Abstract
Altered intestinal microbial composition (dysbiosis) and metabolic products activate aggressive mucosal immune responses that mediate inflammatory bowel diseases (IBD). This dysbiosis impairs the function of regulatory immune cells, which normally promote mucosal homeostasis. Normalizing and maintaining regulatory immune cell function by correcting dysbiosis provides a promising approach to treat IBD patients. However, existing microbe-targeted therapies, including antibiotics, prebiotics, probiotics, and fecal microbial transplantation, provide variable outcomes that are not optimal for current clinical application. This review discusses recent progress in understanding the dysbiosis of IBD and the basis for therapeutic restoration of homeostatic immune function by manipulating an individual patient’s microbiota composition and function. We believe that identifying more precise therapeutic targets and develo** appropriate rapid diagnostic tools will guide more effective and safer microbe-based induction and maintenance treatments for IBD patients that can be applied in a personalized manner.
Similar content being viewed by others
Avoid common mistakes on your manuscript.
Background
Hundreds of trillions of microorganisms, including bacteria, virus, fungi and archaea, reside in our distal intestines and mutually interact with co-evolved host immune cells in a beneficial reciprocal relationship that is influenced by host genetics and environmental factors, including the diet [1,2,3]. The microbiota evolved to colonize specialized ecological niches of the human gastrointestinal tract and to utilize variable diets, while the human mucosal immune system evolved to protect the host from harmful microbial pathogen exposures, yet prevent chronic intestinal inflammation [3, 4]. Enteric resident microbiota exists as a consortium that contains both putative proinflammatory and protective strains [5, 6]. A delicate balance between those functionally distinct populations is maintained in healthy individuals, while patients with inflammatory bowel diseases (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), harbor an altered gut microbial composition (dysbiosis) defined as increased potentially aggressive species in parallel with decreased anti-inflammatory groups [5,6,7,8]. Gut microbial diversity decreases and metabolic functions are altered in IBD patients, suggesting a loss of protective bacteria and their functions in IBD [9,10,11]. Prolonged dysbiotic conditions lead to dysfunction of the host immune system, which is considered the key mediator of the chronic inflammation of IBD [6, 11] (Fig. 1).
Dysbiosis-associated mucosal immune-dysfunction in IBD. Enteric infection, medications including antibiotics, NSAIDs and immunosuppressive drugs, diet, smoking and alcohol, psychological stress in susceptible genetic individuals cause microbial dysbiosis and metabolic changes. Prolonged dysbiotic conditions characterized by increased aggressive bacterial strains and decreased regulatory species lead to dysfunction of mucosal immune response. Aggressive microbial groups activate inflammatory response by inducing Th1/Th17-effector cells, while decreased regulatory species impair the induction and function of regulatory cells that include regulatory T cells (Treg), B cells (Breg), macrophages (MΦ), dendritic cells (DC) and innate lymphoid cells (ILCs). This imbalance of mucosal cytokine profiles in combination with defective barrier function sustains mucosal inflammation and can potentially lead to IBD in susceptible individuals
The activation, migration, proliferation, differentiation and maintenance of a variety of mucosal immune cells are directly regulated by resident microbiota. These activated immune cells cooperate to maintain intestinal homeostasis in normal hosts [4]. Inflammatory immune cells help eliminate invading pathogens by highly effective redundant innate and adaptive immune mechanisms. Microbiota boosts the innate immune response against pathogens by stimulating secretion of antimicrobial peptides and cytokines such as TNFα, IL-22 and IL-17, and activating the inflammasome for anti-pathogen defense [2]. On the other hand, regulatory immune cells including regulatory T cells [12,13,14,15], B cells [16,17,18,19], dendritic cells [20, 21], macrophages [22] and innate lymphoid cells (ILCs) [143].
