The gut microbiome changes in detrimental ways with age. Beneficial populations decline in numbers while harmful populations gain ground at their expense. A large part of the harm done results from an increased burden of inflammatory microbes that aggravate the immune system, resulting in chronic inflammatory signaling that degrades tissue function throughout the body. But the loss of beneficial metabolites generated by microbial species is also increasingly well studied. Butyrate, for example, helps with cognitive function by upregulating BDNF expression, which in turn increases levels of neurogenesis.
In today's open access paper, researchers note an example of the opposite case, a harmful metabolite, isoamylamine, that produces cell death in microglia, a population of supporting immune cells in the brain. Production increases with age, and in aged mice at least, reducing levels of this one metabolite produces gains in cognitive function. We might take this as yet another piece of evidence supporting the value of rejuvenation of the gut microbiome, a goal that can be achieved all at once, rather than bit by bit, via strategies such as flagellin immunization or fecal microbiota transplantation. These approaches should receive more attention from the clinical community, as they can be carried out with little effort at the present time. Running small clinical trials to prove efficacy in human patients is a very feasible prospect, given funding for that project.
Prior research has suggested a strong link between gut bacteria and brain health. In this new effort, the researchers looked into the possible impact on the brain of just one metabolite, isoamylamine (IAA), produced by one family of bacteria in the gut, Ruminococcaceae. They found first that IAA becomes more prevalent in the gut as people age due to the presence of more Ruminococcaceae. Their interest in IAA grew when they learned it could pass through the blood-brain barrier. They found the metabolite binds to a promoter region of the gene S100A8, which allowed for expression of the gene, resulting in production of apoptotic bodies, which lead to cell death. To learn more about what happens when such bindings occur, the researchers fed IAA to young healthy mice and determined that this resulted in a loss of cognitive function. They next blocked production of the metabolite in the guts of older mice and found that it led to improvements in cognitive performance.
The intestinal microbiome releases a plethora of small molecules. Here, we show that the Ruminococcaceae metabolite isoamylamine (IAA) is enriched in aged mice and elderly people, whereas Ruminococcaceae phages, belonging to the Myoviridae family, are reduced. Young mice orally administered IAA show cognitive decline, whereas Myoviridae phage administration reduces IAA levels. Mechanistically, IAA promotes apoptosis of microglial cells by recruiting the transcriptional regulator p53 to the S100A8 promoter region. Specifically, IAA recognizes and binds the S100A8 promoter region to facilitate the unwinding of its self-complementary hairpin structure, thereby subsequently enabling p53 to access the S100A8 promoter and enhance S100A8 expression. Thus, our findings provide evidence that small molecules released from the gut microbiome can directly bind genomic DNA and act as transcriptional coregulators by recruiting transcription factors. These findings further unveil a molecular mechanism that connects gut metabolism to gene expression in the brain with implications for disease development.