Crosstalk between Gut Microbiota and Host Immunity: Impact on Inflammation and Immunotherapy

Abstract

Gut microbes and their metabolites are actively involved in the development and regulation of host immunity, which can influence disease susceptibility. Herein, we review the most recent research advancements in the gut microbiota-immune axis. We discuss in detail how the gut microbiota is a tipping point for neonatal immune development as indicated by newly uncovered phenomenon, such as maternal imprinting, in utero intestinal metabolome, and weaning reaction. We describe how the gut microbiota shapes both innate and adaptive immunity with emphasis on the metabolites short-chain fatty acids and secondary bile acids. We also comprehensively delineate how disruption in the microbiota-immune axis results in immune-mediated diseases, such as gastrointestinal infections, inflammatory bowel diseases, cardiometabolic disorders (e.g., cardiovascular diseases, diabetes, and hypertension), autoimmunity (e.g., rheumatoid arthritis), hypersensitivity (e.g., asthma and allergies), psychological disorders (e.g., anxiety), and cancer (e.g., colorectal and hepatic). We further encompass the role of fecal microbiota transplantation, probiotics, prebiotics, and dietary polyphenols in reshaping the gut microbiota and their therapeutic potential. Continuing, we examine how the gut microbiota modulates immune therapies, including immune checkpoint inhibitors, JAK inhibitors, and anti-TNF therapies. We lastly mention the current challenges in metagenomics, germ-free models, and microbiota recapitulation to a achieve fundamental understanding for how gut microbiota regulates immunity. Altogether, this review proposes improving immunotherapy efficacy from the perspective of microbiome-targeted interventions.

Keywords: adaptive immune system; cancer; fecal microbiota transplantation; gut microbiota dysbiosis; infection; inflammatory bowel diseases; innate immune system.

Figure 1

Possible mechanisms of short-chain fatty acids and bile acids positive effects on immune system in IBD. (A) Short-chain fatty acids (SCFAs) are fermented byproducts of dietary fiber. SCFAs are the ligands for G-protein receptors (GPRs) in which GPR activation upregulates mucin levels in goblet cells, antimicrobial peptides in Paneth cells, and tight junction proteins in intestinal epithelial cells. Moreover, SCFAs inhibit the secretion of pro-inflammatory cytokines (TNF-α, IL-2, IL-6, etc.) by macrophages, inhibit the expression of dendritic cell-migrated proteins (CXCL, CD40), and inhibit HDAC activity. HDAC inhibition allows for acetylation of histone 3 (H3Ac), which induces Treg differentiation and their secretion of anti-inflammatory cytokines, such as IL-10. Similarly, SCFA can promote DC-dependent anti-inflammatory IL-10 secretion. Finally, SCFAs induce IgA production from B cells. (B) Primary bile acids produced in the liver are metabolized by intestinal microbiota into secondary bile acids. Bile acids induce the polarization of macrophages and helper T cells into M2 macrophages and Treg, respectively, promoting anti-inflammatory IL-10 secretion. In addition, bile acids inhibit the secretion of pro-inflammatory cytokines (TNF-α, IL-2, IL-6, etc.) by DCs. Moreover, bile acids inhibit IL-17 secretion from ILC3 and Th17. Likewise, bile acids can promote DC-dependent IL-10 secretion. Overall, SCFA and bile acids reduce gut inflammation. SCFAs: Short-chain fatty acids, AMPs: Antimicrobial peptides, Mφ: Macrophages, DC: Dendritic cells, Tregs: T-Regulatory cells, Th1: T-helper 1, Th17: T helper 17, ILC3: Innate lymphoid cells type 3, IL: Interleukin, HDAC: Histone deacetylase, H3Ac: Acetylation of histone 3, TNF: Tumor necrosis factor, NOS2: Nitric oxide synthase 2, IgA: Immunoglobulin A, and CXCL: Chemokine (C-X-C motif) ligand. Red arrows denote activation, and black arrows denote inhibition.

Figure 2

Gut microbiota dysbiosis gives rise to several pathophysiological conditions. Gut microbiota dysbiosis can be induced by diet, antibiotics, and genetic factors. Gut microbiota dysbiosis can cause and sustain cancers, such as colorectal cancer and hepatocellular carcinoma, along with inflammatory diseases, autoimmune conditions, and cardiometabolic disorders. Gut microbiota dysbiosis-induced immune dysregulation is another etiological factor for disease among the many others listed, including age, sex, and medication.

Figure 3

Modifying the abundance of gut microbiota population may influence the outcomes of immunotherapy. A healthy gut microbiome can increase the bioavailability and efficacy of drugs in the host. Dysbiosis, caused by several depicted factors, may decrease the efficacy of the therapeutic drugs, leading to poor therapeutic outcomes. Modifying gut microbiota could increase the effectiveness of certain immunotherapeutic drugs, such as anti-PD-1 antibody, anti-PD-L1 antibody, and anti-CTL4 antibody treatments. Gut microbiota can be changed by supplementation with either antibiotics, probiotics, prebiotics, secondary bile acids, short-chain fatty acids (e.g., butyrate), inosine, or fecal matter transplantation.