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Regulation of humoral immunity by gut microbial products

Regulation of humoral immunity by gut microbial products GUT MICROBES 2017, VOL. 8, NO. 4, 392–399 https://doi.org/10.1080/19490976.2017.1299311 ADDENDUM a a,b,c,d,e Myunghoo Kim and Chang H. Kim a b Laboratory of Immunology and Hematopoiesis, Department of Comparative Pathobiology, Purdue University, West Lafayette, IN, USA; Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN, USA; Department of Biological Sciences, Purdue University, West d e Lafayette, IN, USA; Purdue Institute of Inflammation, Immunology and Infectious Diseases, Purdue University, West Lafayette, IN, USA; Purdue University Center for Cancer Research, Purdue University, West Lafayette, IN, USA ABSTRACT ARTICLE HISTORY Received 10 January 2017 The intestinal tract provides ideal niches for several different microbial species, which are Revised 8 February 2017 collectively called the gut microbiota. A key host immune effector that controls the microbiota and Accepted 16 February 2017 prevents mucosal infection is IgA. Gut microbiota-derived factors are largely classified into molecular pattern recognition receptor ligands and nutrient-derived metabolites including short- KEYWORDS chain fatty acids and adenosine triphosphate. Along with host-derived factors such as retinoic acid, Gut microbiota; humoral various cytokines and cytokine-like molecules, gut microbial products profoundly shape B cell immunity; short-chain fatty responses. Gut microbial products can directly regulate B cell activation and differentiation. They acids; IgA; B cells can also indirectly affect B cells through epithelial cells, T cells, and myeloid cell subsets. We highlight the various direct and indirect mechanisms by which microbial products regulate humoral immunity. Introduction lumen. Secreted host enzymes process dietary materi- The gastrointestinal tract, rich in dietary materials, als in the upper elementary tract, and the bulk of provides ideal niches for a myriad of microbes, which nutrients are absorbed by epithelial cells in the small are called commensal microbiota. Roughly, a thou- intestine. Some of these metabolites have immune- sand of microbial operational taxonomic units regulatory functions. For example, the roles of versa- (OTUs) dominated by the bacteria kingdom are found tile mucosal immune regulators, vitamin A metabo- 1,2 in various niches of the gut, defined by complex gra- lites (i.e. retinoic acids or RA), are well established. dients of chemical, nutritional, and immunological In the colon, the gut microbiota produce a myriad of factors. The gut microbiota provide important health cellular constituents and metabolites. Some of these benefits to the host such as enhanced energy harvest microbial products promote the population and matu- from diet and homeostatic activation of the immune ration of immune cells in gut-associated lymphoid tis- system. Importantly, the members of the gut micro- sues and effector sites such as intestinal lamina propria and intraepithelial compartments. biota and their relative frequencies are finely con- trolled by diet and the host immune system to ensure Gut microbial products include the ligands that mutually beneficial host-microbial symbiosis. This activate pathogen-associated molecular pattern recep- equilibrium can be altered in pathological conditions tors (PAMPRs) and nutrient-derived microbial caused by adverse metabolic, dietary and immunologi- metabolites. Each day, dietary fiber (20–50 g on aver- cal changes in hosts, leading to dysbiosis conditions. A age), protein (5–10 g), fat, and other dietary constitu- key component of the host immune system important ents (vitamins, catechins, tannins, lignin, polyphenols in regulating the microbiota is the mucosal antibody and other micronutrients) pass into the colon for IgA. The intestine has many tissue and immune cell microbial fermentation. As a consequence, various types in various compartments to regulate the produc- metabolites ranging from short-chain fatty acids tion and/or secretion of antibodies into the intestinal (SCFAs) to secondary bile acids and vitamin B12 are CONTACT Chang H. Kim [email protected] VPTH 126, 725 Harrison Street, Purdue University, West Lafayette, IN 47907, USA. Addendum to: Kim M, Qie Y, Park Y, Kim CH. Gut Microbial Metabolites Fuel Host Antibody Responses. Cell Host & Microbe. 2016 Aug 10;20(2):202-14 © 2017 Taylor & Francis GUT MICROBES 393 produced. These metabolites are used by the host and reduced numbers of IgA-producing plasma cells, and gut microbes to maintain nutritional, physiologic and the gut microbiota are required for normal levels of immunological homeostasis. One of the immunologi- class switch recombination (CSR) from IgM to IgA. B cal targets of the microbial factors is the humoral cells, particularly marginal zone (MZ) B cells, are neg- immunity. We highlight here the recent progress in atively affected in certain restricted flora (RF) mice our understanding of roles of SCFAs and other micro- which have altered commensal microbiota. The bial products in regulating humoral immunity. impaired plasma B cell responses in GF or RF animals were restored by conventionalization of the mice. Also, somatic hypermutation and IgA repertoire diver- IgA and commensal bacteria regulate each other sification were greatly suppressed in GF mice. It has IgA is secreted into the human gut lumen at a rate of been shown that certain microbiota, especially Escheri- 40–60 mg/kg/day of weight, which is translated into chia coli and Bifidobacteria, promote B cell matura- several grams of IgA protein per day. Secreted IgA tion. In gnotobiotic mice, SFB colonization increased binds commensal and pathogenic microbes and their the numbers of IgA-producing cells. Our current products including toxins. Generally, 20–50% of gut understanding of the mechanisms by which the gut bacteria are coated with IgA. IgA-coated commensal microbiota regulate IgA production is discussed below. bacteria appear to be more inflammatory than IgA- noncoated bacteria in inducing colitis. IgA coating of General effects of gut microbiota on B cells bacteria can be mediated by either antigen binding domains or glycan moieties of IgA. In general, patho- The gut microbiota influence the activation and differ- gens and pathogenic commensal bacteria induce the entiation of B cells via direct and indirect mechanisms. production of IgA with