Microbiota in T-cell homeostasis and inflammatory diseases

Naeun Lee, Wan-Uk Kim, Naeun Lee, Wan-Uk Kim

Abstract

The etiology of disease pathogenesis can be largely explained by genetic variations and several types of environmental factors. In genetically disease-susceptible individuals, subsequent environmental triggers may induce disease development. The human body is colonized by complex commensal microbes that have co-evolved with the host immune system. With the adaptation to modern lifestyles, its composition has changed depending on host genetics, changes in diet, overuse of antibiotics against infection and elimination of natural enemies through the strengthening of sanitation. In particular, commensal microbiota is necessary in the development, induction and function of T cells to maintain host immune homeostasis. Alterations in the compositional diversity and abundance levels of microbiota, known as dysbiosis, can trigger several types of autoimmune and inflammatory diseases through the imbalance of T-cell subpopulations, such as Th1, Th2, Th17 and Treg cells. Recently, emerging evidence has identified that dysbiosis is involved in the progression of rheumatoid arthritis, type 1 and 2 diabetic mellitus, and asthma, together with dysregulated T-cell subpopulations. In this review, we will focus on understanding the complicated microbiota-T-cell axis between homeostatic and pathogenic conditions and elucidate important insights for the development of novel targets for disease therapy.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Microbiota diversity is determined by environmental factors and signals to distal organs that contribute the development of diseases. The microbiota is established by other environmental factors, such as dietary fiber, saturated lipids, infection and antibiotics, and its colonization depends on the physiological condition of each tissue. Altered commensal microbiota in the gut or lung could influence the progression of various tissue-specific diseases through signal mediators, including microbes, microbial metabolites and circulating immune cells.
Figure 2
Figure 2
Microbiota mediates T-cell differentiation in homeostatic or pathogenic conditions. In mice under germ-free (GF) conditions, Bacteroides fragilis restores the development of the Th1-associated immune response through a bacterial product, polysaccharide A (PSA)-dependent pathway, while in mice under specific pathogen-free (SPF) conditions, PSA derived from B. fragilis induces Treg cell accumulation. Segmented filamentous bacteria (SFB) induces a Th17 immune response through adenosine 5′-triphosphate (ATP) production or serum amyloid A (SAA) produced by innate cells. Clostridium sp. promotes Treg cells through short-chain fatty acid (SCFA) production. Antigen-presenting cells (APCs) activated by cognate bacterial antigens could facilitate the generation of tissue-specific T cells derived from systemic T cells in a specific tissue environment.

References

    1. Luckheeram RV, Zhou R, Verma AD, Xia B. CD4+ T cells: differentiation and functions. Clin Dev Immunol 2012; 2012: 925135.
    1. Zhu J, Yamane H, Paul WE. Differentiation of effector CD4 T cell populations. Annu Rev Immunol 2010; 28: 445–489.
    1. Harrington LE, Hatton RD, Mangan PR, Turner H, Murphy TL, Murphy KM et al. Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat Immunol 2005; 6: 1123–1132.
    1. Weaver CT, Harrington LE, Mangan PR, Gavrieli M, Murphy KM. Th17: an effector CD4 T cell lineage with regulatory T cell ties. Immunity 2006; 24: 677–688.
    1. Tanoue T, Atarashi K, Honda K. Development and maintenance of intestinal regulatory T cells. Nat Rev Immunol 2016; 16: 295–309.
    1. King C, Tangye SG, Mackay CRT. Follicular helper (TFH) cells in normal and dysregulated immune responses. Annu Rev Immunol 2008; 26: 741–766.
    1. Kaplan MH, Hufford MM, Olson MR. The development and in vivo function of T helper 9 cells. Nat Rev Immunol 2015; 15: 295–307.
    1. NIH HMP Working GroupNIH HMP Working GroupPeterson J, NIH HMP Working GroupGarges S, NIH HMP Working GroupGiovanni M, NIH HMP Working GroupMcInnes P, NIH HMP Working GroupWang L et al. The NIH Human Microbiome Project. Genome Res 2009; 19: 2317–2323.