Fully understanding the interactions between microbiota and the host immune system, in concert with environmental and genetic factors unique to each individual, is necessary to target the most effective therapies for each patient. Personalized diagnostic profiles will require identifying an individual’s metabolic functions and dominant microbial antigens by shotgun metagenomic and metabolomic profiling, in concert with host microbial transcriptomic and genetic profiling. Microbiota reciprocally interacts with each other and the diet to provide immunological signals to host and the same microbe sometimes behaves differently in different individuals [1, 11, 144]. Host genetic and nutritional factors will need to be considered in an integrated and personalized manner to increase the effectiveness and efficacy of microbiota-based therapies [111, 145]. Selection of optimal approaches and therapeutic targets based on analysis of an individual’s microbiota pattern will be important to replace missing or dysfunctional bacterial components. We believe that a combined strategy to promote homeostatic immune responses, improve mucosal barrier function and restore eubiosis by targeting dominant pathobionts and replacing missing protective species or their functions by manipulating the bacterial microbiota and diet may be best. This integrated approach should provide a more physiologic, safer and more cost-effective means to sustained remission of IBD than the current lifelong treatments with immunosuppressives. It is our belief that this approach will be more effective as maintenance therapies once induction of disease remission has been accomplished by traditional therapies, but then toxic induction regimens can be withdrawn to decrease toxicity.
Conclusions and a path to improve personalized treatment
Human IBD includes genetically and clinically heterozygous patient subpopulations with very unique intestinal bacterial compositions and functions that help determine immune responses and disease outcomes. Therefore, we believe that it will be feasible to evaluate the microbe/immune profiles by rapid diagnostic tests of microbiota functional and mucosal immune profiles to direct highly effective and safe treatments in a personalized manner (Fig. 2). Restoring impaired regulatory immune cell activity by correcting dysbiosis and defective microbial metabolic functions is a novel and highly promising therapeutic approach to managing IBD in a more physiologic, safer and sustained manner. Unveiling the mechanisms underlying specific defective bacteria–host interactions in each IBD patient will enable precision editing of microbiota and their function with maximum effectiveness and efficiency.
Current and proposed treatment strategies in microbe-based treatment for IBD. Currently, we diagnose and treat IBD patients based on clinical parameters including fecal calprotectin, serum CRP level, disease activity index (DAI) and endoscopic findings. These clinical observations do not provide insight into the degree of mucosal dysbiosis or impaired regulatory immune response in IBD patients. Therefore, empiric microbe-based therapies are used, such as existing probiotics, prebiotics, antibiotics, fecal microbial transplantation in addition to standard of care anti-TNF agents or immunomodulators (IM). Since these empiric treatments have a limited efficacy in current clinical practice, we propose a more rational and scientific approach based on the fecal microbial and mucosal immune profiles in each IBD patient determined by rapid diagnosis tests. These fecal metabolic profiles and mucosal immune cytokine expression levels allow us to provide more effective and lower toxic microbe-based treatments based on various combinations of protective bacterial strains (LBP live biotherapeutic products) that are then applied in a customized way to restore microbial homeostasis based on dysbiosis in an individual patient. This approach can potentially provide cost-effective, nontoxic treatment and higher quality of life for IBD patients. HC healthy control, Pt IBD patient
References
Rothschild D, Weissbrod O, Barkan E, et al. Environment dominates over host genetics in sha** human gut microbiota. Nature. 2018;555:210–5.
Cheng H-Y, Ning M-X, Chen D-K, et al. Interactions between the gut microbiota and the host innate immune response against pathogens. Front Immunol. 2019;10:607.
Dominguez-Bello MG, Godoy-Vitorino F, Knight R, et al. Role of the microbiome in human development. Gut. 2019;68:1108–14.
Belkaid Y, Hand TW. Role of the microbiota in immunity and inflammation. Cell. 2014;157:121–41.
Nagao-Kitamoto H, Kamada N. Host-microbial cross-talk in Inflammatory Bowel Disease. Immun Netw. 2017;17:1.
Sartor RB, Wu GD. Roles for Intestinal Bacteria, Viruses, and Fungi in Pathogenesis of Inflammatory Bowel Diseases and Therapeutic Approaches. Gastroenterology. 2017;152:327–339.e4.
Harris KG, Chang EB. The intestinal microbiota in the pathogenesis of inflammatory bowel diseases: new insights into complex disease. Clin Sci (Lond.). 2018;132:2013–28.
