryptophan may persist to the colon [6], where they are metabolized by the gut bacteria resulting in a variety of indole derivatives [4]. Apart from its role in protein synthesis, tryptophan and its metabolites such as indole derivatives have increasingly been recognized as essential orchestrators of host physiology, and may contribute to intestinal and systemic homeostasis [2,3,4,7]. New research suggests that microbial tryptophan metabolites may have a positive impact on inflammatory responses [8] and neurological functions [9]
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