high affinity antigen-binding B cell activation and differentiation are triggered by domains. Defective IgA production or secretion due activation of B cell receptor (BCR), CD40, Toll-like to loss of function mutations in the genes encoding receptors (TLRs), cytokine receptors (e.g. IL-21R), activation induced cytidine deaminase (AID), IgA or and/or receptors for B-cell activating factor (BAFF) polymeric immunoglobulin receptor (pIgR) leads to and A Proliferation Inducing Ligand (APRIL). T- dysbiosis, bacterial invasion, and inflammatory dis- dependent B cell antibody production is triggered by 5,6 eases. For example, Aicda mutant mice produce IgA activation of BCR, CD40 and IL-21R, which can be with decreased affinity for gut bacteria due to defective further potentiated by BAFF and APRIL signaling. T- somatic hypermutation and have an altered microbial independent B cell antibody production is largely trig- community such as abnormal overgrowth of seg- gered by activation of TLRs and BAFF/APRIL recep- mented filamentous bacteria (SFB) in the upper small tors. The gut microbiota produce protein and intestine. IgA coating induces immune exclusion of carbohydrate antigens that activate BCR. Also, many gut microbes via agglutination, microbial entrapment microbial products activate TLRs and NOD-like in mucus, and peristalsis-mediated clearance. IgA receptors (NLRs). B cells express TLR1, 2, 4, 6, 7, and coating interferes with the attachment of pathogenic 9, and activation of these TLRs increase B cell survival, microbes and their products to the intestinal epithelial antigen presentation, and antibody production. In surface, thus decreasing their pathogenicity, as evi- steady-states, the gut microbiota produce TLR ligands denced by IgA binding-mediated inhibition of shigella that activate B cells. For example, low levels of lipopo- type 3-secretion (T3S) system. IgA also facilitates the lysaccharides from gram-negative bacteria activate B engulfment of pathogens by Peyer’s patch M cells and cells to induce CSR of the immunoglobulin (Ig) heavy phagocytes, such as neutrophils, dendritic cells and chain gene to produce IgA. Interestingly, the gut macrophages, to mount effective local immune microbiota also increase the number of regulatory B 8-10 responses to pathogens. cells (Bregs), which have anti-inflammatory functions. Gut microbiota induce the development of gut- Gut microbiota colonization induces the production associated lymphoid tissues (GALT), such as isolated of IL-1b and IL-6 by dendritic cells (DCs) and tissue lymphoid follicle (ILF) and Peyer’spatches (PPs), cells to promote na€ ıve B cell differentiation into Bregs which are major inductive sites for IgA-producing in mesenteric lymph node (MLN). Bregs produce plasma B cells. Germ-free (GF) animals have IL-10 to suppress inflammatory T cells and tissue 394 M. KIM AND C. H. KIM inflammation. Thus, the microbiota can exert various increase cellular levels of acetyl-CoA and energy (e.g., effects on B cells beyond antibody production. ATP) and lipid biogenesis to drive plasma B cell differen- tiation. SCFAs are efficient histone deacetylase Impact of gut microbiota on B cell metabolism (HDAC) inhibitors, and this function boosts the expres- sion of genes such as Xbp-1, Aicda and Prdm1,involved Mammals use a significant portion of available energy in plasma B cell differentiation. Activation of the mTOR and metabolic building blocks to maintain immune cells. pathway increases glycolysis in B cells. SCFAs increase In this regard, production of antibodies by B cells is a the level of ATP but decrease that of adenosine mono- metabolically demanding process. Lymphocytes metabo- phosphate (AMP), which is the agonist of 5 AMP-acti- lize nutrients for energy (e.g., Adenosine Triphosphate, vated protein kinase (AMPK). Thus, SCFAs inhibit ATP) production, biogenesis of cellular building blocks, AMPK, and this leads to activation of the mTOR path- and production of effector molecules such as antibodies way. Lipidbiogenesisisimportant forplasmaBcelldif- and cytokines. Glucose, along with fatty acids and amino ferentiation. In this regard, dietary palmitic acid acids, provides the bulk of required energy and building enhances intestinal IgA responses. Additionally, the blocks for B cells. Upon activation of BCR or TLR4, B roles of Retinaldehyde Dehydrogenase 2 (RALDH2)- cells undergo both glycolysis and mitochondrial oxidative expressing mucosal DCs in inducing IgA responses have phosphorylation via a c-Myc dependent pathway. In 25,27 been suggested. Interestingly, it is not just intestinal contrast, activated T cells mainly utilize glycolysis to IgA but also systemic IgG responses that are supported become effector T cells. Both glycolysis and oxidative by SCFAs. We will discuss the roles of non-B cells in phosphorylation are required for B cell activation and mediating the regulatory effects of the gut microbiota on plasma cell differentiation. Increased cell metabolism B cells responses in the next section. generates higher levels of cellular ATP, some of which is secreted out of cells. Necrotic cells also leak ATP into tis- Indirect mechanisms of B cell regulation by sue environments. Moreover, the gut microbiota them- microbiota: Role of epithelial cells selves produce ATP. Extracellular ATP, produced by Intestinal epithelial cells provide not only a physical host and microbes, activates purinergic P2X and P2Y of barrier between the gut microbiota and host tissues colonic DCs to produce IL-6 and TGF-b, which can but actively detect invading microbes and initiate promote CSR for IgA production. Secreted extracellular immune responses. The intestinal epithelial cells use ATP is hydrolyzed eventually to adenosine by host and various PAMPRs to monitor the luminal environment microbial ectonucleotidases. The resulting product, aden- for the presence of pathogenic versus non-pathogenic osine, can activate adenosine receptors on B cells to pro- microbial signals. When triggered by microbial mote Ig gene CSR to produce IgG and IgA (Fig. 1). PAMPR ligands, epithelial cells produce acute inflam- matory cytokines and chemokines to recruit and acti- Regulation of antibody production by SCFAs vate immune cells. To regulate B cells, epithelial cells The gut microbiota process dietary materials and intes- produce B cell-activating or attracting molecules such tine-derived host products such as mucins to produce as IL-6, BAFF, APRIL, CCL20, CCL28, and thymic