Fecal microbiota transplantation from young mice rejuvenates aged hematopoietic stem cells by suppressing inflammation

Abstract

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.

Washed microbiota transplantation improves haemoglobin levels in anaemia of chronic disease

“…Similarly, previous studies have reported that FMT resulted in distinct increases of Lachnospiraceae NK4A136 group and Butyricicoccus in animal models 46–48 . The study by Zeng et al also proved the importance of Lachnospiraceae and Butyricicoccus in mouse models 36 . These results indicate that Lachnospiraceae NK4A136 group and Butyricicoccus are important in WMT for ACD treatment, and could serve as novel therapeutic targets.…”

“…[46][47][48] The study by Zeng et al also proved the importance of Lachnospiraceae and Butyricicoccus in mouse models. 36 These results indicate that Lachnospiraceae NK4A136 group and Butyricicoccus are important in WMT for ACD treatment, and could serve as novel therapeutic targets. Besides, the gut microbiota pathways of fumarate respiration, nitrite ammonification and nitrate reduction, were upregulated in patients with ACD, whereas the fumarate respiration and nitrite ammonification pathways were downregulated after WMT, further supporting the idea that these microbial pathways contribute to ACD.…”

“…FMT can significantly reduce the serum levels of multiple cytokines, including IL‐6 and interferon‐γ, 34,35 which may contribute to improvements in bone marrow haematopoietic function. Furthermore, an animal study by Zeng et al showed that healthy gut microbiota from young mice transplanted into aged mice significantly increased the proportion and the absolute number of haematopoietic stem cells by decreasing the concentration of inflammatory cytokines secreted by bone marrow myeloid cells 36 . (2) Several underlying causes of ACD, such as cancer, chronic kidney disease and autoimmune disease, are associated with gut dysbiosis, 12,13,37 and restoring gut microbial balance through FMT is beneficial for the treatment of these diseases 11,38–40 .…”

“…Furthermore, an animal study by Zeng et al showed that healthy gut microbiota from young mice transplanted into aged mice significantly increased the proportion and the absolute number of haematopoietic stem cells by decreasing the concentration of inflammatory cytokines secreted by bone marrow myeloid cells. 36 (2) Several underlying causes of ACD, such as cancer, chronic kidney disease and autoimmune disease, are associated with gut dysbiosis, 12,13,37 and restoring gut microbial balance through FMT is beneficial for the treatment of these diseases. 11,[38][39][40] Thus, WMT may improve haematopoietic function via treating the primary diseases that contribute to ACD.…”

Blautia Coccoides is a Newly Identified Bacterium Increased by Leucine Deprivation and has a Novel Function in Improving Metabolic Disorders

“…Antibiotic treated HFD recipients were inoculated daily with fecal microbial (200 μL for each mouse) by oral gavage for 30 days. [62,63] Metabolic Parameters, Glucose Tolerance Tests, Insulin Tolerance Tests, and HOMA-IR Index: The body fat composition was determined using the Bruker Minispec mq10 NMR Analyzer (Bruker, Billerica, MA). Serum triglyceride (TG) levels were determined enzymatically using TG reagent (Wako, Japan).…”