Regulation of neutrophils by the microbiota. (A) All vertebrates host a large and diverse bacterial community in their intestine. The microbiota produces a variety of small molecules that can communicate with the host, including microbial components and metabolites. Microbial components, as well as direct contact between specific species such as SFB and the epithelium, induces IL-17 secretion from Th17 cells and ILCs, which induces the synthesis of G-CSF, a master regulator of neutrophil production. (B) The microbial products and metabolites can diffuse into the circulation, directly regulating the function of neutrophils in blood. Nascent neutrophils released from the BM exhibit limited proinflammatory activity. They acquire enhanced capacities of migration, integrin activation, ROS production, and NET formation as they age and sense microbiota-derived signals in the circulation. This process requires the presence of microbiota, and is dependent on TLR/Myd88 pathways. Conversely, microbiota-derived metabolites including SCFAs exhibit anti-inflammatory properties. (C) Microbial products from the microbiota can also diffuse into the BM, and be sensed by MSCs, which produce cytokines that support lineage differentiation from HSCs. In addition, the phagocytic capacities of BM neutrophils are also regulated by microbiota-derived NOD1 ligands. GMP, granulocyte-monocyte progenitors; HSC, hematopoietic stem cell; ILC, innate lymphoid cell; LPS, lipopolysaccharide; PGN, peptidoglycan; MPP, multipotent progenitor; NET, neutrophil extracellular trap; ssDNA, single-stranded DNA.