diverse metabolites. SCFAs, produced from dietary fiber stromal lymphopoietin (TSLP) (Fig. 2). We found that (DF), are the most abundant microbial metabolites in the SCFAs activate gut epithelial cells through SCFA gut. Recently, we reported that SCFAs support plasma B receptors, GPR41 and GPR43, and this activation cell differentiation. SCFA deficiency occurs when DF makes epithelial cells highly efficient in producing levels in diet are low or when the microbiota are sup- inflammatory mediators upon TLR4 activation. pressed by antibiotics or altered due to dysbiosis. In GF TSLP, produced by gut epithelial cells upon TLR acti- mice, the SCFA levels in the colon are decreased to about vation, activates a specialized DC subset that produces one percent of normal levels. In low SCFA conditions TNF-a and iNOS. These DC products induce the due to low DF consumption, serum antibody and muco- expression of APRIL and IL-10, which in turn induce 23,25 sal IgA levels are significantly decreased. Germinal CSR in B cells to produce IgA. Moreover, the develop- center responses in PPs are suppressed in low SCFA con- ment of lymphoid tissue inducer (LTi) cells, a subset ditions but SCFA administration restored antibody pro- of group 3 innate lymphoid cells (ILC3), requires the duction in mice fed a DF-free diet (Fig. 1). SCFAs gut microbiota. LTi cells express LTa1b2 to activate GUT MICROBES 395 Figure 1. Regulation of B cells by microbial products. The gut microbiota generate a wide variety of products that can activate BCR and TLRs. This activation triggers B cell differentiation into plasma B cells. Moreover, gut microbial metabolites such as SCFAs play important roles by serving as nutrients for B cells undergoing activation. SCFAs inhibit HDACs to facilitate gene expression, and this supports plasma B cell differentiation. At the same time, SCFAs are converted into acetyl-CoA which fuels mitochondrial oxidative phosphoryla- tion and fatty acid synthesis. Moreover, The SCFA effect on B cells increases ATP levels but decreases that of AMP (the AMPK ligand), leading to sustained mTOR activation. This boosts glycolysis in B cells for further providing essential energy and building blocks. These events promote plasma B cell generation and increased production of antibodies particularly IgA, which plays a central role in maintain- ing the host-microbial symbiosis. Abbreviations: ATP, adenosine triphosphate; AMP, adenosine monophosphate; AMPK, AMP-activated protein kinase; BCR, B cell receptor; CSR, class switch recombination; HDAC, histone deacetylase; mTOR, mammalian target of rapamycin; NF-kB, nuclear factor kappa-light-chain-enhancer of activated B cells; PC, plasma cells; SCFA, short-chain fatty acid; TF, transcription fac- tor; TLR, toll-like receptor. stromal cells to produce TGFb, which acts on B cells Tregs may either positively or negatively affect B cell to promote IgA production. Thus, gut microbial fac- responses. T follicular helper (Tfh) cells positively regu- tors activate epithelial cells to produce B cell-activat- late plasma B cell differentiation in lymphoid follicles. ing factors in steady-states. Tfh cells activate B cells with CD40L and inducible co- stimulator (ICOS) along with various cytokines such as IL-21, IL-4, IL-10, and IFNg. The gut microbiota pro- Indirect mechanisms of B cell regulation by mote Tfh cell development in the intestine. Tfh cell microbiota: Role of T cells development is deficient in GF mice and can be Depending on functional specialization, T cells either restored by administration of TLR2 ligands in a positively or negatively regulate B cell differentiation MyD88 signaling-dependent manner. T-cell specific into plasma B cells. While at lower than the TLR deletion of MyD88 decreased high-affinity IgA binding expression levels of phagocytes and DCs, T cell subsets, of the microbiota, resulting in microbial dysbiosis. such as Tregs, express TLRs and sense microbial prod- Some FoxP3 T cells can differentiate into Tfh cells in ucts. Forexample,TLRs(TLR2,4,5,7,and 8) are PPs to promote, rather than suppress, antibody produc- C C 33 expressed by CD4 CD25 T regulatory cells (Tregs), tion, which can shift the local immunological balance and TLR2 ligands can expand the number of from immune tolerance toward activation during infec- C C 31 CD4 CD25 Tregs. The effects of TLR activation on tion. SCFAs increase the Treg pool in the MLN by 396 M. KIM AND C. H. KIM Figure 2. Indirect regulation of B cells by gut microbial products through various non-B cell types. In inductive sites such as PPs, epithe- lial cells actively sample antigens and microbial products for homeostatic activation of immune cells such as T cells, macrophages and DCs. Microbial products stimulate DCs and FDCs to produce immune regulatory molecules that activate T cells and B cells. Key molecules that are produced include TGFb1, IL-10, IL-6, and IL-21, which collectively induce Tfh cell generation and facilitate B cell activation and differentiation into IgA-producing B cells. Retinoic acid (RA), produced by mucosal epithelial cells and DCs, skews B cell differentiation into IgA-producing cells. In effector sites such as intestinal lamina propria (LP), microbial factors activate lymphocytes, eosinophils, mac- rophages, DCs, ILCs, and tissue stromal cells. Host cells that are activated by microbial factors produce chemokines, cytokines and other molecules such as CCL20, CCL28, IL-10, BAFF, APRIL, IL-6, TGFb1, and TNFa to promote IgA production by B cells. The B cell-activating molecules and cell types that are activated by microbial factors affect most B cell types including B2, MZ and B1 cells. Abbreviations: APRIL, A Proliferation Inducing Ligand; BAFF, B-cell Activating Factor; Breg, Regulatory B cells; DC, dendritic cell; Eos, eosinophils; FDC, follicular DC; GALT, gut-associated lymphoid tissue; ILCs, innate lymphoid cells; iNOS, Inducible Nitric Oxide Synthase; LP, lamina propria; LTi, lymphoid tissue inducer; Mac, macrophage; MMPs, matrix metalloproteinases; RA, retinoic acid; TLR/NOD, toll-like receptor/NOD-like receptor; Tfh, T follicular helper cells; Tfr, T follicular regulatory cells; Treg, T regulatory cells; TSLP, Thymic Stromal Lymphopoietin. 