Kostic AD, Xavier RJ, Gevers D. The microbiome in inflammatory bowel disease: current status and the future ahead. Gastroenterology. 2014;146:1489–99.
Integrative HMP. (iHMP) Research network consortium. The integrative human microbiome project. Nature. 2019;569:641–8.
Kriss M, Hazleton KZ, Nusbacher NM, et al. Low diversity gut microbiota dysbiosis: drivers, functional implications and recovery. Curr Opin Microbiol. 2018;44:34–40.
Lloyd-Price J, Arze C, Ananthakrishnan AN, et al. Multi-omics of the gut microbial ecosystem in inflammatory bowel diseases. Nature. 2019;569:655–62.
Atarashi K, Tanoue T, Oshima K, et al. Treg induction by a rationally selected mixture of Clostridia strains from the human microbiota. Nature. 2013;500:232–6.
Roers A, Siewe L, Strittmatter E, et al. T cell-specific inactivation of the interleukin 10 gene in mice results in enhanced T cell responses but normal innate responses to lipopolysaccharide or skin irritation. J Exp Med. 2004;200:1289–97.
Groux H, Powrie F. Regulatory T cells and inflammatory bowel disease. Immunol Today. 1999;20:442–6.
Brockmann L, Soukou S, Steglich B, et al. Molecular and functional heterogeneity of IL-10-producing CD4 + T cells. Nat Commun. 2018;9:5457.
Mishima Y, Liu B, Hansen JJ, et al. Resident bacteria-stimulated IL-10-secreting B cells ameliorate T cell-mediated colitis by inducing Tr-1 cells that require IL-27-signaling. Cell Mol Gastroenterol Hepatol. 2015;1:295–310.
Mishima Y, Ishihara S, Aziz MM, et al. Decreased production of interleukin-10 and transforming growth factor-β in Toll-like receptor-activated intestinal B cells in SAMP1/Yit mice. Immunology. 2010;131:473–87.
Mizoguchi A, Mizoguchi E, Takedatsu H, et al. Chronic intestinal inflammatory condition generates IL-10-producing regulatory B cell subset characterized by CD1d upregulation. Immunity. 2002;16:219–30.
Mishima Y, Oka A, Liu B, et al. Microbiota maintain colonic homeostasis by activating TLR2/MyD88/PI3 K signaling in IL-10-producing regulatory B cells. J Clin Invest. 2019;130:pii: 93820.
Liu B, Tonkonogy SL, Sartor RB. Antigen-presenting cell production of IL-10 inhibits T-helper 1 and 17 cell responses and suppresses colitis in mice. Gastroenterology. 2011;141(653–62):662.e1–4.
Rutella S, Locatelli F. Intestinal dendritic cells in the pathogenesis of inflammatory bowel disease. World J Gastroenterol. 2011;17:3761–75.
Shouval DS, Biswas A, Goettel JA, et al. Interleukin-10 receptor signaling in innate immune cells regulates mucosal immune tolerance and anti-inflammatory macrophage function. Immunity. 2014;40:706–19.
Wang S, **a P, Chen Y, et al. Regulatory innate lymphoid cells control innate intestinal inflammation. Cell. 2017;171(201–216):e18.
Giuffrida P, Cococcia S, Delliponti M, et al. Controlling gut inflammation by restoring anti-inflammatory pathways in inflammatory Bowel disease. Cells. 2019;8:397.
Onali S, Favale A, Fantini MC. The resolution of intestinal inflammation: the Peace–Keeper’s Perspective. Cells. 2019;8:344.
Sun M, He C, Cong Y, Liu Z. Regulatory immune cells in regulation of intestinal inflammatory response to microbiota. Mucosal Immunol. 2015;8:969–78.
Ciullini Mannurita S, Gambineri E. Novel molecular defects associated with very early-onset inflammatory bowel. Curr Opin Allergy Clin Immunol. 2017;17:317–24.
Knox NC, Forbes JD, Van Domselaar G, et al. The gut microbiome as a target for ibd treatment: are we there yet? Curr Treat Options Gastroenterol. 2019;17:115–26.
