Intersection of the microbiome and immune metabolism in lupus

Abstract

Systemic lupus erythematosus is a complex autoimmune disease resulting from a dysregulation of the immune system that involves gut dysbiosis and an altered host cellular metabolism. This review highlights novel insights and expands on the interactions between the gut microbiome and the host immune metabolism in lupus. Pathobionts, invasive pathogens, and even commensal microbes, when in dysbiosis, can all trigger and modulate immune responses through metabolic reprogramming. Changes in the microbiota's global composition or individual taxa may trigger a cascade of metabolic changes in immune cells that may, in turn, reprogram their functions. Factors contributing to dysbiosis include changes in intestinal hypoxia, competition for glucose, and limited availability of essential nutrients, such as tryptophan and metal ions, all of which can be driven by host metabolism changes. Conversely, the accumulation of some host metabolites, such as itaconate, succinate, and free fatty acids, could further influence the microbial composition and immune responses. Overall, mounting evidence supports a bidirectional relationship between host immunometabolism and the microbiota in lupus pathogenesis.

Keywords: glucose; lupus; metabolism; microbiome; mitochondria; tryptophan.

FIGURE 1:

Immunometabolic abnormalities in lupus and their effects on the immune response. The four main categories of metabolic alterations in lupus target glucose metabolism (including both anaerobic and aerobic glycolysis), mitochondrial metabolism, mechanistic target of rapamycin (mTOR) signaling, and amino acid metabolism. Broadly, increases in these pathways induce inflammatory effects in B cells, T cells, and phagocytes, increasing autoantibody production and tissue damage as a result of expanded germinal center (GC) B cells, a skewed Th17/Treg cell ratio, and production of inflammatory cytokines. In addition to their individual effects on immune cells, these metabolic categories can also influence each other (represented by the arrows). mTOR signaling is closely linked to mitochondrial and glucose metabolism, and different amino acid metabolites (namely derivatives from tryptophan) have been documented to upregulate mTOR, mitochondrial respiration, and glycolysis.

FIGURE 2.

Gut dysbiosis in lupus pathogenesis. Multiple mechanisms have been proposed for dysbiosis in the gut microbiota to contribute to lupus pathogenesis. In SLE patients and certain strains of lupus-prone mice, there is a decrease in diversity of the gut microbiota, and in the Firmicutes/Bacteroidetes ratio, as well as blooms of the pathobionts such as Enteroccocus gallinarium, Lactobacillus reuteri and Ruminococcus gnavus. Dysbiosis may also impair the intestinal barrier integrity allowing the translocation of gut microbes into the mLN, liver, spleen, and blood, which can then trigger an autoimmune response to produce autoantibodies and type I IFN, which all contribute to increased disease flares. Leaked microbial peptides that are orthologs to lupus autoantigens such as Sm and Ro60 may activate autoreactive CD4+ T cells or B cells through molecular mimicry. Enhanced TLR7 signaling in genetically predisposed hosts is another mechanism that can induce leaky gut and contributes to intestinal microbial changes and increased disease activity. Finaly, dysbiosis may result in the production of tryptophan metabolites that may induce immune activation.

FIGURE 3.

Gut dysbiosis contributes to immunometabolic alterations in lupus. Within an imbalanced gut environment in lupus, commensal microbes, pathobionts and invasive pathogens can activate innate immune cells via pattern recognition receptors (PPRs), changing cellular metabolism to support activation and proliferation. LPS-induced TLR signaling in DCs promotes glycolysis with a reduced mitochondrial respiration. Pro-inflammatory M1 macrophages or anti-inflammatory M2 macrophages will be activated by LPS or fungal and parasites, respectively, and M1 macrophages display an enhanced glycolysis and glutaminolysis, while M2 macrophages signature is fatty acid oxidation. Upon microbe challenge, neutrophils switch from a glycolysis-dominated metabolism to the oxidative pentose phosphate pathway to power oxidative burst. Besides innate immune cells, gut microbes can also regulate the activation and functions of T cells and B cells. Exogenous antigens activate effector T cells with increased glycolysis and mitochondrial oxidative phosphorylation, which can be altered by microbial metabolites, such as tryptophan metabolites. Reduction in SCFAs and secondary bile salts due to dysbiosis may reduce regulatory T cell differentiation or function, but may promote pro-inflammatory cell types, such as M1 macrophages. In addition, microbial autoantigen orthologs may activate T cells and B cells to generate autoantibodies.