Diet-dependent gut microbiota impacts on adult neurogenesis through mitochondrial stress modulation

The influence of dietary factors on brain health and mental function is becoming increasingly recognized. Similarly, mounting evidence supports a role for gut microbiota in modulating central nervous system function and behaviour. Still, the molecular mechanisms responsible for the impact of diet and associated microbiome in adult neurodegeneration are still largely unclear. In this study, we aimed to investigate whether and how changes in diet-associated microbiome and its metabolites impact on adult neurogenesis. Mice were fed a high-fat, choline-deficient diet, developing obesity and several features of the metabolic syndrome, including non-alcoholic steatohepatitis. Strikingly, our results showed, for the first time, that animals fed with this specific diet display premature increased neurogenesis, possibly exhausting the available neural stem cell pool for long-term neurogenesis processes. The high-fat, choline-deficient diet further induced neuroinflammation, oxidative stress, synaptic loss and cell death in different regions of the brain. Notably, this diet-favoured gut dysbiosis in the small intestine and cecum, up-regulating metabolic pathways of short-chain fatty acids, such as propionate and butyrate and significantly increasing propionate levels in the liver. By dissecting the effect of these two specific short-chain fatty acids in vitro, we were able to show that propionate and butyrate enhance mitochondrial biogenesis and promote early neurogenic differentiation of neural stem cells through reactive oxygen species- and extracellular signal-regulated kinases 1/2-dependent mechanism. More importantly, neurogenic niches of high-fat, choline-deficient-fed mice showed increased expression of mitochondrial biogenesis markers, and decreased mitochondrial reactive oxygen species scavengers, corroborating the involvement of this mitochondrial stress-dependent pathway in mediating changes of adult neurogenesis by diet. Altogether, our results highlight a mitochondria-dependent pathway as a novel mediator of the gut microbiota-brain axis upon dietary influences.