Young bugs rejuvenate old blood

In this issue of Blood, Zeng et al¹ show that young fecal microbiota can rejuvenate hematopoietic stem cell (HSC) function in aged mice via a metabolic circuit that suppresses inflammation.

Although the absolute numbers remain the subject of debate, the numerically dominant cell types in our bodies are (1) our intestinal microbiome and (2) our hematopoietic system.² That these abundant cell populations interact biologically is not surprising. Work over the past decade has begun decoding a rich molecular crosstalk consisting of direct (bacterial components) and indirect signals (cytokines and metabolic/endocrine factors) that shape hematopoietic function and the balance between health and disease. Whereas depletion of gut microbiota attenuates hematopoietic activity,³ increased intestinal permeability and infiltration of bacterial components into the bloodstream can increase systemic inflammation levels and exacerbate myeloid differentiation in the context of aging,^4,5 contributing to impaired hematopoietic function and immunosenescence. These observations beg the question as to whether we can turn back the clock on hematopoietic aging. Numerous studies have, therefore, sought to identify factors that can induce hematopoietic rejuvenation.

Zeng et al investigated whether the question of hematopoietic rejuvenation can be answered via the intestinal microbiome (see figure). They eradicated the gut microbiota of old mice (aged 20 to 24 months) with broad-spectrum antibiotics and then transferred fecal matter from young (aged 7 to 8 weeks) animals. Four weeks later, they analyzed the impact of young fecal microbiota transplantation (FMT-YA) on the hematopoietic systems of the aged animals. Strikingly, FMT-YA suppressed the overabundance of myeloid cells in the bone marrow (BM) associated with “myeloid bias” in the aged hematopoietic system while increasing the abundance of B cells. Furthermore, FMT-YA restored long-term functional potential of aged HSCs. On the other hand, FMT-YA did not reverse the expansion of phenotypic HSCs associated with aging. This suggests that the numerical increase in phenotypic HSCs is either governed by distinct aging-related processes or is impacted on a much longer time frame (and potentially both). Mechanistically, the authors leveraged single-cell RNA sequencing to identify reductions in aging-associated proinflammatory gene programs, including interferon (IFN), tumor necrosis factor, and interleukin-1 (IL-1) signaling networks in HSC from FMT-YA mice. Conversely, FMT-YA increased expression of cell adhesion factors such as Cxcr4, self-renewal–associated mechanisms like the FoxO pathway, and lymphoid differentiation genes in aged HSCs. On a systemic level, FMT-YA restored gut integrity and reduced circulating levels of IFN-γ and IL-6, implicating the aged microbiome itself as a trigger for gut dysfunction and systemic inflammation. Altogether, these findings expand current models that identify “inflamm-aging” as a driver of hematopoietic dysfunction in old individuals, with the aged microbiome itself as an instigator of this process.

If the microbiome is driving “inflamm-aging” and HSC dysfunction, can we identify which bacteria modulate the inflammatory phenotype? To address this point, the authors sequenced gut microbiota from FMT-YA mice. Relative to young and aged controls, they identified an increase in the abundance of genus Lachnospiraceae following FMT-YA. Transplant of Lachnospiraceae alone into aged mice reduced gut permeability and restored HSC function. To identify potential mechanisms, the authors performed metabolomics analysis of fecal matter from FMT-YA mice vs aged controls. They observed a significant increase in tryptophan-associated metabolites in FMT-YA, including indole metabolites with antiinflammatory properties.⁶ Because these metabolites were also elevated in the serum and BM of FMT-YA mice, the authors addressed whether dietary supplementation of individual metabolites could restore hematopoietic function. Interestingly, tryptophan or indole-3-carbinol supplementation reduced systemic inflammation and restored long-term HSC function in non-FMT aged mice. Altogether, these data identify the gut microbiome as a regulator of metabolic circuits that impact HSC function.

Collectively, these investigations extend our understanding of how the microbiome regulates HSC function in the context of aging. They also point to intestinal dysbiosis and altered metabolism as potentially targetable triggers for “inflamm-aging” and impaired HSC function. The extent to which dysbiosis interplays with HSC fitness in other settings remains an open question. In the context of hematologic malignancy, reduced microbial diversity related to chemotherapy and/or antibiotic use is associated with reduced progression-free survival following hematopoietic stem cell transplant.^7,8 Likewise, complications such as chronic Clostridium difficile infection, graft-versus-host disease, and overall mortality are associated with loss and/or shifts in microbial diversity.⁹ Thus, identifying approaches that either correct the composition of the microbiome (such as FMT) or compensate for the effects of dysbiosis via dietary supplementation could improve patient outcomes on multiple fronts. Furthermore, the extent to which dysbiosis contributes to premalignant blood phenotypes like clonal hematopoiesis will be important to determine as a means of establishing early intervention approaches.

A common challenge in microbiome studies is the difficulty in fulfilling Koch’s postulates, ie, demonstrating conclusively that changes in a specific microbe or set of microbes are the direct cause of a specific disease state.¹⁰ This is due in large part to the technical hurdles in isolating, culturing, and inoculating obligate anaerobes with fastidious environmental requirements. Here, the authors show inoculation with Lachnospiraceae can rejuvenate HSC activity in aged mice. Interestingly, the authors’ data suggest this bacterial genus may be less abundant in the microbiome of unmanipulated young mice relative to aged animals. Likewise, FMT-YA does not appear to restore a “young” microbiome but rather establishes a distinct set of dysbiotic alterations that exert beneficial effects, such as reduced gut permeability and inflammation. Thus, rather than attempting to restore a fully “youthful” complement of intestinal microbes, this study suggests it may be possible to either supplement the microbiome with a specific complement of bacteria that restore gut integrity and/or “crowd out” strains that promote morbidity. Conversely, it may be more straightforward to supplement needed metabolites via diet. Indeed, a key finding of this study is that microbiota-regulated changes to systemic metabolism, perhaps via translocation of bacteria-derived metabolites to the systemic milieu, lie upstream of aging-related pathogenic features like inflammatory cytokine production. Therapeutic approaches that address metabolism as a target may provide a novel modality for restoring hematopoietic and immune function while addressing potential safety concerns associated with immunosuppressive strategies such as cytokine blockade.

Conflict-of-interest disclosure: The author declares no competing financial interests.