Lung dendritic-cell metabolism underlies susceptibility to viral infection in diabetes.

People with diabetes feature a life-risking susceptibility to respiratory viral infection, including influenza and SARS-CoV-2 (ref. 1), whose mechanism remains unknown. In acquired and genetic mouse models of diabetes, induced with an acute pulmonary viral infection, we demonstrate that hyperglycaemia leads to impaired costimulatory molecule expression, antigen transport and T cell priming in distinct lung dendritic cell (DC) subsets, driving a defective antiviral adaptive immune response, delayed viral clearance and enhanced mortality. Mechanistically, hyperglycaemia induces an altered metabolic DC circuitry characterized by increased glucose-to-acetyl-CoA shunting and downstream histone acetylation, leading to global chromatin alterations. These, in turn, drive impaired expression of key DC effectors including central antigen presentation-related genes. Either glucose-lowering treatment or pharmacological modulation of histone acetylation rescues DC function and antiviral immunity. Collectively, we highlight a hyperglycaemia-driven metabolic-immune axis orchestrating DC dysfunction during pulmonary viral infection and identify metabolic checkpoints that may be therapeutically exploited in mitigating exacerbated disease in infected diabetics.

Tryptophan-metabolizing gut microbes regulate adult neurogenesis via the aryl hydrocarbon receptor.

While modulatory effects of gut microbes on neurological phenotypes have been reported, the mechanisms remain largely unknown. Here, we demonstrate that indole, a tryptophan metabolite produced by tryptophanase-expressing gut microbes, elicits neurogenic effects in the adult mouse hippocampus. Neurogenesis is reduced in germ-free (GF) mice and in GF mice monocolonized with a single-gene tnaA knockout (KO) mutant Escherichia coli unable to produce indole. External administration of systemic indole increases adult neurogenesis in the dentate gyrus in these mouse models and in specific pathogen-free (SPF) control mice. Indole-treated mice display elevated synaptic markers postsynaptic density protein 95 and synaptophysin, suggesting synaptic maturation effects in vivo. By contrast, neurogenesis is not induced by indole in aryl hydrocarbon receptor KO (AhR-/-) mice or in ex vivo neurospheres derived from them. Neural progenitor cells exposed to indole exit the cell cycle, terminally differentiate, and mature into neurons that display longer and more branched neurites. These effects are not observed with kynurenine, another AhR ligand. The indole-AhR-mediated signaling pathway elevated the expression of ß-catenin, Neurog2, and VEGF-α genes, thus identifying a molecular pathway connecting gut microbiota composition and their metabolic function to neurogenesis in the adult hippocampus. Our data have implications for the understanding of mechanisms of brain aging and for potential next-generation therapeutic opportunities.

Regional Diets Targeting Gut Microbial Dynamics to Support Prolonged Healthspan.

In the last 150 years, we have seen a significant increase in average life expectancy, associated with a shift from infectious to non-communicable diseases. The rising incidence of these diseases, for which age is often the largest risk factor, highlights the need for contemporary societies to improve healthy ageing for their growing silver generations. As ageing is an inevitable, non-reversing and highly individualised process, we need to better understand how non-genetic factors like diet choices and commensal gut microbes can modulate the biology of ageing. In this review, we discuss how geographical and ethnic variations influence habitual dietary patterns, nutrient structure, and gut microbial profiles with potential impact on the human healthspan. Several gut microbial genera have been associated with healthy elderly populations but are highly variable across populations. It seems unlikely that a universal pro-longevity gut microbiome exists. Rather, the optimal microbiome appears to be conditional on the microbial functionality acting on regional- and ethnicity-specific trends driven by cultural food context. We also highlight dietary and microbial factors that have been observed to elicit individual and clustered biological responses. Finally, we identify next generation avenues to modify otherwise fixed host functions and the individual ageing trajectory by manipulating the malleable gut microbiome with regionally adapted, personalised food intervention regimens targeted at prolonging human healthspan.