The human microbiome, the complex community of microorganisms residing in and on the human body, plays a crucial role in maintaining host health. Emerging evidence suggests a profound impact of the microbiome on hematopoiesis, the process of blood cell formation, and its dysregulation in various blood disorders. This review explores the intricate interplay between the gut microbiome and hematopoiesis, highlighting the mechanisms through which the microbiome influences hematopoietic stem cell (HSC) function, immune cell development, and erythropoiesis. We discuss the mounting evidence linking alterations in the microbiome composition (dysbiosis) with an increased susceptibility to hematological malignancies, including leukemia and lymphoma, as well as autoimmune disorders like immune thrombocytopenia (ITP). Further, we delve into the therapeutic potential of modulating the microbiome through fecal microbiota transplantation (FMT) and prebiotics/probiotics in ameliorating blood disorders. Understanding the complex interactions between the microbiome and hematopoiesis opens new avenues for developing innovative diagnostic and therapeutic strategies for a wide range of blood disorders.

Hematopoiesis, the continuous process of blood cell generation, is crucial for maintaining homeostasis and protecting against infections. This complex process occurs primarily within the bone marrow, where hematopoietic stem cells (HSCs) differentiate into various blood cell lineages, including erythrocytes, leukocytes, and platelets. The intricate regulation of hematopoiesis involves a complex network of growth factors, cytokines, and transcription factors (Orkin & Zon, 2008). In recent years, the understanding of hematopoiesis has expanded to incorporate the influence of the human microbiome, a diverse community of microorganisms residing primarily in the gut but also found on the skin, oral cavity, and other body sites (Sender, Fuchs, & Milo, 2016).

The microbiome plays a critical role in human health, influencing various physiological processes, including digestion, immune development, and metabolic homeostasis (Cryan & Dinan, 2012). Accumulating evidence suggests that the microbiome can significantly impact hematopoiesis, both in health and disease. This review examines the current understanding of the microbiome's influence on hematopoiesis and its potential implications for the development and treatment of blood disorders.

The Microbiome-Hematopoiesis AxisThe gut microbiome communicates with the host through various mechanisms, including the production of metabolites, immune modulation, and direct interaction with the immune system (Round & Mazmanian, 2009). This bidirectional communication influences hematopoiesis in several ways:

HSCs are the foundation of blood cell production, possessing the ability to self-renew and differentiate into all blood cell lineages. Emerging evidence suggests that the microbiome can influence HSC function and differentiation. For instance, studies have shown that germ-free mice, lacking a microbiome, exhibit altered HSC quiescence and differentiation patterns compared to conventionally raised mice (Eriguchi et al., 2018). These alterations are associated with changes in the expression of HSC-related genes and alterations in the bone marrow microenvironment (BMM). The BMM provides essential signals for HSC maintenance and differentiation, and the microbiome can influence its composition and function through metabolites like short-chain fatty acids (SCFAs).

2. Modulation of Immune Cell Development:

The microbiome plays a crucial role in shaping the immune system, particularly during early life. It influences the development and maturation of immune cells, including lymphocytes, macrophages, and neutrophils, all of which are integral to hematopoiesis regulation (Schultze & Gershon, 2016). For example, studies have demonstrated that the microbiome can influence the differentiation of T cells, impacting the balance between pro-inflammatory and regulatory T cells (Treg cells). This balance is critical in maintaining immune homeostasis and preventing aberrant immune responses that can contribute to blood disorders (Honda & Littman, 2016).

3. Influence on Erythropoiesis:

Erythropoiesis, the process of red blood cell generation, is tightly regulated by erythropoietin (EPO), a hormone produced primarily by the kidneys. Recent studies suggest that the gut microbiome can influence erythropoiesis by modulating EPO production and iron metabolism (Rhee et al., 2018). Specific bacterial species, such as Lactobacillus and Bifidobacterium, have been shown to promote EPO production and improve iron absorption, leading to increased red blood cell counts. Additionally, dysbiosis can contribute to iron deficiency anemia through alterations in iron absorption and utilization (Olsvik et al., 2015).