    1. Human Microbiome Project Consortium. Structure, function and diversity of the healthy human microbiome. Nature 2012; 486: 207–214.
    1. Schroeder BO, Bäckhed F. Signals from the gut microbiota to distant organs in physiology and disease. Nat Med 2016; 22: 1079–1089.
    1. Tamburini S, Shen N, Wu HC, Clemente JC. The microbiome in early life: implications for health outcomes. Nat Med 2016; 22: 713–722.
    1. Wu HJ, Wu E. The role of gut microbiota in immune homeostasis and autoimmunity. Gut Microbes 2012; 3: 4–14.
    1. Belkaid Y, Hand TW. Role of the microbiota in immunity and inflammation. Cell 2014; 157: 121–141.
    1. Kim D, Yoo SA, Kim WU. Gut microbiota in autoimmunity: potential for clinical applications. Arch Pharm Res 2016; 39: 1565–1576.
    1. Atarashi K, Tanoue T, Shima T, Imaoka A, Kuwahara T, Momose Y et al. Induction of colonic regulatory T cells by indigenous Clostridium species. Science 2011; 331: 337–341.
    1. Gaboriau-Routhiau V, Rakotobe S, Lécuyer E, Mulder I, Lan A, Bridonneau C et al. The key role of segmented filamentous bacteria in the coordinated maturation of gut helper T cell responses. Immunity 2009; 31: 677–689.
    1. Mazmanian SK, Liu CH, Tzianabos AO, Kasper DL. An immunomodulatory molecule of symbiotic bacteria directs maturation of the host immune system. Cell 2005; 122: 107–118.
    1. Smith K, McCoy KD, Macpherson AJ. Use of axenic animals in studying the adaptation of mammals to their commensal intestinal microbiota. Semin Immunol 2007; 19: 59–69.
    1. Ivanov II, Atarashi K, Manel N, Brodie EL, Shima T, Karaoz U et al. Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell 2009; 139: 485–498.
    1. Round JL, Lee SM, Li J, Tran G, Jabri B, Chatila TA et al. The toll-like receptor 2 pathway establishes colonization by a commensal of the human microbiota. Science 2011; 332: 974–977.
    1. Longman RS, Yang Y, Diehl GE, Kim SV, Littman DR, Microbiota. Host interactions in mucosal homeostasis and systemic autoimmunity. Cold Spring Harb Symp Quant Biol 2013; 78: 193–201.
    1. McInnes IB, Schett G. The pathogenesis of rheumatoid arthritis. N Engl J Med 2011; 365: 2205–2219.
    1. McInnes IB, Schett G. Cytokines in the pathogenesis of rheumatoid arthritis. Nat Rev Immunol 2007; 7: 429–442.
    1. van den Berg WB, Miossec P. IL-17 as a future therapeutic target for rheumatoid arthritis. Nat Rev Rheumatol 2009; 5: 549–553.
    1. Gaffen SL. The role of interleukin-17 in the pathogenesis of rheumatoid arthritis. Curr Rheumatol Rep 2009; 11: 365–370.
    1. Leipe J, Grunke M, Dechant C, Reindl C, Kerzendorf U, Schulze-Koops H et al. Role of Th17 cells in human autoimmune arthritis. Arthritis Rheum 2010; 62: 2876–2885.
    1. Wu X, He B, Liu J, Feng H, Ma Y, Li D et al. Molecular insight into gut microbiota and rheumatoid arthritis. Int J Mol Sci 2016; 17: 431.
    1. Vaahtovuo J, Munukka E, Korkeamäki M, Luukkainen R, Toivanen P. Fecal microbiota in early rheumatoid arthritis. J Rheumatol 2008; 35: 1500–1505.
