Your Mind on Microbes: How Molecules Secreted By Gut Bacteria Boost New Brain Cell Formation
It was once thought that neurogenesis — the creation of new neurons — ceases after the first few years of life. However, it turns out that the birth of new brain cells extends well into adulthood, providing exciting new options for supporting the injured, diseased, or aged brain.
Although we’ve made leaps and bounds in understanding this process over the past few decades, one largely untapped area is if and how our gut microbes are involved. Also known as the gut microbiome, this vast collection of bacteria living in our gastrointestinal tracts — both good and bad — has been found in recent years to play a much more significant role in our health than previously thought. Now, a primarily London- and Singapore-based research team uncover that certain gut microbes that break down the amino acid tryptophan cause the secretion of small molecules called indoles — and these indoles are a key factor in stimulating neurogenesis in the adult brain.
Nurturing New Neurons With Neurogenesis
Neurogenesis is a subset of brain health referred to as plasticity, or the adult brain’s ability to adapt, change its structure, and rewire connections called synapses in response to new experiences. A brain with high levels of plasticity would better repair itself after injury, leading to improved cognitive vitality and a slower aging process. Neural plasticity also allows the brain to acquire new skills, improve emotional control and memory consolidation, and continually enhance cognitive ability.
One of the primary areas in the brain where neurogenesis occurs is in the dentate gyrus of the hippocampus. Also known as a “neurogenic niche,” the brain’s hippocampal region plays a vital role in learning and consolidating short- and long-term memories. The hippocampal cells that facilitate neurogenesis, called adult neural stem cells, are primarily dormant but can be activated in response to external stimuli. But, exercise and some antioxidant compounds, like curcumin and resveratrol, can boost neurogenesis — and the secretion of indoles by our gut microbes may be another stimulating factor.
The Healthspan-Increasing Effects of Indoles
Indoles are metabolites, or small byproduct compounds of metabolism, that arise from the gut microbial breakdown of dietary tryptophan — the amino acid most commonly referenced for its sleep-inducing role after eating Thanksgiving turkey. Previous research has found that indoles improve health outcomes in various animal models, including worms, flies, and mice.
The beneficial effects of indoles on health depend upon a protein called the aryl hydrocarbon receptor (AHR), which controls the activation and activity level of certain genes, including those related to cell growth and maturation. In adults, the AHR is localized in adult neural stem cells in the hippocampal dentate gyrus, leading researchers to pinpoint this receptor as a key step in stimulating neurogenesis.
AHR is a target of metabolites that arise from tryptophan breakdown, including indoles. In studies with older animals, indole has been found to bind to AHR and boost the activity of genes associated with increased health- and lifespan. Although indoles are found in several foods, like broccoli and cabbage, an alternate production pathway is through gut microbes.
Our gut microbiome is ever-evolving, changing day by day based on our diet, lifestyle, and environment. These microbes secrete hundreds of metabolites that are involved in various bodily functions — including neurogenesis. As co-author of this paper, Professor Paul Matthews, states, "There is increasing interest in our microbiomes and the connection between gut and brain health. This study is another intriguing piece of the puzzle highlighting the importance of lifestyle factors and diet.”
How Our Gut Microbes Modulate Neurogenesis
In this study published in the Proceedings of the National Academy of Sciences, Wei and colleagues aim to uncover how these gut microbes and their metabolites regulate neural growth, starting with experiments on germ-free mice. These animals are the gold standard for microbiome research because they have been birthed and raised without any bacterial contact, allowing for studying animals in the complete absence of microbes or the generation of animals exclusively colonized by a specific bacteria.
The research team found that young adult germ-free mice (about 30 in human years) had reduced adult neurogenesis rates combined with elevated tryptophan levels — because they don’t have gut microbes available to break down this amino acid — and reduced indole levels.
They also looked at neurogenic activity in mice who were colonized to contain just one type of bacteria (E. coli) — with half of these E. coli mice also containing a dysfunctional version of the enzyme needed to break down tryptophan. The mono-colonized mice who could not metabolize tryptophan into indoles showed significantly reduced neurogenesis and indole levels than mice with the working version of the enzyme.
Next, they added indoles to the drinking water of both the germ-free mice and the dysfunctional tryptophan-metabolizing E. coli mice, finding that five weeks of indole supplementation significantly boosted neurogenesis. This highlights the importance of indoles in creating new adult neurons — and that gut microbes are necessary for neurogenesis unless the route is bypassed with supplemental indoles.
These mice also showed increased activity in genes related to brain plasticity, synaptic functioning, blood vessel formation, and neurite outgrowth — the process of growing new projections on developing neurons. Similarly, mice raised without the enzyme needed to break down tryptophan (which would result in less indole production) also reduced adult neurogenesis rates in the hippocampus.
Lastly, Wei and colleagues looked at the importance of the AHR signaling pathway in this process. In mice without this receptor, indole supplementation failed to increase neurogenesis and did not boost the brain-related gene activity seen previously, suggesting the essentiality of indoles binding to AHR for neurogenesis to occur in young adult mice.
Can Boosting Indoles Benefit the Human Brain?
Given that our body’s indole levels tend to decline with age, it’s possible that boosting indoles internally — either through direct indole supplementation or tryptophan consumption — may support a healthier aging process.
As the senior author of this study, Professor Sven Pettersson, states, “This finding is exciting because it provides a mechanistic explanation of how gut-brain communication is translated into brain cell renewal, through gut microbe-produced molecules stimulating the formation of new nerve cells in the adult brain. These findings bring us closer to the possibility of novel treatment options to slow down memory loss.”
However, we don’t yet know if these results will translate to increased neurogenesis in the human adult brain. Until we know for sure, eating indole-rich vegetables (like broccoli, Brussels sprouts, cabbage, cauliflower, kale, and turnips) and tryptophan-loaded proteins (like chicken, turkey, and eggs) likely has no downside and may have the added bonus of boosting neuron growth.
Phillips C. Lifestyle Modulators of Neuroplasticity: How Physical Activity, Mental Engagement, and Diet Promote Cognitive Health during Aging. Neural Plast. 2017;2017:3589271. doi:10.1155/2017/3589271
Sonowal R, Swimm A, Sahoo A, et al. Indoles from commensal bacteria extend healthspan. Proc Natl Acad Sci U S A. 2017;114(36): E7506-E7515. doi:10.1073/pnas.1706464114
Wei GZ, Martin KA, Xing PY, et al. Tryptophan-metabolizing gut microbes regulate adult neurogenesis via the aryl hydrocarbon receptor. Proc Natl Acad Sci U S A. 2021;118(27):e2021091118. doi:10.1073/pnas.2021091118