Neurogenesis and prolongevity signaling in young germ-free mice transplanted with the gut microbiota of old mice

Abstract

The gut microbiota evolves as the host ages, yet the effects of these microbial changes on host physiology and energy homeostasis are poorly understood. To investigate these potential effects, we transplanted the gut microbiota of old or young mice into young germ-free recipient mice. Both groups showed similar weight gain and skeletal muscle mass, but germ-free mice receiving a gut microbiota transplant from old donor mice unexpectedly showed increased neurogenesis in the hippocampus of the brain and increased intestinal growth. Metagenomic analysis revealed age-sensitive enrichment in butyrate-producing microbes in young germ-free mice transplanted with the gut microbiota of old donor mice. The higher concentration of gut microbiota–derived butyrate in these young transplanted mice was associated with an increase in the pleiotropic and prolongevity hormone fibroblast growth factor 21 (FGF21). An increase in FGF21 correlated with increased AMPK and SIRT-1 activation and reduced mTOR signaling. Young germ-free mice treated with exogenous sodium butyrate recapitulated the prolongevity phenotype observed in young germ-free mice receiving a gut microbiota transplant from old donor mice. These results suggest that gut microbiota transplants from aged hosts conferred beneficial effects in responsive young recipients.

The Circadian Clock as an Essential Molecular Link Between Host Physiology and Microorganisms

“…A recent report demonstrated the involvement of the intestinal microflora in maturation and function of microglial cells in the CNS through SCFA signaling pathway in the brain (Erny et al, 2015). Moreover, sodium butyrate enhanced hippocampal neurogenesis in germ-free mice (Kundu et al, 2019).…”

Faecal microbiota transplant from aged donor mice affects spatial learning and memory via modulating hippocampal synaptic plasticity- and neurotransmission-related proteins in young recipients

“…Thus, it is plausible to hypothesize that age-associated changes in the microbiota composition have a direct effect on the CNS, potentially contributing to the decline of cognitive function seen in the elderly. Recently, it has been reported that FMT from aged donor mice into young germ-free (GF) recipients increased hippocampal neurogenesis, intestinal growth, and activation of the prolongevity signaling pathways in the liver [16]; however, up to date the direct impact of the ageing microbiota on cognitive functioning and activity has not been addressed. We report that FMT from aged mice led to a decline of spatial learning and memory in young adult (henceforth termed adult) recipients via modulation of synaptic plasticity-and neurotransmission-related proteins in the hippocampus, an area of the CNS known to be heavily affected by the ageing process [17].…”

Prospects for microbiota-oriented therapy in neurorehabilitology

“…В одной из последних статей P. Kundu и соавт. [8] приведены результаты экспериментального исследования, где убедительно доказана тесная связь между микробиотой кишечника и возрастными изменениями мозга. В этой работе исследователи пересадили кишечную микробиоту от старых мышей к молодым, что способствовало росту новых нейронов в области гиппокампа наряду с увеличением общей площади поверхности кишечника у реципиентов.…”

“…Обнаруженный факт стимуляции роста новых нейронов теоретически можно было связать с действием мозгового нейротрофического фактора BDNF, терапевтический потенциал которого при повреждении головного мозга достаточно хорошо известен [10]. Действительно, в поиске возможных причин активации нейрогенеза у мышей под влиянием «молодой» микробиоты исследователи обнаружили повышенный уровень BDNF, причем было показано, что активация этого белка происходила под влиянием бутирата -одной из короткоцепочечных жирных кислот ключевого микробного метаболита через увеличение уровня фактора роста фибробластов 21 (FGF21) -сигнального антивозрастного белка [8].…”