34 35,36 HDAC inhibition-mediated FoxP3 expression. In line and other B cell-activating molecules. TLR activa- with this, SCFAs increase Tfh cell differentiation in tion also enhances follicular dendritic cells (FDCs) to vitro via metabolic regulation. Thus, microbial prod- activate B cells by secreting BAFF, APRIL, and TGF- ucts support B cell-regulating T cells. b1 Moreover, SCFAs up-regulate RALDH2 in DCs to increase RA production. Thus, it is possible that RA produced by SCFA-activated DCs can promote IgA- Indirect mechanisms of B cell regulation by producing plasma B cells. RA is produced mainly in microbiota: Roles of myeloid cell populations the small intestine, whereas SCFAs are mainly pro- 25,27 DCs produce cytokines and present antigens to T cells, duced in the colon. Therefore, this pathway is and this function is also required to generate Tfh and likely to be effective mainly in MLN which drains T follicular regulatory (Tfr) cells. DCs express several metabolites from both small and large intestines rather TLRs and are activated by TLR ligands. DCs sense than in effector sites of the intestines where SCFAs microbial products not only within tissues but also in and RA are produced in different locations. the gut lumen using their membrane extensions across SCFAs activate GPCRs such as GPR41, GPR43 and the epithelial barrier. DCs also directly activate B cells GP109A. Myeloid cells, such as neutrophils, macro- with cytokines and cell-surface ligands (e.g., BAFF phages and DCs, variably express GPR43 and GP109A. and APRIL). Therefore, the effect of microbial prod- Therefore, SCFAs have the potential to indirectly regulate ucts on DCs can indirectly regulate B cell activation B cells through myeloid cells. For example, SCFAs 38,39 and differentiation. For example, MyD88 is required increase IL-10 production by macrophages and DCs. for DCs to enhance antibody responses by enhancing via either SCFA-receptor signaling or HDAC inhibition the production of cytokines (IL-6, IL-10 and TGFb1) (Fig. 1). RA and IL-10, produced from SCFA-regulated GUT MICROBES 397 myeloid cells, can promote antibody production, particu- microbiota produce many factors that activate B and larly IgA. In contrast, T and B cells do not significantly non-B cell types. A major group of microbial factors express SCFA receptors. important for B cell regulation includes TLR and Eosinophils, abundant in the intestinal lamina related microbial PAMPR ligands. Another emerging propria, sense microbial signals and regulate B cells. group of microbial factors important for mucosal anti- Eosinophils, when activated by commensal bacterial body production includes microbial metabolites such products, produce various B cell-activating molecules, as SCFAs and ATP. SCFAs exert their functions such as BAFF, APRIL, IL-6 and matrix metalloprotei- through GPCR receptors primarily expressed by epi- nase 9 (MMP9), which can promote the differentia- thelial cells and some myeloid cells. Also, SCFAs are tion and survival of IgA plasma cells. Eosinophil- integrated into cellular metabolism following their deficient mice (DdblGATA-1 and PHIL mice) have conversion to acetyl-CoA, and this greatly affects the reduced numbers of IgA plasma cells but increased cellular metabolism in T and B cells. Because SCFAs numbers of IgG1 cells in PPs. Eosinophil-deficient work through several different pathways in SCFA mice also have decreased numbers of CD103 DC receptor-dependent and independent pathways in and Tregs but increased production of Th2 cytokines many cell types, it is not easy to determine the func- (IL-4 and IL-5) by Tfh cells in PPs The gut micro- tional significance of individual pathways in vivo. biota activate epithelial cells for production of IL-25, More studies are required in the future to dissect the which in turn activates eosinophils. For example, Tri- functions of SCFAs and other metabolites in regulat- trichomonas muris, a symbiotic protozoon in mice, ing B cell responses. It appears that these microbial induces IL-25 production by specialized epithelial cells metabolites not only affect the immune cells in the called Tuft cells. Tuft cell-derived IL-25 mounts a type intestine but also the cells in systemic sites and organs. 2 innate lymphoid cell (ILC2) response and produce This is because microbial metabolites can be trans- IL-5 and IL-13, which can increase eosinophil ported through the blood circulation. Whether anti- responses and affect B cell responses in the gut. body responses to specific pathogens are effectively Antibodies are produced by several B cell types includ- supported by any of the metabolites is an important ingB2, B1 andmarginalzone(MZ)Bcells.TLR ligands question to answer. More studies are needed to estab- activate TLRs of B1 and MZ B cells for antibody produc- lish the roles of these microbial metabolites in regulat- tion. IFN-g and type I IFNs are produced following TLR ing antibody-mediated inflammatory diseases such as activation, and these cytokines promote the production lupus and rheumatoid arthritis. Moreover, it is impor- of antigen-specific antibodies (IgG2c, IgG2a and IgM) by tant to devise strategies to prevent infection and MZ B cells. Microbial products activate neutrophils to enhance immunity using the B cell-helping microbial regulate B cells. For example, the neutrophils that reside factors. in the peri-MZ of the spleen support MZ B cells. The microbiota are required for colonization of neutrophils Disclosure of potential conflicts of interest in the peri-MZ and their maturation into B cell-helping No potential conflicts of interest were disclosed. neutrophils. These neutrophils produce BAFF, APRIL and IL-21 to induce T-independent antibody responses to type 2 thymus-independent (TI-2) antigens such as Funding bacterial capsular antigens. Thus, many cell types mediate This study was supported, in part, from grants from NIH the regulatory effects of the gut microbiota on B cells. (R01AI121302 and R01AI080769) to CHK. Conclusions and questions References IgA is a key regulator of the gut microbiota. We have [1] Kim CH. Retinoic acid, immunity, and inflammation. witnessed a significant progress in our understanding Vitam Horm 2011; 86:83-101; PMID:21419268 of the diverse functions of gut host and microbial fac- [2] Larange A, Cheroutre H. Retinoic acid and retinoic acid tors in regulating IgA production. There are many receptors as pleiotropic modulators of the immune system. direct and indirect mechanisms by which the gut Ann Rev Immunol 2016; 34:369-94; PMID:27168242; microbiota regulate antibody production. 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Regulation of humoral immunity by gut microbial products

Kim, Myunghoo; Kim, Chang H.
