Calorie Restriction Suppresses Generation of Immune Cells via Changes to the Gut Microbiome
An interesting set of connections are made in this paper, in which researchers show that favorable changes to the gut microbiome produced by the practice of calorie restriction lead to greater butyrate production, generally thought to be a positive change, as butyrate can improve neurogenesis, among other beneficial effects. However butyrate supplementation also suppresses the generation of new immune cells, an outcome also known to be a feature of calorie restriction and fasting. Whether this suppression is outright harmful is an open question; certainly fasting has been shown to help clear damaged immune cells following cancer therapy, to pick one example, and repeated reductions in circulating immune cells may be beneficial in the long term in healthy individuals via partial clearance of problem immune cell populations.
Dietary restriction (DR) is one of the most robust interventions shown to extend health-span and remains on the forefront of anti-aging intervention studies, though conflicting results have been shown on its effect on lifespan both in rodents and primates. The severe inhibitory effects on the lymphoid lineage by DR remains one of its major negative downsides which reduces its overall beneficial effects on organismal health. Yet, the underlying mechanism of how DR suppresses the lymphoid system remains to be explored.
Here, we show that antibiotic ablation of gut microbiota significantly rescued the inhibition of lymphopoiesis by DR. Interestingly, glycolysis in lymphocytes was significantly down-regulated in DR mice and pharmacological inhibition of glycolysis reverted this rescue effect of lymphopoiesis in DR mice with ablated gut microbiota. Furthermore, DR remarkably reconstructed gut microbiota with a significant increase in butyrate-producing bacterial taxa and in expression of But, a key gene involved in butyrate synthesis. Moreover, supplemental butyrate feeding in AL mice suppressed glycolysis in lymphoid cells and mimicked the inhibition of lymphopoiesis in AL mice.
Together, our study reveals that gut microbiota mediates the inhibition on lymphopoiesis via down-regulation of glycolysis under DR conditions, which is associated with increased butyrate-synthesis. Our study uncovered a candidate that could potentially be targeted for ameliorating the negative effects of DR on lymphopoiesis, and therefore may have important implications for the wider application of DR and promoting healthy aging.