The Host Microbiome Regulates and Maintains Human Health: A Primer and Perspective for Non-Microbiologists

Abstract

Humans consider themselves discrete autonomous organisms, but recent research is rapidly strengthening the appreciation that associated microorganisms make essential contributions to human health and well being. Each person is inhabited and also surrounded by his/her own signature microbial cloud. A low diversity of microorganisms is associated with a plethora of diseases, including allergy, diabetes, obesity, arthritis, inflammatory bowel diseases, and even neuropsychiatric disorders. Thus, an interaction of microorganisms with the host immune system is required for a healthy body. Exposure to microorganisms from the moment we are born and appropriate microbiome assembly during childhood are essential for establishing an active immune system necessary to prevent disease later in life. Exposure to microorganisms educates the immune system, induces adaptive immunity, and initiates memory B and T cells that are essential to combat various pathogens. The correct microbial-based education of immune cells may be critical in preventing the development of autoimmune diseases and cancer. This review provides a broad overview of the importance of the host microbiome and accumulating knowledge of how it regulates and maintains a healthy human system. Cancer Res; 77(8); 1783-812. ©2017 AACR.

Figure 1. Early endosomes localize mainly to the periphery of colon mucosa and muscularis

(A) Peripheral localization in a colony of human colonic Caco-2 cells. Cells were stained with the early endosomal marker EEA1 (green) or DAPI to visualize cell nuclei (blue) and processed for immunofluorescence microscopy. (B) Peripheral localization in murine colon mucosa processed as above. (C). Peripheral localization in murine colon muscular processed as above.

Figure 2. Late endosomes locate throughout colon mucosa and muscularis

(A) Punctate cytosolic localization in a colony of human colonic Caco-2 cells. Cells were stained with Beclin1, an autophagic regulator associated with late endosomes (green), or DAPI to visualize cell nuclei (blue) and processed for immunofluorescence microscopy. (B) Cytosolic localization in murine colon mucosa processed as above. (C). Cytosolic localization in murine colon muscularis processed as above.

Figure 3. Dysbiosis: an immunocompromised state characterized by pathobiont colonization that leads to hyperinflammation, dysplasia and tumorigenesis

(Left) Symbiosis: A symbiotic gut microbiota operates under a functional intestinal epithelial cell (IEC) barrier, with steady state proportions of mucus, pattern recognition receptors (PRRs), antimicrobial peptides, and secretory IgA, which in turn contain the microbiota in the intestinal lumen. Under tight control by IECs, the intestinal immune system within the gut lamina propria becomes largely tolerant to the resident commensals. Signaling cascades that occur downstream of toll-like receptors (TLRs) are used by IECs to detect microbes through PRRs. Upon lipopolysaccharide (LPS) stimulation of TLRs, the MYD88 protein is recruited, activating the NF-κB pathway, leading to production of antimicrobial proteins and proinflammatory cytokines. In a symbiotic gut, IECs are desensitized by repeated exposure to LPS or are attenuated by LPS-mediated downregulation of the IL-1 receptor–associated kinase 1 (IRAK1), an activator of the NF-κB cascade. Exposure to LPS induces epithelial cells to secrete TGF-β, B-cell-activating factor of the TNF family (BAFF), and a proliferation-inducing ligand (APRIL), all of which promote the development of tolerogenic responses to the microbiota. CD103⁺ dendritic cells (DCs) support the development of regulatory T (T_reg) cells to secrete IL-10 and TGF-β, and together they stimulate the production of commensal-specific IgA. (Right) Dysbiosis: Increased intestinal exposure of diverse PAMPs, pro-inflammatory cytokines, apoptotic debris, and toxins leads to microbial dysbiosis and overgrowth of “pathobionts”, transformed symbiotic bacteria now under pathologic conditions. Pathobiont overgrowth leads to the loss of barrier integrity and a breach in the IEC barrier. Translocation of bacteria and bacterial components triggers the intestinal immune system through TLR activation, resulting in potentially harmful effector T cell responses set to clear invading bacteria. Ultimately, the secretion of IL-1 and IL-6 from IECs fuels a T_H1 and T_H17 response by DCs and macrophages and leads to higher levels of commensal-specific IgG by B cells.

Figure 4. Gut microbiome directs the efficacy of immune checkpoint therapy

Both anti-CTLA-4 and anti-PD-L1 therapies rely on gut microbiota for efficacy in immune activation. Anti-PD-L1 therapy has been shown to rely on the pre-existence of sufficient Bifidobacterium species, which are also thought to augment responses via PD-L1 binding on antigen-presenting cells such as DCs and macrophages. Subsequent ligation results in the prevention of suppressive signals to PD-1-expressing T cells. Similarly, anti-CTLA-4 indirectly alters the intestinal flora and enriches the Bacteroides species, possibly by promoting deterioration of the IEC barrier via activation of local lymphocytes. These bacteria then promote the activation of DCs, which present tumor antigens to prime and maintain anti-tumor T cell responses. Anti-CTLA-4 holds additional activation functions, including 1) preventing CTLA-4 from blocking activation of the co-stimulatory molecule CD28 on T cells and 2) blocking the immune-suppressive function of Tregs, which are required in deactivation of immune responses against tumors.