Nishida A, Inoue R, Inatomi O, et al. Gut microbiota in the pathogenesis of inflammatory bowel disease. Clin J Gastroenterol. 2018;11:1–10.
Ni J, Wu GD, Albenberg L, et al. Gut microbiota and IBD: causation or correlation? Nat Rev Gastroenterol Hepatol. 2017;14:573–84.
Lewis JD, Chen EZ, Baldassano RN, et al. Inflammation, antibiotics, and diet as environmental stressors of the gut microbiome in pediatric crohn’s disease. Cell Host Microbe. 2015;18:489–500.
Albenberg L, Esipova TV, Judge CP, et al. Correlation between intraluminal oxygen gradient and radial partitioning of intestinal microbiota. Gastroenterology. 2014;147(1055–63):e8.
Fang FC, Vázquez-Torres A. Reactive nitrogen species in host-bacterial interactions. Curr Opin Immunol. 2019;60:96–102.
Wang S, El-Fahmawi A, Christian DA, et al. Infection-induced intestinal dysbiosis is mediated by macrophage activation and nitrate production. MBio. 2019;10:pii: e00935-19.
Eun CS, Mishima Y, Wohlgemuth S, et al. Induction of bacterial antigen-specific colitis by a simplified human microbiota consortium in gnotobiotic interleukin-10-/- mice. Infect Immun. 2014;82:2239–46.
Hansen JJ, Huang Y, Peterson DA, et al. The colitis-associated transcriptional profile of commensal Bacteroides thetaiotaomicron enhances adaptive immune responses to a bacterial antigen. PLoS One. 2012;7:e42645.
Hansen JJ. Immune responses to intestinal microbes in inflammatory Bowel diseases. Curr Allergy Asthma Rep. 2015;15:61.
Lengfelder I, Sava IG, Hansen JJ, et al. Complex bacterial consortia reprogram the colitogenic activity of enterococcus faecalis in a gnotobiotic mouse model of chronic. Immun Med Colitis Front Immunol. 2019;10:1420.
Gevers D, Kugathasan S, Denson LA, et al. The treatment-naive microbiome in new-onset Crohn’s disease. Cell Host Microbe. 2014;15:382–92.
Knights D, Silverberg MS, Weersma RK, et al. Complex host genetics influence the microbiome in inflammatory bowel disease. Genome Med. 2014;6:107.
Lamas B, Richard ML, Leducq V, et al. CARD9 impacts colitis by altering gut microbiota metabolism of tryptophan into aryl hydrocarbon receptor ligands. Nat Med. 2016;22:598–605.
Byndloss MX, Olsan EE, Rivera-Chávez F, et al. Microbiota-activated PPAR-γ signaling inhibits dysbiotic Enterobacteriaceae expansion. Science. 2017;357:570–5.
Örtqvist AK, Lundholm C, Halfvarson J, et al. Fetal and early life antibiotics exposure and very early onset inflammatory bowel disease: a population-based study. Gut. 2019;68:218–25.
Schaubeck M, Clavel T, Calasan J, et al. Dysbiotic gut microbiota causes transmissible Crohn’s disease-like ileitis independent of failure in antimicrobial defence. Gut. 2016;65:225–37.
Britton GJ, Contijoch EJ, Mogno I, et al. Microbiotas from Humans with Inflammatory Bowel Disease Alter the Balance of Gut Th17 and RORγt + Regulatory T Cells and Exacerbate Colitis in Mice. Immunity. 2019;50(212–224):e4.
Nagao-Kitamoto H, Shreiner AB, Gillilland MG, et al. Functional characterization of inflammatory bowel disease-associated gut dysbiosis in gnotobiotic mice. Cell Mol Gastroenterol Hepatol. 2016;2:468–81.
Round JL, Palm NW. Causal effects of the microbiota on immune-mediated diseases. Sci Immunol. 2018;3:eaao1603.
Ahluwalia B, Moraes L, Magnusson MK, et al. Immunopathogenesis of inflammatory bowel disease and mechanisms of biological therapies. Scand J Gastroenterol. 2018;53:379–89.
Ivanov II, Atarashi K, Manel N, et al. Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell. 2009;139:485–98.