    1. Liu X, Zou Q, Zeng B, Fang Y, Wei H. Analysis of fecal Lactobacillus community structure in patients with early rheumatoid arthritis. Curr Microbiol 2013; 67: 170–176.
    1. Scher JU, Sczesnak A, Longman RS, Segata N, Ubeda C, Bielski C et al. Expansion of intestinal Prevotella copri correlates with enhanced susceptibility to arthritis. Elife 2013; 2: e01202.
    1. Chen J, Wright K, Davis JM, Jeraldo P, Marietta EV, Murray J et al. An expansion of rare lineage intestinal microbes characterizes rheumatoid arthritis. Genome Med 2016; 8: 43.
    1. Duan J, Kasper DL. Regulation of T cells by gut commensal microbiota. Curr Opin Rheumatol 2011; 23: 372–376.
    1. Atarashi K, Nishimura J, Shima T, Umesaki Y, Yamamoto M, Onoue M et al. ATP drives lamina propria T(H)17 cell differentiation. Nature 2008; 455: 808–812.
    1. Ivanov II, Frutos Rde L, Manel N, Yoshinaga K, Rifkin DB, Sartor RB et al. Specific microbiota direct the differentiation of IL-17-producing T-helper cells in the mucosa of the small intestine. Cell Host Microbe 2008; 4: 337–349.
    1. Telesford KM, Yan W, Ochoa-Reparaz J, Pant A, Kircher C, Christy MA et al. A commensal symbiotic factor derived from Bacteroides fragilis promotes human CD39(+) Foxp3(+) T cells and Treg function. Gut Microbes 2015; 6: 234–242.
    1. Wu HJ, Ivanov II, Darce J, Hattori K, Shima T, Umesaki Y et al. Gut-residing segmented filamentous bacteria drive autoimmune arthritis via T helper 17 cells. Immunity 2010; 32: 815–827.
    1. Lochner M, Peduto L, Cherrier M, Sawa S, Langa F, Varona R et al. In vivo equilibrium of proinflammatory IL-17+ and regulatory IL-10+ Foxp3+ RORgamma t+ T cells. J Exp Med 2008; 205: 1381–1393.
    1. Zhou L, Chong MM, Littman DR. Plasticity of CD4+ T cell lineage differentiation. Immunity 2009; 30: 646–655.
    1. Abdollahi-Roodsaz S, Joosten LA, Koenders MI, Devesa I, Roelofs MF, Radstake TR et al. Stimulation of TLR2 and TLR4 differentially skews the balance of T cells in a mouse model of arthritis. J Clin Invest 2008; 118: 205–216.
    1. Maeda Y, Kurakawa T, Umemoto E, Motooka D, Ito Y, Gotoh K et al. Dysbiosis contributes to arthritis development via activation of autoreactive T cells in the intestine. Arthritis Rheumatol 2016; 68: 2646–2661.
    1. Liu X, Zeng B, Zhang J, Li W, Mou F, Wang H et al. Role of the gut microbiom in modulating arthritis progression in mice. Sci Rep 2016; 6: 30594.
    1. Scher JU, Abramson SB. Periodontal disease, Porphyromonas gingivalis, and rheumatoid arthritis: what triggers autoimmunity and clinical disease? Arthritis Res Ther 2013; 15: 122.
    1. Mikuls TR, Payne JB, Yu F, Thiele GM, Reynolds RJ, Cannon GW et al. Periodontitis and Porphyromonas gingivalis in patients with rheumatoid arthritis. Arthritis Rheumatol 2014; 66: 1090–1100.
    1. Moutsopoulos NM, Kling HM, Angelov N, Jin W, Palmer RJ, Nares S et al. Porphyromonas gingivalis promotes Th17 inducing pathways in chronic periodontitis. J Autoimmun 2012; 39: 294–303.
    1. Rosenstein ED, Greenwald RA, Kushner LJ, Weissmann G. Hypothesis: the humoral immune response to oral bacteria provides a stimulus for the development of rheumatoid arthritis. Inflammation 2004; 28: 311–318.