Gut Microbes , Volume 8 (4): 8 – Jul 4, 2017
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1949-0984
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1949-0976
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10.1080/19490976.2017.1299311
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Abstract

GUT MICROBES 2017, VOL. 8, NO. 4, 392–399 https://doi.org/10.1080/19490976.2017.1299311 ADDENDUM a a,b,c,d,e Myunghoo Kim and Chang H. Kim a b Laboratory of Immunology and Hematopoiesis, Department of Comparative Pathobiology, Purdue University, West Lafayette, IN, USA; Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN, USA; Department of Biological Sciences, Purdue University, West d e Lafayette, IN, USA; Purdue Institute of Inflammation, Immunology and Infectious Diseases, Purdue University, West Lafayette, IN, USA; Purdue University Center for Cancer Research, Purdue University, West Lafayette, IN, USA ABSTRACT ARTICLE HISTORY Received 10 January 2017 The intestinal tract provides ideal niches for several different microbial species, which are Revised 8 February 2017 collectively called the gut microbiota. A key host immune effector that controls the microbiota and Accepted 16 February 2017 prevents mucosal infection is IgA. Gut microbiota-derived factors are largely classified into molecular pattern recognition receptor ligands and nutrient-derived metabolites including short- KEYWORDS chain fatty acids and adenosine triphosphate. Along with host-derived factors such as retinoic acid, Gut microbiota; humoral various cytokines and cytokine-like molecules, gut microbial products profoundly shape B cell immunity; short-chain fatty responses. Gut microbial products can directly regulate B cell activation and differentiation. They acids; IgA; B cells can also indirectly affect B cells through epithelial cells, T cells, and myeloid cell subsets. We highlight the various direct and indirect mechanisms by which microbial products regulate humoral immunity. Introduction lumen. Secreted host enzymes process dietary materi- The gastrointestinal tract, rich in dietary materials, als in the upper elementary tract, and the bulk of provides ideal niches for a myriad of microbes, which nutrients are absorbed by epithelial cells in the small are called commensal microbiota. Roughly, a thou- intestine. Some of these metabolites have immune- sand of microbial operational taxonomic units regulatory functions. For example, the roles of versa- (OTUs) dominated by the bacteria kingdom are found tile mucosal immune regulators, vitamin A metabo- 1,2 in various niches of the gut, defined by complex gra- lites (i.e. retinoic acids or RA), are well established. dients of chemical, nutritional, and immunological In the colon, the gut microbiota produce a myriad of factors. The gut microbiota provide important health cellular constituents and metabolites. Some of these benefits to the host such as enhanced energy harvest microbial products promote the population and matu- from diet and homeostatic activation of the immune ration of immune cells in gut-associated lymphoid tis- system. Importantly, the members of the gut micro- sues and effector sites such as intestinal lamina propria and intraepithelial compartments. biota and their relative frequencies are finely con- trolled by diet and the host immune system to ensure Gut microbial products include the ligands that mutually beneficial host-microbial symbiosis. This activate pathogen-associated molecular pattern recep- equilibrium can be altered in pathological conditions tors (PAMPRs) and nutrient-derived microbial caused by adverse metabolic, dietary and immunologi- metabolites. Each day, dietary fiber (20–50 g on aver- cal changes in hosts, leading to dysbiosis conditions. A age), protein (5–10 g), fat, and other dietary constitu- key component of the host immune system important ents (vitamins, catechins, tannins, lignin, polyphenols in regulating the microbiota is the mucosal antibody and other micronutrients) pass into the colon for IgA. The intestine has many tissue and immune cell microbial fermentation. As a consequence, various types in various compartments to regulate the produc- metabolites ranging from short-chain fatty acids tion and/or secretion of antibodies into the intestinal (SCFAs) to secondary bile acids and vitamin B12 are CONTACT Chang H. Kim [email protected] VPTH 126, 725 Harrison Street, Purdue University, West Lafayette, IN 47907, USA. Addendum to: Kim M, Qie Y, Park Y, Kim CH. Gut Microbial Metabolites Fuel Host Antibody Responses. Cell Host & Microbe. 2016 Aug 10;20(2):202-14 © 2017 Taylor & Francis GUT MICROBES 393 produced. These metabolites are used by the host and reduced numbers of IgA-producing plasma cells, and gut microbes to maintain nutritional, physiologic and the gut microbiota are required for normal levels of immunological homeostasis. One of the immunologi- class switch recombination (CSR) from IgM to IgA. B cal targets of the microbial factors is the humoral cells, particularly marginal zone (MZ) B cells, are neg- immunity. We highlight here the recent progress in atively affected in certain restricted flora (RF) mice our understanding of roles of SCFAs and other micro- which have altered commensal microbiota. The bial products in regulating humoral immunity. impaired plasma B cell responses in GF or RF animals were restored by conventionalization of the mice. Also, somatic hypermutation and IgA repertoire diver- IgA and commensal bacteria regulate each other sification were greatly suppressed in GF mice. It has IgA is secreted into the human gut lumen at a rate of been shown that certain microbiota, especially Escheri- 40–60 mg/kg/day of weight, which is translated into chia coli and Bifidobacteria, promote B cell matura- several grams of IgA protein per day. Secreted IgA tion. In gnotobiotic mice, SFB colonization increased binds commensal and pathogenic microbes and their the numbers of IgA-producing cells. Our current products including toxins. Generally, 20–50% of gut understanding of the mechanisms by which the gut bacteria are coated with IgA. IgA-coated commensal microbiota regulate IgA production is discussed below. bacteria appear to be more inflammatory than IgA- noncoated bacteria in inducing colitis. IgA coating of General effects of gut microbiota on B cells bacteria can be mediated by either antigen binding domains or glycan moieties of IgA. In general, patho- The gut microbiota influence the activation and differ- gens and pathogenic commensal bacteria induce