Atarashi K, Tanoue T, Ando M, et al. Th17 cell induction by adhesion of microbes to intestinal epithelial cells. Cell. 2015;163:367–80.
Omenetti S, Bussi C, Metidji A, et al. The intestine harbors functionally distinct homeostatic tissue-resident and inflammatory Th17 Cells. Immunity. 2019;51:77–89.e6.
Viladomiu M, Kivolowitz C, Abdulhamid A, et al. IgA-coated E. coli enriched in Crohn’s disease spondyloarthritis promote TH17-dependent inflammation. Sci Transl Med. 2017;9:pii: eaaf9655.
Kim SC, Tonkonogy SL, Albright CA, et al. Variable phenotypes of enterocolitis in interleukin 10-deficient mice monoassociated with two different commensal bacteria. Gastroenterology. 2005;128:891–906.
Atarashi K, Suda W, Luo C, et al. Ectopic colonization of oral bacteria in the intestine drives TH1 cell induction and inflammation. Science. 2017;358:359–65.
Teigen LM, Geng Z, Sadowsky MJ, et al. Dietary factors in sulfur metabolism and pathogenesis of ulcerative colitis. Nutrients. 2019;11:931.
Wilson A, Teft WA, Morse BL, et al. Trimethylamine-N-oxide: a novel biomarker for the identification of inflammatory bowel disease. Dig Dis Sci. 2015;60:3620–30.
Tilg H, Moschen AR. Food, immunity, and the microbiome. Gastroenterology. 2015;148:1107–19.
Smith PM, Howitt MR, Panikov N, et al. The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis. Science. 2013;341:569–73.
Brown EM, Ke X, Hitchcock D, et al. Bacteroides-derived sphingolipids are critical for maintaining intestinal homeostasis and symbiosis. Cell Host Microbe. 2019;25(668–680):e7.
Chen ML, Takeda K, Sundrud MS. Emerging roles of bile acids in mucosal immunity and inflammation. Mucosal Immunol. 2019;12:851–61.
Van den Bossche L, Hindryckx P, Devisscher L, et al. Ursodeoxycholic acid and its taurine- or glycine-conjugated species reduce colitogenic dysbiosis and equally suppress experimental colitis in mice. Appl Environ Microbiol Am Soc Microbiol. 2017;83:e02766-16.
Ding L, Yang L, Wang Z, et al. Bile acid nuclear receptor FXR and digestive system diseases. Acta Pharm Sin B. 2015;5:135–44.
Nagahashi M, Takabe K, Liu R, et al. Conjugated bile acid-activated S1P receptor 2 is a key regulator of sphingosine kinase 2 and hepatic gene expression. Hepatology. 2015;61:1216–26.
Aoki R, Aoki-Yoshida A, Suzuki C, et al. Indole-3-pyruvic acid, an aryl hydrocarbon receptor activator, suppresses experimental colitis in mice. J Immunol. 2018;201:3683–93.
Naganuma M, Sugimoto S, Mitsuyama K, et al. Efficacy of indigo naturalis in a multicenter randomized controlled trial of patients with ulcerative colitis. Gastroenterology. 2018;154:935–47.
Zelante T, Iannitti RG, Cunha C, et al. Tryptophan catabolites from microbiota engage aryl hydrocarbon receptor and balance mucosal reactivity via interleukin-22. Immunity. 2013;39:372–85.
Monteleone I, Rizzo A, Sarra M, et al. Aryl hydrocarbon receptor-induced signals up-regulate IL-22 production and inhibit inflammation in the gastrointestinal tract. Gastroenterology. 2011;141(237–48):248.e1.
Levast B, Li Z, Madrenas J. The role of IL-10 in microbiome-associated immune modulation and disease tolerance. Cytokine. 2015;75:291–301.
Shouval DS, Ouahed J, Biswas A, et al. Interleukin 10 receptor signaling: master regulator of intestinal mucosal homeostasis in mice and humans. Adv Immunol. 2014;122:177–210.
Franke A, Balschun T, Karlsen TH, et al. Sequence variants in IL10, ARPC2 and multiple other loci contribute to ulcerative colitis susceptibility. Nat Genet. 2008;40:1319–23.