    1. Scher JU, Joshua V, Artacho A, Abdollahi-Roodsaz S, Öckinger J, Kullberg S et al. The lung microbiota in early rheumatoid arthritis and autoimmunity. Microbiome 2016; 4: 60.
    1. American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care 2009; 32: S62–S67.
    1. Todd JA. Etiology of type 1 diabetes. Immunity 2010; 32: 457–467.
    1. Alam C, Bittoun E, Bhagwat D, Valkonen S, Saari A, Jaakkola U et al. Effects of a germ-free environment on gut immune regulation and diabetes progression in non-obese diabetic (NOD) mice. Diabetologia 2011; 54: 1398–1406.
    1. Bevan MJ. Helping the CD8+ T-cell response. Nat Rev Immunol 2004; 4: 595–602.
    1. Savinov AY, Wong FS, Chervonsky AV. IFN-gamma affects homing of diabetogenic T cells. J Immunol 2001; 167: 6637–6643.
    1. Lehuen A, Diana J, Zaccone P, Cooke A. Immune cell crosstalk in type 1 diabetes. Nat Rev Immunol 2010; 10: 501–513.
    1. Sarvetnick N, Liggitt D, Pitts SL, Hansen SE, Stewart TA. Insulin-dependent diabetes mellitus induced in transgenic mice by ectopic expression of class II MHC and interferon-gamma. Cell 1988; 52: 773–782.
    1. Rabinovitch A. Immunoregulatory and cytokine imbalances in the pathogenesis of IDDM. Therapeutic intervention by immunostimulation? Diabetes 1994; 43: 613–621.
    1. Zaccone P, Raine T, Sidobre S, Kronenberg M, Mastroeni P, Cooke A. Salmonella typhimurium infection halts development of type 1 diabetes in NOD mice. Eur J Immunol 2004; 34: 3246–3256.
    1. Raine T, Zaccone P, Mastroeni P, Cooke A. Salmonella typhimurium infection in nonobese diabetic mice generates immunomodulatory dendritic cells able to prevent type 1 diabetes. J Immunol 2006; 177: 2224–2233.
    1. Mueller R, Krahl T, Sarvetnick N. Pancreatic expression of interleukin-4 abrogates insulitis and autoimmune diabetes in nonobese diabetic (NOD) mice. J Exp Med 1996; 184: 1093–1099.
    1. Cooke A, Tonks P, Jones FM, O'Shea H, Hutchings P, Fulford AJ et al. Infection with Schistosoma mansoni prevents insulin dependent diabetes mellitus in non-obese diabetic mice. Parasite Immunol 1999; 21: 169–176.
    1. Saunders KA, Raine T, Cooke A, Lawrence CE. Inhibition of autoimmune type 1 diabetes by gastrointestinal helminth infection. Infect Immun 2007; 75: 397–407.
    1. Wang B, Gonzalez A, Hoglund P, Katz JD, Benoist C, Mathis D. Interleukin-4 deficiency does not exacerbate disease in NOD mice. Diabetes 1998; 47: 1207–1211.
    1. Satoh J, Seino H, Abo T, Tanaka S, Shintani S, Ohta S et al. Recombinant human tumor necrosis factor alpha suppresses autoimmune diabetes in nonobese diabetic mice. J Clin Invest 1989; 84: 1345–1348.
    1. Emamaullee JA, Davis J, Merani S, Toso C, Elliott JF, Thiesen A et al. Inhibition of Th17 cells regulates autoimmune diabetes in NOD mice. Diabetes 2009; 58: 1302–1311.
    1. Kriegel MA, Sefik E, Hill JA, Wu HJ, Benoist C, Mathis D. Naturally transmitted segmented filamentous bacteria segregate with diabetes protection in nonobese diabetic mice. Proc Natl Acad Sci USA 2011; 108: 11548–11553.