the entiation of B cells via direct and indirect mechanisms. production of IgA with high affinity antigen-binding B cell activation and differentiation are triggered by domains. Defective IgA production or secretion due activation of B cell receptor (BCR), CD40, Toll-like to loss of function mutations in the genes encoding receptors (TLRs), cytokine receptors (e.g. IL-21R), activation induced cytidine deaminase (AID), IgA or and/or receptors for B-cell activating factor (BAFF) polymeric immunoglobulin receptor (pIgR) leads to and A Proliferation Inducing Ligand (APRIL). T- dysbiosis, bacterial invasion, and inflammatory dis- dependent B cell antibody production is triggered by 5,6 eases. For example, Aicda mutant mice produce IgA activation of BCR, CD40 and IL-21R, which can be with decreased affinity for gut bacteria due to defective further potentiated by BAFF and APRIL signaling. T- somatic hypermutation and have an altered microbial independent B cell antibody production is largely trig- community such as abnormal overgrowth of seg- gered by activation of TLRs and BAFF/APRIL recep- mented filamentous bacteria (SFB) in the upper small tors. The gut microbiota produce protein and intestine. IgA coating induces immune exclusion of carbohydrate antigens that activate BCR. Also, many gut microbes via agglutination, microbial entrapment microbial products activate TLRs and NOD-like in mucus, and peristalsis-mediated clearance. IgA receptors (NLRs). B cells express TLR1, 2, 4, 6, 7, and coating interferes with the attachment of pathogenic 9, and activation of these TLRs increase B cell survival, microbes and their products to the intestinal epithelial antigen presentation, and antibody production. In surface, thus decreasing their pathogenicity, as evi- steady-states, the gut microbiota produce TLR ligands denced by IgA binding-mediated inhibition of shigella that activate B cells. For example, low levels of lipopo- type 3-secretion (T3S) system. IgA also facilitates the lysaccharides from gram-negative bacteria activate B engulfment of pathogens by Peyer’s patch M cells and cells to induce CSR of the immunoglobulin (Ig) heavy phagocytes, such as neutrophils, dendritic cells and chain gene to produce IgA. Interestingly, the gut macrophages, to mount effective local immune microbiota also increase the number of regulatory B 8-10 responses to pathogens. cells (Bregs), which have anti-inflammatory functions. Gut microbiota induce the development of gut- Gut microbiota colonization induces the production associated lymphoid tissues (GALT), such as isolated of IL-1b and IL-6 by dendritic cells (DCs) and tissue lymphoid follicle (ILF) and Peyer’spatches (PPs), cells to promote na€ ıve B cell differentiation into Bregs which are major inductive sites for IgA-producing in mesenteric lymph node (MLN). Bregs produce plasma B cells. Germ-free (GF) animals have IL-10 to suppress inflammatory T cells and tissue 394 M. KIM AND C. H. KIM inflammation. Thus, the microbiota can exert various increase cellular levels of acetyl-CoA and energy (e.g., effects on B cells beyond antibody production. ATP) and lipid biogenesis to drive plasma B cell differen- tiation. SCFAs are efficient histone deacetylase Impact of gut microbiota on B cell metabolism (HDAC) inhibitors, and this function boosts the expres- sion of genes such as Xbp-1, Aicda and Prdm1,involved Mammals use a significant portion of available energy in plasma B cell differentiation. Activation of the mTOR and metabolic building blocks to maintain immune cells. pathway increases glycolysis in B cells. SCFAs increase In this regard, production of antibodies by B cells is a the level of ATP but decrease that of adenosine mono- metabolically demanding process. Lymphocytes metabo- phosphate (AMP), which is the agonist of 5 AMP-acti- lize nutrients for energy (e.g., Adenosine Triphosphate, vated protein kinase (AMPK). Thus, SCFAs inhibit ATP) production, biogenesis of cellular building blocks, AMPK, and this leads to activation of the mTOR path- and production of effector molecules such as antibodies way. Lipidbiogenesisisimportant forplasmaBcelldif- and cytokines. Glucose, along with fatty acids and amino ferentiation. In this regard, dietary palmitic acid acids, provides the bulk of required energy and building enhances intestinal IgA responses. Additionally, the blocks for B cells. Upon activation of BCR or TLR4, B roles of Retinaldehyde Dehydrogenase 2 (RALDH2)- cells undergo both glycolysis and mitochondrial oxidative expressing mucosal DCs in inducing IgA responses have phosphorylation via a c-Myc dependent pathway. In 25,27 been suggested. Interestingly, it is not just intestinal contrast, activated T cells mainly utilize glycolysis to IgA but also systemic IgG responses that are supported become effector T cells. Both glycolysis and oxidative by SCFAs. We will discuss the roles of non-B cells in phosphorylation are required for B cell activation and mediating the regulatory effects of the gut microbiota on plasma cell differentiation. Increased cell metabolism B cells responses in the next section. generates higher levels of cellular ATP, some of which is secreted out of cells. Necrotic cells also leak ATP into tis- Indirect mechanisms of B cell regulation by sue environments. Moreover, the gut microbiota them- microbiota: Role of epithelial cells selves produce ATP. Extracellular ATP, produced by Intestinal epithelial cells provide not only a physical host and microbes, activates purinergic P2X and P2Y of barrier between the gut microbiota and host tissues colonic DCs to produce IL-6 and TGF-b, which can but actively detect invading microbes and initiate promote CSR for IgA production. Secreted extracellular immune responses. The intestinal epithelial cells use ATP is hydrolyzed eventually to adenosine by host and various PAMPRs to monitor the luminal environment microbial ectonucleotidases. The resulting product, aden- for the presence of pathogenic versus non-pathogenic osine, can activate adenosine receptors on B cells to pro- microbial signals. When triggered by microbial mote Ig gene CSR to produce IgG and IgA (Fig. 1). PAMPR ligands, epithelial cells produce acute inflam- matory cytokines and chemokines to recruit and acti- Regulation of antibody production by SCFAs vate immune cells. To regulate B cells, epithelial cells The gut microbiota process dietary materials and intes- produce B cell-activating or attracting molecules such tine-derived host products such as mucins to produce as IL-6, BAFF, APRIL, CCL20, CCL28, and