The gut microbiome changes with age. This affects health in part because beneficial microbial populations produce metabolites, such as butyrate, that act to stimulate helpful processes in the body and brain, such as neurogenesis. Many of these populations tend to decline in later life, for reasons that include dietary shifts, immune system decline, and a range of other processes that, taken as a whole, are poorly understood.
The work here, placing gut microbes from old mice into germ-free mice that have no gut microbes, provides a different viewpoint on the beneficial nature of butyrate production by the gut microbiome, and on the processes that might be balancing different populations of microbes. The young germ-free mice are no doubt possessed of immune systems better able to keep harmful populations in check, and can thus benefit even when transplanted with a mixed bag of harmful and helpful microbes from old mice. It would be interesting to see how old germ-free mice fared under the same circumstances; less well, I suspect.
A number of possible approaches to treatment exist for age-related changes in the gut microbiome, including supplementation with those metabolites for which production is known to be lost with age, delivery of a more youthful mix of gut microbes via fecal transplantation, and more adventurous treatments such as immunization against flagellin. None are yet all that close to widespread use, even though some are technically straightforward to implement.
Researchers transplanted gut microbes from old mice (24 months old) into young, germ-free mice (6 weeks old). After eight weeks, the young mice had increased intestinal growth and production of neurons in the brain, known as neurogenesis. The team showed that the increased neurogenesis was due to an enrichment of gut microbes that produce a specific short chain fatty acid, called butyrate. Butyrate is produced through microbial fermentation of dietary fibres in the lower intestinal tract and stimulates production of a pro-longevity hormone called FGF21, which plays an important role in regulating the body's energy and metabolism. As we age, butyrate production is reduced. The researchers then showed that giving butyrate on its own to the young germ-free mice had the same adult neurogenesis effects.
The team also explored the effects of gut microbe transplants from old to young germ-free mice on the functions of the digestive system. With age, the viability of small intestinal cells is reduced, and this is associated with reduced mucus production that make intestinal cells more vulnerable to damage and cell death. However, the addition of butyrate helps to better regulate the intestinal barrier function and reduce the risk of inflammation. The team found that mice receiving microbes from the old donor gained increases in length and width of the intestinal villi - the wall of the small intestine.
"It is intriguing that the microbiome of an aged animal can promote youthful phenotypes in a young recipient. This suggests that the microbiota with aging have been modified to compensate for the accumulating deficits of the host and leads to the question of whether the microbiome from a young animal would have greater or less effects on a young host. The findings move forward our understanding of the relationship between the microbiome and its host during ageing and set the stage for the development of microbiome-related interventions to promote healthy longevity."
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.