The composition of the gut microbiome changes with age. A variety of factors likely contribute, including reduced physical activity, changes in diet, and a decline in the ability of the immune system to keep unwanted microbial populations in check. With age, microbes capable of provoking inflammation grow in number while microbes responsible for generating beneficial metabolites diminish in number. This is not an inevitable fate: the composition of the gut microbiome can be permanently changed by fecal microbiota transplantation. Studies have shown rejuvenation of the aged gut microbiome, improved health, and extended life span following fecal microbiota transplantation from young donor animals to old recipient animals.
In human medicine, fecal microbiota transplantation was up until recently conducted in something of a gray area of regulation, with its use focused on severe cases of bacterial overgrowth and intestinal dysfunction, such as C. difficile infection. A specific approach to sourcing and preparing donor material is now blessed with FDA approval, but this is a fairly recent development. Despite an underground of people conducting fecal microbiota transplantation on their own for various reasons, and suppliers like Human Microbes facilitating this cottage industry, there is little firm human data for the use of fecal microbiota transplantation in the context of aging and age-related disease. This will likely continue to be the case given that is hard to generate strong, defensible intellectual property for fecal microbiota transplantation, and the potential for monopoly granted by intellectual property is required in order to attract the sizable funded needed for regulated clinical development.
One way past this roadblock is for some research group, and later company, to produce a well defined probiotic approach to rejuvenation of the gut microbiome and demonstrate its specific advantages. This would have to involve a sizable advance on present priobiotic use and manufacture, most likely the culturing and quality control of specific combinations of dozens to hundreds of microbial species in order to mimic a youthful gut microbiome in the ways that matter, and thus permanently change a patient's gut microbiome composition following treatment. That seems the most likely outcome, rather than any great expansion of the use of fecal microbiota transplantion, given the incentives placed upon the research and medical industries.
Microbiota from young mice restore the function of aged ISCs
The intestinal epithelium depends on intestinal stem cells (ISCs) for maintaining homeostasis. The intestinal epithelium shows a reduced rate of turnover with age, which is at least in part due to a decline in ISC function. Aged ISCs show a reduced ability to self-renew and differentiate compared to young ISCs. This overall decline in regenerative capacity of ISCs results in slower recovery from damage and, therefore, renders the intestine more vulnerable to injury. The reduced function of aged ISCs is, in part, due to a decline in canonical Wnt signaling within ISCs, driven by lower levels of canonical Wnts in aged ISCs themselves and as well as in aged crypts.
The intestine is an organ that harbors a vast collection of microbiota like bacteria, viruses, fungi, and protozoans. Microbiota protect the host from the invasion of pathogenic microbes and support the maintenance of intestinal epithelium by regulating various signaling mechanisms that influence intestinal epithelial cells directly or indirectly through niche cells. The composition of the intestinal microbiota changes upon aging. In older mice, the diversity of beneficial microbes decreases, while the population of pathogenic microbes increases. In aged humans, microbial diversity is lower compared to young.
We show here that aging-associated changes in microbiota can modulate Ascl2-based canonical Wnt signaling and the regenerative function of ISCs. Fecal microbiota transfer from young to aged mice, resulting in a more young-like microbiota in aged mice, restored Ascl2 and Lgr5 gene expression in crypts and ISCs and enhanced mitotic activity in crypts and the regenerative function of ISCs.
The transfer of an aged microbiota to young mice only marginally affected Wnt signaling and the function of young ISCs. It is a possibility that young crypts are more resistant to acute changes in the relative composition of the microbiota compared to aged crypts. On the other hand, a strong reduction of the overall level of microbiota as in antibiotic-treated animals does significantly affect Wnt signaling and mitotic activity in young crypts. Microbiota-induced changes in signaling in intestine are also not confined to ISCs but are also seen in Paneth cells, the niche cells that secrete Wnt that supports ISC function.
The composition of the intestinal microbiota thus plays a critical role in regulating the function of ISCs. Our data implies potential therapeutic approaches via modulation of the composition of microbiota for aging-associated changes in the function of ISCs.
View the full article at FightAging