thymic diverse metabolites. SCFAs, produced from dietary fiber stromal lymphopoietin (TSLP) (Fig. 2). We found that (DF), are the most abundant microbial metabolites in the SCFAs activate gut epithelial cells through SCFA gut. Recently, we reported that SCFAs support plasma B receptors, GPR41 and GPR43, and this activation cell differentiation. SCFA deficiency occurs when DF makes epithelial cells highly efficient in producing levels in diet are low or when the microbiota are sup- inflammatory mediators upon TLR4 activation. pressed by antibiotics or altered due to dysbiosis. In GF TSLP, produced by gut epithelial cells upon TLR acti- mice, the SCFA levels in the colon are decreased to about vation, activates a specialized DC subset that produces one percent of normal levels. In low SCFA conditions TNF-a and iNOS. These DC products induce the due to low DF consumption, serum antibody and muco- expression of APRIL and IL-10, which in turn induce 23,25 sal IgA levels are significantly decreased. Germinal CSR in B cells to produce IgA. Moreover, the develop- center responses in PPs are suppressed in low SCFA con- ment of lymphoid tissue inducer (LTi) cells, a subset ditions but SCFA administration restored antibody pro- of group 3 innate lymphoid cells (ILC3), requires the duction in mice fed a DF-free diet (Fig. 1). SCFAs gut microbiota. LTi cells express LTa1b2 to activate GUT MICROBES 395 Figure 1. Regulation of B cells by microbial products. The gut microbiota generate a wide variety of products that can activate BCR and TLRs. This activation triggers B cell differentiation into plasma B cells. Moreover, gut microbial metabolites such as SCFAs play important roles by serving as nutrients for B cells undergoing activation. SCFAs inhibit HDACs to facilitate gene expression, and this supports plasma B cell differentiation. At the same time, SCFAs are converted into acetyl-CoA which fuels mitochondrial oxidative phosphoryla- tion and fatty acid synthesis. Moreover, The SCFA effect on B cells increases ATP levels but decreases that of AMP (the AMPK ligand), leading to sustained mTOR activation. This boosts glycolysis in B cells for further providing essential energy and building blocks. These events promote plasma B cell generation and increased production of antibodies particularly IgA, which plays a central role in maintain- ing the host-microbial symbiosis. Abbreviations: ATP, adenosine triphosphate; AMP, adenosine monophosphate; AMPK, AMP-activated protein kinase; BCR, B cell receptor; CSR, class switch recombination; HDAC, histone deacetylase; mTOR, mammalian target of rapamycin; NF-kB, nuclear factor kappa-light-chain-enhancer of activated B cells; PC, plasma cells; SCFA, short-chain fatty acid; TF, transcription fac- tor; TLR, toll-like receptor. stromal cells to produce TGFb, which acts on B cells Tregs may either positively or negatively affect B cell to promote IgA production. Thus, gut microbial fac- responses. T follicular helper (Tfh) cells positively regu- tors activate epithelial cells to produce B cell-activat- late plasma B cell differentiation in lymphoid follicles. ing factors in steady-states. Tfh cells activate B cells with CD40L and inducible co- stimulator (ICOS) along with various cytokines such as IL-21, IL-4, IL-10, and IFNg. The gut microbiota pro- Indirect mechanisms of B cell regulation by mote Tfh cell development in the intestine. Tfh cell microbiota: Role of T cells development is deficient in GF mice and can be Depending on functional specialization, T cells either restored by administration of TLR2 ligands in a positively or negatively regulate B cell differentiation MyD88 signaling-dependent manner. T-cell specific into plasma B cells. While at lower than the TLR deletion of MyD88 decreased high-affinity IgA binding expression levels of phagocytes and DCs, T cell subsets, of the microbiota, resulting in microbial dysbiosis. such as Tregs, express TLRs and sense microbial prod- Some FoxP3 T cells can differentiate into Tfh cells in ucts. Forexample,TLRs(TLR2,4,5,7,and 8) are PPs to promote, rather than suppress, antibody produc- C C 33 expressed by CD4 CD25 T regulatory cells (Tregs), tion, which can shift the local immunological balance and TLR2 ligands can expand the number of from immune tolerance toward activation during infec- C C 31 CD4 CD25 Tregs. The effects of TLR activation on tion. SCFAs increase the Treg pool in the MLN by 396 M. KIM AND C. H. KIM Figure 2. Indirect regulation of B cells by gut microbial products through various non-B cell types. In inductive sites such as PPs, epithe- lial cells actively sample antigens and microbial products for homeostatic activation of immune cells such as T cells, macrophages and DCs. Microbial products stimulate DCs and FDCs to produce immune regulatory molecules that activate T cells and B cells. Key molecules that are produced include TGFb1, IL-10, IL-6, and IL-21, which collectively induce Tfh cell generation and facilitate B cell activation and differentiation into IgA-producing B cells. Retinoic acid (RA), produced by mucosal epithelial cells and DCs, skews B cell differentiation into IgA-producing cells. In effector sites such as intestinal lamina propria (LP), microbial factors activate lymphocytes, eosinophils, mac- rophages, DCs, ILCs, and tissue stromal cells. Host cells that are activated by microbial factors produce chemokines, cytokines and other molecules such as CCL20, CCL28, IL-10, BAFF, APRIL, IL-6, TGFb1, and TNFa to promote IgA production by B cells. The B cell-activating molecules and cell types that are activated by microbial factors affect most B cell types including B2, MZ and B1 cells. Abbreviations: APRIL, A Proliferation Inducing Ligand; BAFF, B-cell Activating Factor; Breg, Regulatory B cells; DC, dendritic cell; Eos, eosinophils; FDC, follicular DC; GALT, gut-associated lymphoid tissue; ILCs, innate lymphoid cells; iNOS, Inducible Nitric Oxide Synthase; LP, lamina propria; LTi, lymphoid tissue inducer; Mac, macrophage; MMPs, matrix metalloproteinases; RA, retinoic acid; TLR/NOD, toll-like receptor/NOD-like receptor; Tfh, T follicular helper cells; Tfr, T follicular regulatory cells; Treg, T regulatory cells; TSLP, Thymic Stromal Lymphopoietin. 