Summary
Commensal microbes and the host immune system have been co‐evolved for mutual regulation. Microbes regulate the host immune system, in part, by producing metabolites. A mounting body of ...evidence indicates that diverse microbial metabolites profoundly regulate the immune system via host receptors and other target molecules. Immune cells express metabolite‐specific receptors such as P2X7, GPR41, GPR43, GPR109A, aryl hydrocarbon receptor precursor (AhR), pregnane X receptor (PXR), farnesoid X receptor (FXR), TGR5 and other molecular targets. Microbial metabolites and their receptors form an extensive array of signals to respond to changes in nutrition, health and immunological status. As a consequence, microbial metabolite signals contribute to nutrient harvest from diet, and regulate host metabolism and the immune system. Importantly, microbial metabolites bidirectionally function to promote both tolerance and immunity to effectively fight infection without developing inflammatory diseases. In pathogenic conditions, adverse effects of microbial metabolites have been observed as well. Key immune‐regulatory functions of the metabolites, generated from carbohydrates, proteins and bile acids, are reviewed in this article.
The gut microbiota produce many metabolites. Production of metabolites is altered in many chronic inflammatory and malignant diseases. Microbial metabolites promote both immunity and immune tolerance.
A mounting body of evidence indicates that dietary fiber (DF) metabolites produced by commensal bacteria play essential roles in balancing the immune system. DF, considered nonessential nutrients in ...the past, is now considered to be necessary to maintain adequate levels of immunity and suppress inflammatory and allergic responses. Short-chain fatty acids (SCFAs), such as acetate, propionate, and butyrate, are the major DF metabolites and mostly produced by specialized commensal bacteria that are capable of breaking down DF into simpler saccharides and further metabolizing the saccharides into SCFAs. SCFAs act on many cell types to regulate a number of important biological processes, including host metabolism, intestinal functions, and immunity system. This review specifically highlights the regulatory functions of DF and SCFAs in the immune system with a focus on major innate and adaptive lymphocytes. Current information regarding how SCFAs regulate innate lymphoid cells, T helper cells, cytotoxic T cells, and B cells and how these functions impact immunity, inflammation, and allergic responses are discussed.
Antibody production is a metabolically demanding process that is regulated by gut microbiota, but the microbial products supporting B cell responses remain incompletely identified. We report that ...short-chain fatty acids (SCFAs), produced by gut microbiota as fermentation products of dietary fiber, support host antibody responses. In B cells, SCFAs increase acetyl-CoA and regulate metabolic sensors to increase oxidative phosphorylation, glycolysis, and fatty acid synthesis, which produce energy and building blocks supporting antibody production. In parallel, SCFAs control gene expression to express molecules necessary for plasma B cell differentiation. Mice with low SCFA production due to reduced dietary fiber consumption or microbial insufficiency are defective in homeostatic and pathogen-specific antibody responses, resulting in greater pathogen susceptibility. However, SCFA or dietary fiber intake restores this immune deficiency. This B cell-helping function of SCFAs is detected from the intestines to systemic tissues and conserved among mouse and human B cells, highlighting its importance.
Display omitted
•Short-chain fatty acids (SCFAs) produced by gut microbiota promote antibody responses•SCFAs activate B cell metabolism for production of energy and building blocks•SCFAs control gene expression for plasma B cell differentiation•SCFAs boost antibody responses during infection, decreasing susceptibility to pathogens
Kim et al. demonstrate that short-chain fatty acids (SCFAs), produced by the gut microbiota as fermentation products of dietary fiber, support host antibody responses by regulating gene expression and enhancing cellular metabolism and plasma B cell differentiation. SCFAs boost mucosal and systemic antibody responses during steady state and infection.
Immune tolerance deletes or suppresses autoreactive lymphocytes and is established at multiple levels during the development, activation and effector phases of T and B cells. These mechanisms are ...cell-intrinsically programmed and critical in preventing autoimmune diseases. We have witnessed the existence of another type of immune tolerance mechanism that is shaped by lifestyle choices, such as diet, microbiome and microbial metabolites. Short-chain fatty acids (SCFAs) are the most abundant microbial metabolites in the colonic lumen and are mainly produced by the microbial fermentation of prebiotics, such as dietary fiber. This review focuses on the preventive and immunomodulatory effects of SCFAs on autoimmunity. The tissue- and disease-specific effects of dietary fiber, SCFAs and SCFA-producing microbes on major types of autoimmune diseases, including type I diabetes, multiple sclerosis, rheumatoid arthritis and lupus, are discussed. Additionally, their key regulatory mechanisms for lymphocyte development, tissue barrier function, host metabolism, immunity, autoantibody production, and inflammatory effector and regulatory lymphocytes are discussed. The shared and differential effects of SCFAs on different types and stages of autoimmune diseases are discussed.
