The human microbiome in hematopoiesis and hematologic disorders

Abstract

Humans are now understood to be in complex symbiosis with a diverse ecosystem of microbial organisms, including bacteria, viruses, and fungi. Efforts to characterize the role of these microorganisms, commonly referred as the microbiota, in human health have sought to answer the fundamental questions of what organisms are present, how are they functioning to interact with human cells, and by what mechanism are these interactions occurring. In this review, we describe recent efforts to describe the microbiota in healthy and diseased individuals, summarize the role of various molecular technologies (ranging from 16S ribosomal RNA to shotgun metagenomic sequencing) in enumerating the community structure of the microbiota, and explore known interactions between the microbiota and humans, with a focus on the microbiota's role in hematopoiesis and hematologic diseases.

Figure 1

The role of the gut microbiota and associated products in shaping the intestinal immune system. Commensal organisms, such as bacteria in the phyla Bacteriodes and Firmicutes, colonize the gastrointestinal tract. SCFAs are produced as a result of carbohydrate fermentation, which increases the production of IL-10 and decreases the production of IL-6 and tumor necrosis factor (TNF)-α. Retinoic acid, which is produced by intestinal dendritic cells, leads to an increased differentiation of Tregs and decreased differentiation of inflammatory Th17 cells. The microfold (M)-cells of Peyer patches uptake antigen from the lumen and deliver it to the dendritic cells and other antigen-presenting cells located in the lamina propria. These cells become activated, and B cells secrete immunoglobulin (Ig)A into the lumen. These bacteria-specific IgA molecules thus serve to modulate the luminal microbiota composition. Paneth cells, an intestinal epithelial cell subtype that is prevalent in the small intestine and ascending colon, also shape the microbial composition by secreting α-defensins and other antimicrobial proteins in response to bacterial antigens binding to toll-like receptors (TLRs). TLRs line the gastrointestinal tract, and microbial products such as lipopolysaccharide (LPS) and flagellin bind to TLR4 and TLR5, respectively, upregulating the expression of RegIIIγ, a secreted antibacterial lectin that limits infection from Gram-positive bacteria. FDC, follicular dendritic cell; IL, interleukin; SCFA, short chain fatty acid; Treg, regulatory T cell; Th, helper T.