34 35,36 HDAC inhibition-mediated FoxP3 expression. In line and other B cell-activating molecules. TLR activa- with this, SCFAs increase Tfh cell differentiation in tion also enhances follicular dendritic cells (FDCs) to vitro via metabolic regulation. Thus, microbial prod- activate B cells by secreting BAFF, APRIL, and TGF- ucts support B cell-regulating T cells. b1 Moreover, SCFAs up-regulate RALDH2 in DCs to increase RA production. Thus, it is possible that RA produced by SCFA-activated DCs can promote IgA- Indirect mechanisms of B cell regulation by producing plasma B cells. RA is produced mainly in microbiota: Roles of myeloid cell populations the small intestine, whereas SCFAs are mainly pro- 25,27 DCs produce cytokines and present antigens to T cells, duced in the colon. Therefore, this pathway is and this function is also required to generate Tfh and likely to be effective mainly in MLN which drains T follicular regulatory (Tfr) cells. DCs express several metabolites from both small and large intestines rather TLRs and are activated by TLR ligands. DCs sense than in effector sites of the intestines where SCFAs microbial products not only within tissues but also in and RA are produced in different locations. the gut lumen using their membrane extensions across SCFAs activate GPCRs such as GPR41, GPR43 and the epithelial barrier. DCs also directly activate B cells GP109A. Myeloid cells, such as neutrophils, macro- with cytokines and cell-surface ligands (e.g., BAFF phages and DCs, variably express GPR43 and GP109A. and APRIL). Therefore, the effect of microbial prod- Therefore, SCFAs have the potential to indirectly regulate ucts on DCs can indirectly regulate B cell activation B cells through myeloid cells. For example, SCFAs 38,39 and differentiation. For example, MyD88 is required increase IL-10 production by macrophages and DCs. for DCs to enhance antibody responses by enhancing via either SCFA-receptor signaling or HDAC inhibition the production of cytokines (IL-6, IL-10 and TGFb1) (Fig. 1). RA and IL-10, produced from SCFA-regulated GUT MICROBES 397 myeloid cells, can promote antibody production, particu- microbiota produce many factors that activate B and larly IgA. In contrast, T and B cells do not significantly non-B cell types. A major group of microbial factors express SCFA receptors. important for B cell regulation includes TLR and Eosinophils, abundant in the intestinal lamina related microbial PAMPR ligands. Another emerging propria, sense microbial signals and regulate B cells. group of microbial factors important for mucosal anti- Eosinophils, when activated by commensal bacterial body production includes microbial metabolites such products, produce various B cell-activating molecules, as SCFAs and ATP. SCFAs exert their functions such as BAFF, APRIL, IL-6 and matrix metalloprotei- through GPCR receptors primarily expressed by epi- nase 9 (MMP9), which can promote the differentia- thelial cells and some myeloid cells. Also, SCFAs are tion and survival of IgA plasma cells. Eosinophil- integrated into cellular metabolism following their deficient mice (DdblGATA-1 and PHIL mice) have conversion to acetyl-CoA, and this greatly affects the reduced numbers of IgA plasma cells but increased cellular metabolism in T and B cells. Because SCFAs numbers of IgG1 cells in PPs. Eosinophil-deficient work through several different pathways in SCFA mice also have decreased numbers of CD103 DC receptor-dependent and independent pathways in and Tregs but increased production of Th2 cytokines many cell types, it is not easy to determine the func- (IL-4 and IL-5) by Tfh cells in PPs The gut micro- tional significance of individual pathways in vivo. biota activate epithelial cells for production of IL-25, More studies are required in the future to dissect the which in turn activates eosinophils. For example, Tri- functions of SCFAs and other metabolites in regulat- trichomonas muris, a symbiotic protozoon in mice, ing B cell responses. It appears that these microbial induces IL-25 production by specialized epithelial cells metabolites not only affect the immune cells in the called Tuft cells. Tuft cell-derived IL-25 mounts a type intestine but also the cells in systemic sites and organs. 2 innate lymphoid cell (ILC2) response and produce This is because microbial metabolites can be trans- IL-5 and IL-13, which can increase eosinophil ported through the blood circulation. Whether anti- responses and affect B cell responses in the gut. body responses to specific pathogens are effectively Antibodies are produced by several B cell types includ- supported by any of the metabolites is an important ingB2, B1 andmarginalzone(MZ)Bcells.TLR ligands question to answer. More studies are needed to estab- activate TLRs of B1 and MZ B cells for antibody produc- lish the roles of these microbial metabolites in regulat- tion. IFN-g and type I IFNs are produced following TLR ing antibody-mediated inflammatory diseases such as activation, and these cytokines promote the production lupus and rheumatoid arthritis. Moreover, it is impor- of antigen-specific antibodies (IgG2c, IgG2a and IgM) by tant to devise strategies to prevent infection and MZ B cells. Microbial products activate neutrophils to enhance immunity using the B cell-helping microbial regulate B cells. For example, the neutrophils that reside factors. in the peri-MZ of the spleen support MZ B cells. The microbiota are required for colonization of neutrophils Disclosure of potential conflicts of interest in the peri-MZ and their maturation into B cell-helping No potential conflicts of interest were disclosed. neutrophils. These neutrophils produce BAFF, APRIL and IL-21 to induce T-independent antibody responses to type 2 thymus-independent (TI-2) antigens such as Funding bacterial capsular antigens. Thus, many cell types mediate This study was supported, in part, from grants from NIH the regulatory effects of the gut microbiota on B cells. (R01AI121302 and R01AI080769) to CHK. Conclusions and questions References IgA is a key regulator of the gut microbiota. We have [1] Kim CH. Retinoic acid, immunity, and inflammation. witnessed a significant progress in our understanding Vitam Horm 2011; 86:83-101; PMID:21419268 of the diverse functions of gut host and microbial fac- [2] Larange A, Cheroutre H. Retinoic acid and retinoic acid tors in regulating IgA production. There are many receptors as pleiotropic modulators of the immune system. direct and indirect mechanisms by which the gut Ann Rev Immunol 2016; 34:369-94; PMID:27168242; microbiota regulate antibody production. 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Journal

Gut Microbes – Taylor & Francis

Published: Jul 4, 2017

Keywords: Gut microbiota; humoral immunity; short-chain fatty acids; IgA; B cells

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