Distinct groups of innate lymphoid cells (ILCs) such as ILC1, ILC2, and ILC3 populate the intestine, but how these ILCs develop tissue tropism for this organ is unclear. We report that prior to ...migration to the intestine ILCs first undergo a “switch” in their expression of homing receptors from lymphoid to gut homing receptors. This process is regulated by mucosal dendritic cells and the gut-specific tissue factor retinoic acid (RA). This change in homing receptors is required for long-term population and effector function of ILCs in the intestine. Only ILC1 and ILC3, but not ILC2, undergo the RA-dependent homing receptor switch in gut-associated lymphoid tissues. In contrast, ILC2 acquire gut homing receptors in a largely RA-independent manner during their development in the bone marrow and can migrate directly to the intestine. Thus, distinct programs regulate the migration of ILC subsets to the intestine for regulation of innate immunity.
Display omitted
•Innate lymphoid cells undergo a homing receptor switch to migrate to the gut•This process is regulated by the gut-specific tissue factor retinoic acid•Only ILC1 and ILC3, but not ILC2, undergo the homing receptor switch•ILC2 acquire gut homing receptors during their development in the bone marrow
The intestine is populated with innate lymphoid cells (ILCs) but how these cells acquire tissue tropism is unclear. Kim and colleagues show that group 1 ILCs (ILC1) and ILC3 undergo retinoic-acid-dependent upregulation of trafficking receptors, whereas ILC2 acquire gut homing receptors during development in the bone marrow.
DNA double-strand breaks (DSBs) are the most dangerous type of DNA damage because they can result in the loss of large chromosomal regions. In all mammalian cells, DSBs that occur throughout the cell ...cycle are repaired predominantly by the non-homologous DNA end joining (NHEJ) pathway. Defects in NHEJ result in sensitivity to ionizing radiation and the ablation of lymphocytes. The NHEJ pathway utilizes proteins that recognize, resect, polymerize and ligate the DNA ends in a flexible manner. This flexibility permits NHEJ to function on a wide range of DNA-end configurations, with the resulting repaired DNA junctions often containing mutations. In this Review, we discuss the most recent findings regarding the relative involvement of the different NHEJ proteins in the repair of various DNA-end configurations. We also discuss the shunting of DNA-end repair to the auxiliary pathways of alternative end joining (a-EJ) or single-strand annealing (SSA) and the relevance of these different pathways to human disease.
Perovskite-based solar cells have recently been catapulted to the cutting edge of thin-film photovoltaic research and development because of their promise for high-power conversion efficiencies and ...ease of fabrication. Two types of generic perovskites compounds have been used in cell fabrication: either Pb- or Sn-based. Here, we describe the performance of perovskite solar cells based on alloyed perovskite solid solutions of methylammonium tin iodide and its lead analogue (CH3NH3Sn1–x Pb x I3). We exploit the fact that, the energy band gaps of the mixed Pb/Sn compounds do not follow a linear trend (the Vegard’s law) in between these two extremes of 1.55 and 1.35 eV, respectively, but have narrower bandgap (<1.3 eV), thus extending the light absorption into the near-infrared (∼1,050 nm). A series of solution-processed solid-state photovoltaic devices using a mixture of organic spiro-OMeTAD/lithium bis(trifluoromethylsulfonyl)imide/pyridinium additives as hole transport layer were fabricated and studied as a function of Sn to Pb ratio. Our results show that CH3NH3Sn0.5Pb0.5I3 has the broadest light absorption and highest short-circuit photocurrent density ∼20 mA cm–2 (obtained under simulated full sunlight of 100 mW cm–2).
We examined the number of tropical cyclones and cyclone days as well as tropical cyclone intensity over the past 35 years, in an environment of increasing sea surface temperature. A large increase ...was seen in the number and proportion of hurricanes reaching categories 4 and 5. The largest increase occurred in the North Pacific, Indian, and Southwest Pacific Oceans, and the smallest percentage increase occurred in the North Atlantic Ocean. These increases have taken place while the number of cyclones and cyclone days has decreased in all basins except the North Atlantic during the past decade.
PDF