    1. Martin-Orozco N, Chung Y, Chang SH, Wang YH, Dong C. Th17 cells promote pancreatic inflammation but only induce diabetes efficiently in lymphopenic hosts after conversion into Th1 cells. Eur J Immunol 2009; 39: 216–224.
    1. Atarashi K, Tanoue T, Oshima K, Suda W, Nagano Y, Nishikawa H et al. Treg induction by a rationally selected mixture of Clostridia strains from the human microbiota. Nature 2013; 500: 232–236.
    1. Arpaia N, Campbell C, Fan X, Dikiy S, van der Veeken J, deRoos P et al. Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation. Nature 2013; 504: 451–455.
    1. Rubtsov YP, Rasmussen JP, Chi EY, Fontenot J, Castelli L, Ye X et al. Regulatory T cell-derived interleukin-10 limits inflammation at environmental interfaces. Immunity 2008; 28: 546–558.
    1. Li MO, Wan YY, Flavell RA. T cell-produced transforming growth factor-β1 controls T cell tolerance and regulates Th1- and Th17-cell differentiation. Immunity 2007; 26: 579–591.
    1. Geuking MB, Cahenzli J, Lawson MA, Ng DC, Slack E, Hapfelmeier S et al. Intestinal bacterial colonization induces mutualistic regulatory T cell responses. Immunity 2011; 34: 794–806.
    1. Feuerer M, Herrero L, Cipolletta D, Naaz A, Wong J, Nayer A et al. Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters. Nat Med 2009; 15: 930–939.
    1. Donath MY, Shoelson SE. Type 2 diabetes as an inflammatory disease. Nat Rev Immunol 2011; 11: 98–107.
    1. Lumeng CN, Bodzin JL, Saltiel AR. Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J Clin Invest 2007; 117: 75–184.
    1. Nishimura S, Manabe I, Nagasaki M, Eto K, Yamashita H, Ohsugi M et al. CD8+ effector T cells contribute to macrophage recruitment and adipose tissue inflammation in obesity. Nat Med 2009; 15: 914–920.
    1. Garidou L, Pomié C, Klopp P, Waget A, Charpentier J, Aloulou M et al. The gut microbiota regulates intestinal CD4 T cells expressing RORγt and controls metabolic disease. Cell Metab 2015; 22: 100–112.
    1. Cani PD, Bibiloni R, Knauf C, Waget A, Neyrinck AM, Delzenne NM et al. Changes in gut microbiota control metabolic endotoxemia-induced inflammation in high-fat diet-induced obesity and diabetes in mice. Diabetes 2008; 57: 1470–1481.
    1. Turnbaugh PJ, Ley RE, Mahowald MA, Magrini V, Mardis ER, Gordon JI et al. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature 2006; 444: 1027–1031.
    1. Céline P, Lucile G, Rémy B. Intestinal RORgt-generated Th17 cells control type 2 diabetes: a first antidiabetic target identified from the host to microbiota crosstalk. Inflamm Cell Signal 2016; 3: e1074.
    1. Karlsson FH, Tremaroli V, Nookaew I, Bergström G, Behre CJ, Fagerberg B et al. Gut metagenome in European women with normal, impaired and diabetic glucose control. Nature 2013; 498: 99–103.
    1. Qin J, Li Y, Cai Z, Li S, Zhu J, Zhang F et al. A metagenome-wide association study of gut microbiota in type 2 diabetes. Nature 2012; 490: 55–60.
    1. Lambrecht BN, Hammad H. The immunology of asthma. Nat Immunol 2015; 16: 45–56.
    1. Robinson DS, Hamid Q, Ying S, Tsicopoulos A, Barkans J, Bentley AM et al. Predominant TH2-like bronchoalveolar T-lymphocyte population in atopic asthma. N Engl J Med 1992; 326: 298–304.
    1. Cohn L, Elias JA, Chupp GL. Asthma: mechanisms of disease persistence and progression. Annu Rev Immunol 2004; 22: 789–815.
