Edited by: Laurel L. Lenz, University of Colorado, United States
Reviewed by: Christopher Michael Reilly, Edward via College of Osteopathic Medicine, United States; Maryam Dadar, Razi Vaccine and Serum Research Institute, Iran
This article was submitted to Microbial Immunology, a section of the journal Frontiers in Immunology
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
The interplay between the immune system and the microbiota in the human intestine dictates states of health vs. disease. Polysaccharide capsules are critical elements of bacteria that protect bacteria against environmental and host factors, including the host immune system. This review summarizes the mechanisms by which polysaccharide capsules from commensal and pathogenic bacteria in the gut microbiota modulate the innate and adaptive immune systems in the intestine. A deeper understanding of the roles of polysaccharide capsules in microbiota-immune interactions will provide a basis to harness their therapeutic potential to advance human health.
The dynamic interactions between the gut microbiota and immune system determine whether immune tolerance or inflammation and disease develop in the human intestine. One component of bacteria that has been found to play an important role in regulating immune responses in the gut are polysaccharide capsules. Polysaccharide capsules are long polysaccharide chains that form the outermost layer of bacteria and can be several 100 μm thick (
One striking feature of the capsules in general is their chemical and structural diversity within a given bacterial species. They can be composed of different monosaccharides, which can also vary in their stereoisomers (D or L), number of carbon molecules forming the sugar ring structure (furanose or pyranose), and configuration of the anomeric center of each sugar (Cα or Cβ) (
Polysaccharide capsules have been shown to enhance bacterial survival in the gut by multiple mechanisms. Capsule composition varies with diet and different capsules may provide optimal access to various nutrients and more efficient use of the bacterial cell's resources (
Some bacteria, especially the
The two main types of polysaccharide capsules are exopolysaccharides (EPSs) and capsular polysaccharides (CPSs). EPSs contain glycans that are loosely associated with microbial cell surfaces, while CPSs are composed of glycans that are firmly attached to the cell surface (
Summary of the effects of bacterial polysaccharide capsules in the intestine on the immune system.
Gram + | Commensal | EPS | Mannose (88%), glucose (11.9%), |
Macrophages | Signals through TLR4/MyD88 pathway to induce M2 macrophages, which inhibit CD4+ T cells via TGF-β and CD8+ T cells via TGF-β and PD-L1; protects against C. rodentium-induced colitis | Macrophage skewing; T cell activation | ( |
|
Gram − | Commensal | CPS | Acetamido-amino-2,4,6-trideoxygalactose (AATGal) amino sugar; zwitterionic | Monocytes | Induces IL-10 and CD25+FoxP3+CD127-CTLA-4+ Tregs; attenuates TNBS-induced colitis | Cytokine production; T cell activation | ( |
|
Gram − | Commensal | CPS: PSA | Tetrasaccharide repeating unit containing 4,6-pyruvate attached to a d-galactopyranose, 2,4-dideoxy-4-amino-d-FucNAc, d-N-acetylgalactosamine, and d-galactofuranose with one positively charged free amine and one negatively charged carboxylate; zwitterionic | Dendritic cells | Enhances antigen presentation by upregulating MHC II, CD80, and CD86; phagocytosed by APCs and displayed on MHC II to activate CD4+ T cells in a TLR2-dependent manner; corrects CD4+ T cell deficiencies and TH1/TH2 imbalance in germ-free mice by upregulating the production of IFN-γ+ TH1 T cells through CD11c+ DCs and the IL-12/STAT4 pathway; represses TH17 responses; induces IL-10 producing FoxP3+ Tregs in a TLR2-dependent manner; protects against TNBS-induced colitis and |
Antigen presentation; T cell activation | ( |
|
Gram − | Commensal | CPS: CPS 1-8 | CPS1: 22% N-acetyl-glucosamine, 33% glucose, 9% mannose, 36% galacturonic acid CPS2: 8% N-acetyl-glucosamine, 85% glucose, 7% mannose!!!break!!! CPS3: 18% N-acetyl-glucosamine, 42% glucose, 34% mannose, 6% galacturonic acid!!!break!!! CPS4: 61% N-acetyl-glucosamine, 21% glucose, 18% galacturonic acid!!!break!!! CPS5: 10% N-acetyl-galactosamine, 7% N-acetyl-glucosamine, 27% galactose, 49% glucose, 8% mannose!!!break!!! CPS6: 23% N-acetyl-galactosamine, 8% N-acetyl-glucosamine, 37% galactose, 23% glucose, 6% mannose, 3% glucuronic acid!!!break!!! CPS8: 19% N-acetyl-glucosamine, 2% galactose, 63% glucose, 14% mannose, 1% glucuronic acid | Dendritic cells, macrophages | CPS2, CPS4, CPS5, CPS6, and WT are more resistant to complement; CPS1-6 inhibit APC phagocytosis and antigen presentation likely due to increased capsule thickness and decrease IL-6 and TNF-α production in a MyD88-dependent manner; CPS5 promotes evasion of IgA responses; CPS1 represses polyclonal and antigen-specific T cell activation and differentiation to IFN-γ+ IL-17A+ T cells; OMVs | Complement evasion; phagocytosis; antigen presentation; cytokine production; evasion of antibody responses; T cell activation | ( |
