Gut microbe play a key role in supporting the formation of new nerve cells in the adult brain


The billions of microbes living in your gut could play a key role in supporting the formation of new nerve cells in the adult brain, with the potential to possibly prevent memory loss in old age and help to repair and renew nerve cells after injury, an international research team spanning Singapore, UK, Australia, Canada, US, and Sweden has discovered.

The international investigating team led by Principal Investigator Professor Sven Pettersson, National Neuroscience Institute of Singapore, and Visiting Professor at Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore (NTU Singapore), and Sunway University, Malaysia, found that gut microbes that metabolize tryptophan – an essential amino acid – secrete small molecules called indoles, which stimulate the development of new brain cells in adults.

Prof Pettersson and his team also demonstrated that the indole-mediated signals elicit key regulatory factors known to be important for the formation of new adult neurons in the hippocampus, an area of the brain also associated with memory and learning. Memory loss is a common sign of accelerated aging and often an early sign of the Alzheimer’s disease (AD).

The discovery was published today in the Proceedings of the National Academy of Sciences (PNAS).

“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, which is a common problem with aging and neurodegenerative diseases including but not limited to Alzheimer’s disease.

These include drugs to mimic the action of indoles to stimulate the production of new neurons in the hippocampus or to replace neurons damaged by stroke and spinal injury, as well as designing dietary intervention using food products enriched with indoles as a preventive measure to slow down aging,” said Prof Pettersson.

“The work reported in this paper addresses the formation of neurons in the adult brain. We are currently assessing whether indoles can also stimulate early formation of neurons during brain development. Another area of potential intervention interest is in situations of stroke or spinal injury where there is an urgent need to generate new neurons. It is an interesting and exciting time ahead of us,” said Prof Pettersson.

Study co-author Professor Paul Matthews, Centre Director at UK Dementia Research Institute at Imperial College London, Edmond and Lily Safra Chair, NIHR Senior Investigator, and Head of the Department of Brain Sciences, says that “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. Importantly, it also points to new much-needed treatment opportunities for the diseases that cause dementia – now the leading cause of death in the UK.”

Dietary factors are well known to influence neurological function and brain health. In fact, unbalanced dietary habits, particularly calorie-dense foods, are risk factors for impaired cognitive function and psychiatric disorders (Gomez-Pinilla, 2008). Similarly, mice fed a high-fat diet were shown to present cognitive deficits, anxiety and depressive-like behaviour (Almeida-Suhett et al., 2017).

Diet also affects molecular events related to energy metabolism which, in turn, modulates neuronal signalling, synaptic plasticity and, ultimately, neuronal function (Gomez-Pinilla and Tyagi, 2013). As such, a better understanding of the signalling pathways connecting diet and brain function may allow for the development of novel non-invasive therapeutic strategies against neurological and psychiatric disorders.

Dietary nutrients are strong modulators of microbiota composition, function and metabolism, which in turn also impacts on host physiology (Gentile and Weir, 2018). The relevance of gut microbiota in the regulation of brain function has recently gained extensive interest (Khanna and Tosh, 2014).

In fact, although the mechanisms that mediate this cross-talk remaining largely unknown, a microbiota–gut–brain axis has already been recognized. It is worth noting that gut microbiota is not only composed by bacteria but also by many other micro-organisms such as archaea, viruses, phages and fungus.

However, although phages are known to exceed bacteria in both number and diversity, bacteria and their bacterial products are the most studied group of gut microbiota, with crucial roles in food processing, vitamin synthesis, inhibition of pathogens, host homeostasis (Ramakrishna, 2013) and even brain development (Heijtz et al., 2011; Rogers et al., 2016).

Thus, disturbances in this symbiotic microbiota–host relationship might lead to pathological disorders in different organs, including the brain. In fact, gut dysbiosis has been shown to associate with neurological disorders, such as psychiatric disorders—depression and anxiety—autism and neurodegenerative diseases (Lurie et al., 2015; Rogers et al., 2016).

Curiously, microbiota composition is highly dynamic and sensitive to lifecycle, environmental, immune and nutritional factors. Along with changes in bacterial abundance, microbial metabolism also adjusts to surrounding fluctuations, leading to different bacterial products, which in turn modulate host physiology, metabolism, immune system and gene expression (Nicholson et al., 2012; Fung et al., 2017).

Bacteria-derived molecules encompass lipopolysaccharides, peptidoglycans, short-chain fatty acids (SCFA), neurotransmitters and gaseous molecules (Cani and Knauf, 2016). Short-chain fatty acids, including acetate, propionate and butyrate, result from fermentation of non-digestible carbohydrates and some proteins in the cecum and large intestine (Koh et al., 2016), and embody powerful mitochondrial regulators.

Apart from being used as bacterial energy substrates, SCFAs regulate fatty acid and glucose metabolism through an AMPK-PGC-1α-dependent mechanism, and are also capable of increasing mitochondrial bioenergetics and biogenesis (Rose et al., 2018; Uittenbogaard et al., 2018). Therefore, mitochondrial-sensitive processes are deeply prone to SCFA-mediated gut microbiota regulation.

The adult mammalian brain has the ability to generate new neurons through neurogenesis in a mitochondria-dependent process (Fang et al., 2016; Khacho et al., 2016). In the adult mammalian brain, neurogenesis occurs in two main neurogenic niches, including the sub-ventricular zone (SVZ) and the sub-granular zone (SGZ) in the dentate gyrus (DG) of the hippocampus. Neural stem cells (NSCs) self-renew, proliferate and differentiate into different neural cells (Zhao et al., 2008). In the case of SVZ, NSCs migrate until they reach the olfactory bulb (OB), where neural precursor cells mature and integrate.

Interestingly, reduction of adult hippocampal neurogenesis has been reported in animal models of memory loss (Donovan et al., 2006; Hamilton and Holscher, 2012) and psychiatric disorders, particularly depression and anxiety (Petrik et al., 2012; Fang et al., 2018), whereas an increased rate of SGZ neurogenesis induced by treatment with antidepressants improves psychiatric disorders (Perera et al., 2011), suggesting an important role of adult neurogenesis on neurological disorders. Importantly, mitochondrial metabolism was shown to finely tune NSC self-renewal and fate decision.

In fact, mitochondrial mass, as well as oxidative phosphorylation and by-product reactive oxygen species (ROS) increase during neuronal differentiation in response to higher cellular energetic demands, and promoting transcription of neurogenic genes (Khacho et al., 2016).

Besides mitochondrial biogenesis, alterations in mitochondrial dynamics—fusion and fission events—also regulate NSC cell-cycle progression and fate, namely by modulating mitochondrial bioenergetics and oxidative stress (Mitra, 2013). Although the impact of diet and gut microbiota on neuroplasticity has already been described, the underlying molecular mechanisms remain largely unknown.

Here, we demonstrate that gut microbiota-derived metabolites, produced upon dietary changes, modulate adult neurogenesis in a mitochondria-dependent manner. In particular, we show that a high-fat, choline-deficient (HFCD) diet induces gut dysbiosis to favour the production of propionate and butyrate from gut microbiota in the small intestine and in the cecum.

Alterations in these specific SCFAs increase mitochondrial biogenesis in NSCs and induce premature neurogenic differentiation through a ROS- and ERK1/2-dependent manner, leading to rapid NSC pool depletion in both neurogenic niches.

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More information: George Zhang Wei el al., “Tryptophan-metabolizing gut microbes regulate adult neurogenesis via the aryl hydrocarbon receptor,” PNAS (2021).


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