    1. Earl CS, An SQ, Ryan RP. The changing face of asthma and its relation with microbes. Trends Microbiol 2015; 23: 408–418.
    1. Molet S, Hamid Q, Davoine F, Nutku E, Taha R, Pagé N et al. IL-17 is increased in asthmatic airways and induces human bronchial fibroblasts to produce cytokines. J Allergy Clin Immunol 2001; 108: 430–438.
    1. Wang YH, Wills-Karp M. The potential role of interleukin-17 in severe asthma. Curr Allergy Asthma Rep 2011; 11: 388–394.
    1. Fujimura KE, Lynch SV. Microbiota in allergy and asthma and the emerging relationship with the gut microbiome. Cell Host Microbe 2015; 17: 592–602.
    1. Lighthart B. Mini-review of the concentration variations found in the alfresco atmospheric bacterial populations. Aerobiologia 2000; 16: 7–16.
    1. Dickson RP, Erb-Downward JR, Huffnagle GB. Homeostasis and its disruption in the lung microbiome. Am J Physiol Lung Cell Mol Physiol 2015; 309: L1047–L1055.
    1. Segal LN, Clemente JC, Tsay JC, Koralov SB, Keller BC, Wu BG et al. Enrichment of the lung microbiome with oral taxa is associated with lung inflammation of a Th17 phenotype. Nat Microbiol 2016; 1: 16031.
    1. Wu W, Huang J, Duan B, Traficante DC, Hong H, Risech M et al. Th17-stimulating protein vaccines confer protection against Pseudomonas aeruginosa pneumonia. Am J Respir Crit Care Med 2012; 186: 420–427.
    1. Herbst T, Sichelstiel A, Schär C, Yadava K, Bürki K, Cahenzli J et al. Dysregulation of allergic airway inflammation in the absence of microbial colonization. Am J Respir Crit Care Med 2011; 184: 198–205.
    1. Sutherland ER, Martin RJ. Asthma and atypical bacterial infection. Chest 2007; 132: 1962–1966.
    1. Huang YJ, Nelson CE, Brodie EL, Desantis TZ, Baek MS, Liu J et al. Airway microbiota and bronchial hyperresponsiveness in patients with suboptimally controlled asthma. J Allergy Clin Immunol 2011; 127: 372–381, e1–3.
    1. Goleva E, Jackson LP, Harris JK, Robertson CE, Sutherland ER, Hall CF et al. The effects of airway microbiome on corticosteroid responsiveness in asthma. Am J Respir Crit Care Med 2013; 188: 1193–1201.
    1. Marri PR, Stern DA, Wright AL, Billheimer D, Martinez FD. Asthma-associated differences in microbial composition of induced sputum. J Allergy Clin Immunol 2013; 131: 346–352.
    1. Gollwitzer ES, Saglani S, Trompette A, Yadava K, Sherburn R, McCoy KD et al. Lung microbiota promotes tolerance to allergens in neonates via PD-L1. Nat Med 2014; 20: 642–647.
    1. Durack J, Boushey HA, Lynch SV. Airway microbiota and the implications of dysbiosis in asthma. Curr Allergy Asthma Rep 2016; 16: 52.
    1. Green BJ, Wiriyachaiporn S, Grainge C, Rogers GB, Kehagia V, Lau L et al. Potentially pathogenic airway bacteria and neutrophilic inflammation in treatment resistant severe asthma. PLoS ONE 2014; 9: e100645.
    1. Mejía-León ME, Barca AM. Diet, microbiota and immune system in type 1 diabetes development and evolution. Nutrients 2015; 7: 9171–9984.
    1. Simpson JL, Daly J, Baines KJ, Yang IA, Upham JW, Reynolds PN et al. Airway dysbiosis: Haemophilus influenzae and Tropheryma in poorly controlled asthma. Eur Respir J 2016; 47: 792–800.

Source: PubMed

Sponsorit ja yhteistyökumppanit

Sairaudet

Huumeiden interventiot

3
Tilaa