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.

Inflammation alters bone marrow hematopoiesis to favor the production of innate immune effector cells at the expense of lymphoid cells and erythrocytes. Furthermore, proinflammatory cytokines inhibit steady-state erythropoiesis, which leads to the development of anemia in diseases with chronic inflammation. Acute anemia or hypoxic stress induces stress erythropoiesis, which generates a wave of new erythrocytes to maintain erythroid homeostasis until steady-state erythropoiesis can resume. Although hypoxia-dependent signaling is a key component of stress erythropoiesis, we found that inflammation also induced stress erythropoiesis in the absence of hypoxia. Using a mouse model of sterile inflammation, we demonstrated that signaling through Toll-like receptors (TLRs) paradoxically increased the phagocytosis of erythrocytes (erythrophagocytosis) by macrophages in the spleen, which enabled expression of the heme-responsive gene encoding the transcription factor SPI-C. Increased amounts of SPI-C coupled with TLR signaling promoted the expression of Gdf15 and Bmp4, both of which encode ligands that initiate the expansion of stress erythroid progenitors (SEPs) in the spleen. Furthermore, despite their inhibition of steady-state erythropoiesis in the bone marrow, the proinflammatory cytokines TNF-α and IL-1β promoted the expansion and differentiation of SEPs in the spleen. These data suggest that inflammatory signals induce stress erythropoiesis to maintain erythroid homeostasis when inflammation inhibits steady-state erythropoiesis.

Consumption of a low-fiber, high-fat, Western-style diet (WSD) induces adiposity and adipose inflammation characterized by increases in the M1:M2 macrophage ratio and proinflammatory cytokine expression, both of which contribute to WSD-induced metabolic syndrome. WSD-induced adipose inflammation might result from endoplasmic reticulum stress in lipid-overloaded adipocytes and/or dissemination of gut bacterial products, resulting in activation of innate immune signaling. Hence, we aimed to investigate the role of the gut microbiota, and its detection by innate immune signaling pathways, in WSD-induced adipose inflammation. Mice were fed grain-based chow or a WSD for 8 weeks, assessed metabolically, and intestinal and adipose tissue were analyzed by flow cytometry and quantitative reverse transcription polymerase chain reaction. Microbiota was ablated via antibiotics and use of gnotobiotic mice that completely lacked microbiota (germ-free mice) or had a low-complexity microbiota (altered Schaedler flora). Innate immune signaling was ablated by genetic deletion of Toll-like receptor signaling adaptor myeloid differentiation primary response 88. Ablation of microbiota via antibiotic, germ-free, or altered Schaedler flora approaches did not significantly impact WSD-induced adiposity, yet dramatically reduced WSD-induced adipose inflammation as assessed by macrophage populations and cytokine expression. Microbiota ablation also prevented colonic neutrophil and CD103- dendritic cell infiltration. Such reduced indices of inflammation correlated with protection against WSD-induced dysglycemia, hypercholesterolemia, and liver dysfunction. Genetic deletion of myeloid differentiation primary response 88 also prevented WSD-induced adipose inflammation. These results indicate that adipose inflammation, and some aspects of metabolic syndrome, are not purely a consequence of diet-induced adiposity per se but, rather, may require disturbance of intestine-microbiota interactions and subsequent activation of innate immunity.

Owing to their health benefits, dietary fermentable fibers, such as refined inulin, are increasingly fortified in processed foods to enhance their nutritional value. However, we previously demonstrated that when inulin was fed to Toll-like receptor 5 deficient (T5KO) mice susceptible to dysbiosis, a subset of them developed cholestasis and subsequently liver cancer in a gut microbiota-dependent manner. Therefore, we hypothesized that clearance of bacterial taxa, and thereby gut metabolites, involved in the onset and progression to liver cancer could abate the disease in these mice. Such a reshaping of microbiota by vancomycin treatment was sufficient to halt the development of liver cancer in inulin-fed T5KO mice; however, this intervention did not remedy disease penetrance for cholestatic liver injury and its sequelae, including hyperbilirubinemia, hypolipidemia, cholemia and liver fibrosis. Selective depletion of gut bacterial communities was observed in vancomycin-treated mice, including Gram-positive Lachnospiraceae and Ruminococcaceae belonging to the phylum Firmicutes, Bifidobacteria of the phylum Actinobacteria, which ferment fibers, and Clostridium cluster XIVa, which produce secondary bile acids. Lack of liver cancer in vancomycin-treated mice strongly correlated with the substantial loss of secondary bile acids in circulation. Although cholemia was unabated by vancomycin, the composition of serum bile acids shifted toward an abundance of hydrophilic primary bile acids, denoted by the increase in conjugated-to-unconjugated bile acid ratio. Taken together, the present study suggests that microbiotal regulation of bile acid metabolism is one of the critical mediators of fermentable fiber-induced liver cancer in dysbiotic mice.

Enterobactin (Ent), a prototypical bacterial siderophore known for its unparalleled affinity for iron, is widely conserved among members of the Enterobacteriaceae family of Gram-negative bacteria. In this study, we demonstrated that, aside from mediating iron acquisition, Ent also dampened the macrophages (MΦs) antimicrobial responses against intracellular infection by Salmonella enterica serovar Typhimurium. Accordingly, the loss of Ent expression (ΔentB) in Salmonella demoted their survivability against MΦs. Addition of exogenous Ent not only rescued the survival of ΔentB Salmonella, but also augmented WT Salmonella to better withstand the microbicidal activity of MΦs. The protection conferred to WT Salmonella was observed only when Ent was administered as iron-free, thus indicating the requirement of iron chelation in this context. In contrast, the exogenous iron-bound Ent retained its ability to promote the survival of ΔentB Salmonella, albeit modestly. Assessment on MΦs labile iron pool (LIP) revealed that iron-free Ent is able to permeate into MΦs, chelate the intracellular LIP, and regulate the expression of several key iron-regulatory proteins, i.e., divalent metal transporter 1, ferroportin, and hepcidin. Chelation of iron by Ent was also observed to promote the MΦs towards M2 polarization. Collectively, our findings demonstrated that Ent not only facilitates bacterial iron uptake but also disrupts MΦs iron homeostasis and M1/M2 polarization to safeguard intracellular bacteria against the anti-bacterial effects of their host.