The Role of Microbiome Dysbiosis in Blood Disorders

Dysbiosis, an imbalance in the composition and function of the microbiome, has been implicated in a wide range of diseases, including blood disorders. Several studies have linked specific alterations in the microbiome with an increased risk of hematological malignancies and autoimmune disorders.

1. Hematological Malignancies:

Hematological malignancies, such as leukemia and lymphoma, arise from the clonal expansion of abnormal blood cells. Growing evidence suggests that microbiome dysbiosis can contribute to the development of these malignancies through various mechanisms. For instance, certain bacterial species can produce genotoxic metabolites that can damage DNA and promote tumorigenesis (Naik et al., 2016). Moreover, dysbiosis can lead to chronic inflammation and immune suppression, creating a favorable environment for the development of hematological malignancies. Studies have shown that patients with leukemia often exhibit distinct microbiome profiles compared to healthy individuals (Jenq et al., 2012).

2. Autoimmune Blood Disorders:

Autoimmune disorders like immune thrombocytopenia (ITP) are characterized by an immune response against the body's own blood cells. The microbiome can play a crucial role in the pathogenesis of these disorders by modulating immune tolerance and influencing autoantibody production (Kappelman, 2005). Dysbiosis can lead to an imbalance in the gut immune environment, leading to enhanced immune activation and increased susceptibility to autoimmune disorders. Studies have suggested that specific bacterial species can contribute to ITP by inducing the production of autoantibodies against platelets (Maiuolo et al., 2016).

Therapeutic Applications: Modulating the Microbiome

Given the evidence supporting the role of the microbiome in blood disorders, there is increasing interest in developing microbiome-based therapies for these conditions.

1. Fecal Microbiota Transplantation (FMT):

FMT, the transfer of fecal material from a healthy donor to a recipient, has emerged as a promising treatment for various conditions, including recurrent Clostridium difficile infection. Recent studies have explored the potential of FMT for treating blood disorders. For example, FMT has shown promising results in improving immune responses and reducing inflammation in patients with inflammatory bowel disease (IBD), a condition that can be associated with increased risk of blood disorders (Kelly et al., 2015). While still in its early stages, FMT holds potential for restoring a healthy microbiome and mitigating the impact of dysbiosis on hematopoiesis.

2. Prebiotics and Probiotics:

Prebiotics are non-digestible food ingredients that promote the growth of beneficial bacteria in the gut, while probiotics are live microorganisms that can confer health benefits when administered in adequate amounts. Both prebiotics and probiotics have shown promise in modulating the microbiome and improving immune function (Hill et al., 2014). In the context of blood disorders, specific prebiotics and probiotics have been investigated for their potential to improve hematopoiesis, reduce inflammation, and mitigate the risk of complications. Further research is needed to determine the optimal prebiotic/probiotic combinations and their efficacy in various blood disorders.

The interplay between the gut microbiome and hematopoiesis is a rapidly evolving field with significant clinical implications. This review has highlighted the multifaceted ways in which the microbiome shapes hematopoiesis, influencing HSC function, immune cell development, and erythropoiesis. Furthermore, we have explored the mounting evidence linking microbiome dysbiosis with a range of blood disorders, including hematological malignancies and autoimmune disorders. The therapeutic potential of modulating the microbiome through FMT, prebiotics, and probiotics offers a promising avenue for developing innovative treatment strategies.

Moving forward, future research should focus on dissecting the complex mechanisms underlying microbiome-hematopoiesis interactions. Identifying specific bacterial species and their metabolites that contribute to blood disorders is crucial for developing targeted therapeutic interventions. Furthermore, large-scale clinical trials are needed to evaluate the efficacy and safety of microbiome-based therapies in various blood disorders. Understanding the complex interplay between the microbiome and hematopoiesis holds immense potential for improving our understanding and treatment of these disorders.