|
Gram + | Commensal | CPS | Mixture of four neutrally charged cell surface β-glucan/galactan (CSGG) polysaccharides: β-(1 → 6)-glucan, β-(1 → 4)-galactan, β-(1 → 6)-galactan, β-galactofuranan and starch | Dendritic cells | induces IL-10 and FoxP3+ Tregs through TLR2-mediated mechanism on DCs; attenuates colitis in T cell transfer model of colitis | Cytokine production; T cell activation | ( |
|
Gram + | Commensal | EPS | Glucose, galactose and/or the N-acetylated versions of these two sugars | B cells | Decreases numbers of B cells and antigen-specific total Ig, IgG3, IgG1, IgG2a, and fecal IgA titers; elicits weaker antibody responses by masking surface antigens | B cell activation; masks surface antigens | ( |
|
Gram + | Commensal | EPS | Branched hexasaccharide repeating unit with two galactoses, two glucoses, galacturonic acid, and the unusual sugar 6-deoxytalose | Neutrophils, macrophages, dendritic cells, NK cells | Decrease IFN-γ, IL-12, TNF-α, IL-17, IL-6 production; prevents phagocytosis; represses TH17 recruitment; protects against T cell transfer model of colitis | Cytokine production; phagocytosis; T cell activation | ( |
|
Gram − | Pathogen | CPS | Heptoses in unusual configurations (e.g., ido, gulo, and altro) and non-stoichiometric modifications on the sugars, including ethanolamine, aminoglycerol, and O-methyl phosphoramidate (MeOPN) | Dendritic cells, macrophages | Blocks antibody binding and activation of complement; decreases activation of TLR4 and production of IL-1β, IFN-γ, and IL-6 | Complement evasion | ( |
|
Enteropathogenic |
Gram − | Pathogen | CPS: Gp 4 capsule | Linear tetrasaccharide made of L-fucose, D-galactose and two N-acetyl-galactosamines | Human α-defensin 5 | Uses its anionic charges to prevent cationic human α-defensin 5 from reaching the bacterial membrane | Innate immune evasion of antimicrobial peptides | ( |
Gram + | Commensal | EPS | Unknown | Dendritic cells | Decreases IL-12p70 and IFN-γ and increases IL-10 secretion through TLR2 signaling by |
Cytokine production; attenuates DSS-colitis | ( |
|
Gram − | Pathobiont | CPS | α-mannose and α-glucose sugars | Macrophages | Signals through TLR2/MyD88 pathway to activate MSK/CREB pathway and induce IL-10 | Innate immune tolerance | ( |
|
Gram + | Commensal | EPS | MMMP1: main chain of 1,6-β-D-Galfs with non-stoichiometric 2-O-glucosylation. MMMP2: a repeat unit → 3)-β-D-Glcp-(1 → 3)-β-D-Galf-(1 → 6)-[2-α-D-Glcp]β-D-Galf-(1 → | Unknown | Induces IgA production | Enhances IgA production | ( |
|
Gram + | Commensal | EPS | EPS-1: branched dextran with every backbone residue substituted with a 2-linked glucose unit and polysaccharides partially occupied by 1-phosphoglycerol and O-acetyl groups; EPS-2: repeating unit with−6)-α-Glcp-(1–3)-β-Glcp-(1–5)-β-Galf-(1–6)-α-Glcp-(1–4)-β-Galp-(1–4)-β-Glcp-(1- and polysaccharides partially occupied by single O-acetyl group | Unknown | Masks cell surface epitopes from antibodies | Masks surface antigens | ( |
|
Gram + | Commensal | EPS | Equal proportions of glucose and galactose | Induces IgA production | Enhances IgA production | ( |
||
Gram + | Commensal | EPS | 70% galactose, 19% rhamnose, and 10% glucose | LL-37/human cationic protein 18; complement | Resists cationic LL-37/human cationic protein 18 by forming protective shield with long and neutral EPS; protects against complement activation and lysis via lack of mannose | Innate immune evasion of antimicrobial peptides; complement evasion | ( |
|
Gram + | Commensal | EPS | Glucose and fructose | Unknown | Induces IgA production, retinoic acid synthase, and TGF-β; increases number of CD4+ and CD8+ T cells | Enhances IgA production; cytokine production; T cell activation | ( |
|
Gram + | Commensal | EPS | 2-substituted (1,3)-β-d-glucan | Macrophages | Decreases TNF-α and IL-8 production | Cytokine production | ( |
|
Gram − | Pathogen | CPS: Gp 4 cp (O-ag CPS) | Repeating units of glucose, mannose, and galactose | Complement; macrophages | Decreases C3 surface deposition; decreases production of IL-6 and TNF-α in a TLR-dependent manner | Complement evasion; cytokine production | ( |
|
Gram − | Pathogen | CPS: Vi | Homopolymer of (1,4)-2-acetamido-3- |
T cells | Represses T cell responses by binding to T cells through the prohibitin complex and inhibiting IL-2 secretion; prevents C3 deposition, phagocytosis, and complement receptor 3-mediated clearance | Represses T cells; complement evasion | ( |
|
Gram − | Pathogen | CPS: Gp 4 cp (O-ag CPS) | High molecular weight polysaccharide containing FucNAc4N and L-AltNAcA residues in 1:1 ratio | Complement | Resists direct complement-mediated killing | Complement evasion | ( |
|
Gram + | Commensal | EPS | 12.9% rhamnose, 26% glucose, 60.9% galactose, 0.25% mannose | Unknown | Decreases IFN-γ, IL-6, and TNF-α production | Cytokine production | ( |
|
Gram − | Pathogen | CPS (O-antigen CPS) | Polymerized O-antigen subunits composed of N-acetylglucosamine, N-acetyl-quinovosamine, galacturonic acid, galactose andcolitose | Complement | Resists complement-mediated bacteriolysis likely by promoting binding of negative regulatory proteins and inhibiting efficient complement fixation at the bacterial surface | Complement evasion | ( |