Amre DK, Mack DR, Morgan K, et al. Interleukin 10 (IL-10) gene variants and susceptibility for paediatric onset Crohn’s disease. Aliment Pharmacol Ther. 2009;29:1025–31.
Glocker EEO, Kotlarz D, Boztug K, et al. Inflammatory bowel disease and mutations affecting the interleukin-10 receptor. N Engl J Med. 2009;361:2033–45.
Marlow GJ, van Gent D, Ferguson LR. Why interleukin-10 supplementation does not work in Crohn’s disease patients. World J Gastroenterol. 2013;19:3931–41.
Schreiber S, Fedorak RN, Nielsen OH, et al. Safety and efficacy of recombinant human interleukin 10 in chronic active Crohn’s disease. Gastroenterology. 2000;119:1461–72.
Colombel J-F, Rutgeerts P, Malchow H, et al. Interleukin 10 (Tenovil) in the prevention of postoperative recurrence of Crohn’s disease. Gut. 2001;49:42–6.
Steidler L, Hans W, Schotte L, et al. Treatment of murine colitis by Lactococcus lactis secreting interleukin-10. Science. 2000;289:1352–5.
Braat H, Rottiers P, Hommes DW, et al. A phase I trial with transgenic bacteria expressing interleukin-10 in Crohn’s disease. Clin Gastroenterol Hepatol. 2006;4:754–9.
Atarashi K, Tanoue T, Shima T, et al. Induction of colonic regulatory T cells by indigenous Clostridium species. Science. 2011;331:337–41.
Round JL, Lee SM, Li J, et al. The Toll-like receptor 2 pathway establishes colonization by a commensal of the human microbiota. Science. 2011;332:974–7.
Furusawa Y, Obata Y, Hase K. Commensal microbiota regulates T cell fate decision in the gut. Semin Immunopathol. 2015;37:17–25.
Quévrain E, Maubert MA, Michon C, et al. Identification of an anti-inflammatory protein from Faecalibacterium prausnitzii, a commensal bacterium deficient in Crohn’s disease. Gut. 2016;65:415–25.
Sokol H, Pigneur B, Watterlot L, et al. Faecalibacterium prausnitzii is an anti-inflammatory commensal bacterium identified by gut microbiota analysis of Crohn disease patients. Proc Natl Acad Sci. 2008;105:16731–6.
Yang B-H, Hagemann S, Mamareli P, et al. Foxp3(+) T cells expressing RORγt represent a stable regulatory T-cell effector lineage with enhanced suppressive capacity during intestinal inflammation. Mucosal. Immunol. 2016;9:444–57.
Lochner M, Peduto L, Cherrier M, et al. In vivo equilibrium of proinflammatory IL-17 + and regulatory IL-10 + Foxp3 + RORgamma t + T cells. J Exp Med. 2008;205:1381–93.
Sefik E, Geva-Zatorsky N, Oh S, et al. Mucosal immunology. Individual intestinal symbionts induce a distinct population of RORγ+ regulatory T cells. Science. 2015;349:993–7.
Furusawa Y, Obata Y, Fukuda S, et al. Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature. 2013;504:446–50.
Parada Venegas D, De la Fuente MK, Landskron G, et al. Short chain fatty acids (SCFAs)-mediated gut epithelial and immune regulation and its relevance for inflammatory bowel diseases. Front Immunol. 2019;10:277.
Louis P, Flint HJ. Formation of propionate and butyrate by the human colonic microbiota. Environ Microbiol. 2017;19:29–41.
Ray A, Wang L, Dittel BN. IL-10-independent regulatory B-cell subsets and mechanisms of action. Int Immunol. 2015;27:531–6.
Hanson ML, Hixon JA, Li W, et al. Oral delivery of IL-27 recombinant bacteria attenuates immune colitis in mice. Gastroenterology. 2014;1:210–221.e13.
Sichien D, Lambrecht BN, Guilliams M, et al. Development of conventional dendritic cells: from common bone marrow progenitors to multiple subsets in peripheral tissues. Mucosal. Immunol. 2017;10:831–44.
