Using 16S rRNA sequencing, it is possible to accurately measure the composition of the gut microbiome from a stool sample, producing a comprehensive picture of the distribution of microbial species. Given this capability, now widely available at low cost, researchers have shown that the gut microbiome changes with age in characteristic ways. Microbial species that provoke chronic inflammation or otherwise deliver harmful metabolites into the body increase in number. Species that deliver beneficial metabolites, such as the butyrate that is known to upregulate BDNF expression and improve neurogenesis, decline in number. A large part of this shift may be due to the age-related decline of the immune system, but given that significant changes in the gut microbiome occur as young as mid-30s, lifestyle choices may play a significant role.
Importantly, the ability to measure the microbiome allows researchers to assess whether specific interventions can restore a more youthful gut microbiome to older individuals. The use of fecal microbiota transplant from young to old animals has shown that restoration is possible, producing a lasting improvement in the microbiome following a single treatment, and consequent benefits to health and life span. Today's research materials are an example of the type, showing that fecal microbiota transplant from young donors in mice improves aging immune function.
This ability to produce lasting change suggests that the aging of the microbiome is only loosely coupled to the aging of the body; presumably it will continue to degrade at some pace following improvement, but that pace is slow enough to make such an improvement an attractive form of therapy. Beyond fecal microbiota transplantation, other interventions have shown some ability to produce lasting improvement in the gut microbiome, such as flagellin immunization in order to provoke the immune system into more aggressively removing harmful microbes. In principle probiotics might be able to achieve the same goal, but as yet the available probiotics represent only a small fraction of the species delivered by fecal microbiota transplantation, and do not appear to produce lasting effects.
Hematopoietic stem cell (HSC) aging is accompanied by hematopoietic reconstitution dysfunction, including loss of regenerative and engraftment ability, myeloid differentiation bias and elevated risks of hematopoietic malignancies. Gut microbiota, a key regulator of host health and immunity, has been recently reported to impact hematopoiesis. However, there is currently limited empirical evidence elucidating the direct impact of gut microbiome on aging hematopoiesis.
In this study, we performed fecal microbiota transplantation (FMT) from young mice to aged mice and observed significant increment in lymphoid differentiation and decrease in myeloid differentiation in aged recipient mice. Further, FMT from young mice rejuvenated aged HSCs with enhanced short-term and long-term hematopoietic repopulation capacity. Mechanistically, single-cell RNA sequencing deciphered that FMT from young mice mitigated inflammatory signals, upregulated FoxO signaling pathway and promoted lymphoid differentiation of HSCs during aging. Finally, integrated microbiome and metabolome analyses uncovered that FMT reshaped gut microbiota construction and metabolite landscape, and Lachnospiraceae and tryptophan-associated metabolites promoted the recovery of hematopoiesis and rejuvenated aged HSCs.
Together, our study highlights the paramount importance of the gut microbiota in HSC aging and provides insights into therapeutic strategies for aging-related hematologic disorders.