The innate immune system is the first line of defense against many pathogens, and MPGs have been shown to be critical for regulating innate immune responses in the gut. One mechanism the innate system uses to combat bacterial infection is the production of antimicrobial peptides such as defensins and cathelicidins by the intestinal epithelium. MPGS can block the bactericidal activity of antimicrobial factors, enabling bacteria to evade these innate immune responses. For example, wild-type (WT) enteropathogenic
Another method the innate immune system uses to recognize and destroy bacteria is complement. MPGs can block the deposition of complement on bacterial surfaces, which prevents bacteria from being targeted for destruction by the immune system. EPS from LGG also protected against complement-mediated lysis as an EPS− LGG strain, but not an EPS+ LGG strain, had a reduction in viability after incubation with normal human serum (
MPGs can also directly block bacterial uptake by innate immune cells, which prevents phagocytic cells from killing bacteria and antigen presenting cells from presenting antigenic peptides on the surfaces that may activate the adaptive immune system. For example,
Innate immune responses to bacteria can also be thwarted by MPGs that promote immune tolerance by inducing innate immune cells to release anti-inflammatory cytokines in the intestine. A large soluble polysaccharide released by the Gram-negative
Other MPGs protect bacteria from innate immune responses by reducing the production of pro-inflammatory cytokines by innate immune cells. Anti-stimulatory CPSs expressed on
The host immune system also consists of adaptive immunity, especially B and T cells, which protect the intestine from bacterial pathogens in an antigen-specific manner and induce immunological memory that leads to enhanced immune responses to consequent encounters with pathogens. Bacteria also encounter the adaptive immune system in the intestine, and the ability of MPGs to evade adaptive immune responses is crucial to their fitness and survival in the gut. One mechanism MPGs use to modulate the adaptive immune system is regulating the interactions between B cells, antibodies, and bacteria. Many MPGs inhibit B cell and antibody responses to bacteria. For example, EPS+
Many MPGs can also modulate T cell responses in the intestine, including by functioning as T cell antigens and by regulating both polyclonal and antigen-specific T cells. Most polysaccharides are classically considered to be T cell-independent antigens that do not induce the activation of helper T cells that stimulate Ig class switching in B cells or immunologic memory (
MPGs have also been shown to be critical for maturation of the host immune system, especially the development of T cells. Although germ-free mice that lack the bacterial microflora are known to exhibit immunological defects,
MPGs can also modulate the activation of polyclonal T cell responses, especially by directing T cell differentiation. Most T cell effects of MPGs that have been studied induce a state of immune tolerance by suppressing T cell responses. In the Powrie model of colitis, EPS+
In addition to modulating polyclonal T cell responses, MPGs can regulate T cell responses to dominant antigens. Using a
MPGs play critical roles in regulating the immune responses to the microbiota in the intestine. Many MPGs enable bacteria to evade innate and adaptive immune responses by forming protecting shields around bacteria. For example, MPGs can protect bacteria from antimicrobial factors, complement deposition, and phagocytosis by innate immune cells. MPGs also promote immune tolerance by inducing the innate immune system to produce more anti-inflammatory cytokines or fewer pro-inflammatory cytokines as well as maturation of innate immune cells to make them better APCs for the adaptive immune system. Adaptive immune responses can also be modulated by MPGs as MPGs can block B cell and antibody responses, especially by masking surface antigens. In addition, MPGs, even on OMVs, can regulate T cell responses by directly serving as the T cell antigen or by controlling the activation and differentiation of polyclonal and antigen-specific T cells.
MPGs are critical components of the gut microbiota, and deciphering the roles of MPGs in microbiota-immune interactions in the intestine is crucial for improving human health. Despite the progress in understanding how MPGs modulate immune responses to intestinal bacteria, many immunoregulatory functions of MPGs are still poorly understood. For example, why some non-zwitterionic MPGs are anti-stimulatory whereas others are pro-stimulatory is not known. In addition, bacteriophages can regulate the immune system (
SH and PA conceived the topic of this review. SH wrote the review and PA edited it.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
We thank the Allen lab, Eric Martens, Thad Stappenbeck and their respective labs for their contributions to this project. This article was submitted as a preprint to