The microbiome in infectious disease and inflammation

Abstract

The mammalian alimentary tract harbors hundreds of species of commensal microorganisms (microbiota) that intimately interact with the host and provide it with genetic, metabolic, and immunological attributes. Recent reports have indicated that the microbiota composition and its collective genomes (microbiome) are major factors in predetermining the type and robustness of mucosal immune responses. In this review, we discuss the recent advances in our understanding of host-microbiota interactions and their effect on the health and disease susceptibility of the host.

Figure 1

Causes and pathological outcomes of dysbiosis. The composition of the gut microbiota is readily affected by diet, inflammation (including infection by pathogens), and host genotypes. An unfavorable alteration of the community structure of the gut microbiota is termed dysbiosis, which includes an outgrowth of potential pathogenic bacteria (pathobionts) and a reduced diversity of the community structure of the microbiota. Dysbiosis is associated with the increased predisposition to immune system activation, which leads to aberrant immune responses against commensal microbiota and diet. The dysregulated activation of the immune system leads to the worsening of the dysfunction of the microbiota, which may result in sustained inflammation in the intestine (i.e., IBD) and other organs.

Figure 2

Morphology (a) and immunological effects (b) of segmented filamentous bacteria (SFB). SFB are also known as Arthromitus. They are yet-to-be-cultured, gram-positive, spore-forming, and commonly considered nonpathogenic and host-specific members of the gut microbiota in numerous species including mammals, birds, fish, and insects (although it is currently unclear whether SFB are present in the human intestine). (a) Scanning electron microscopy shows that SFB colonize mainly the small intestine and exhibit a characteristic long filamentous morphology comprising multiple segments with well-defined septa. Each bacterium is likely to originate from a single cell that tightly adheres to and even embeds itself among the microvilli on the epithelial cell surface. (b) The attachment of SFB induces morphological changes in the epithelial cell, such as the accumulation of filamentous actin around the attachment site. SFB activate IECs to induce expression of MHC class II molecules and fucosyltransferase 2 (Fut2). Fut2 fucosylates host glycoproteins on the IECs, such as asialoGM1 glycolipids. SFB are potent stimuli of the IgA response and the recruitment of TCR αβ⁺ IELs in the small intestine. Furthermore, SFB induce the accumulation of Th17 cells. SFB colonization leads to an increase in local SAA production (perhaps in IECs), which can act on LP DCs to stimulate the induction of Th17 cells.

Figure 3

Clostridium species from clusters XIVa and IV and their effect on the host immune system. (a) Clostridium spp. belonging to clusters XIVa and IV mainly colonize the cecum and proximal colon, have a fusiform shape, and form a thick layer on the mucosal epithelium as shown by scanning electron microscopy (left panel). The right panel shows a higher magnification of a representative bacterium. (b) Clostridium spp. belonging to clusters XIVa and IV can normalize the enlarged cecum of GF mice. The interaction between these Clostridium species and IECs results in the production of matrix metalloproteinases (MMPs) from colonic epithelial cells to convert TGF-β from the latent to the active form. Together with indoleamine 2,3-dioxygenase (IDO) produced by IECs, the active form of TGF-β induces the accumulation of Helios⁻ Treg cells that express high levels of IL-10 and cytotoxic T lymphocyte antigen 4 ( CTLA-4). Clostridium spp. also act as potent stimuli for the IgA response and the recruitment of TCRαβ⁺ IELs in the colon.