Kayama H, Nishimura J, Takeda K. Regulation of intestinal homeostasis by innate immune cells. Immun Netw. 2013;13:227–34.
Yagi S, Abe M, Yamashita M, et al. Carbonic anhydrate I epitope peptide improves inflammation in a murine model of inflammatory Bowel disease. Inflamm Bowel Dis. 2016;22:1835–46.
Scott CL, Aumeunier AM, Mowat AM. Intestinal CD103 + dendritic cells: master regulators of tolerance? Trends Immunol. 2011;32:412–9.
Bain CC, Montgomery J, Scott CL, et al. TGFβR signalling controls CD103 + CD11b + dendritic cell development in the intestine. Nat Commun. 2017;8:620.
Nakahashi-Oda C, Udayanga KGS, Nakamura Y, et al. Apoptotic epithelial cells control the abundance of Treg cells at barrier surfaces. Nat Immunol. 2016;17:441–50.
Wynn TA, Chawla A, Pollard JW. Macrophage biology in development, homeostasis and disease. Nature. 2013;496:445–55.
Mowat AM, Scott CL, Bain CC. Barrier-tissue macrophages: functional adaptation to environmental challenges. Nat Med. 2017;23:1258–70.
Orecchioni M, Ghosheh Y, Pramod AB, et al. Macrophage polarization: different gene signatures in M1(LPS +) vs. classically and M2(LPS-) vs. alternatively activated macrophages. Front Immunol. 2019;10:1084.
Na YR, Stakenborg M, Seok SH, et al. Macrophages in intestinal inflammation and resolution: a potential therapeutic target in IBD. Nat. Rev. Gastroenterol. Hepatol. 2019;16:531–43.
Bernardo D, Marin AC, Fernández-Tomé S, et al. Human intestinal pro-inflammatory CD11chighCCR101 + CX3CR101 + macrophages, but not their tolerogenic CD11c-CCR101-CX3CR101-ounterparts, are expanded in inflammatory bowel disease. Mucosal Immunol. 2018;11:1114–26.
Biagioli M, Capobianco D, Carino A, et al. Divergent effectiveness of multispecies probiotic preparations on intestinal microbiota structure depends on metabolic properties. Nutrients. 2019;11:pii: E325.
Biagioli M, Carino A, Cipriani S, et al. The bile acid receptor GPBAR1 regulates the M1/M2 phenotype of intestinal macrophages and activation of GPBAR1 rescues mice from murine colitis. J Immunol. 2017;199:718–33.
Vivier E, Artis D, Colonna M, et al. Innate lymphoid cells: 10 years On. Cell. 2018;174:1054–66.
Klose CSN, Artis D. Innate lymphoid cells as regulators of immunity, inflammation and tissue homeostasis. Nat Immunol. 2016;17:765–74.
Ford AC, Sandborn WJ, Khan KJ, et al. Efficacy of biological therapies in inflammatory bowel disease: systematic review and meta-analysis. Am J Gastroenterol. 2011;106:644–59.
Abraham C, Dulai PS, Vermeire S, et al. Lessons learned from trials targeting cytokine pathways in patients with inflammatory bowel diseases. Gastroenterology. 2017;152:374–388.e4.
Kugathasan S, Denson LA, Walters TD, et al. Prediction of complicated disease course for children newly diagnosed with Crohn’s disease: a multicentre inception cohort study. Lancet (Lond Engl.). 2017;389:1710–8.
Murthy SK, Begum J, Benchimol EI, et al. Introduction of anti-TNF therapy has not yielded expected declines in hospitalisation and intestinal resection rates in inflammatory bowel diseases: a population-based interrupted time series study. Gut. 2019.https://doi.org/10.1136/gutjnl-2019-318440.
Sartor RB. Therapeutic correction of bacterial dysbiosis discovered by molecular techniques. Proc Natl Acad Sci USA. 2008;105:16413–4.
Cohen LJ, Cho JH, Gevers D, et al. Genetic factors and the intestinal microbiome guide development of microbe-based therapies for inflammatory bowel diseases. Gastroenterology. 2019;156:2174–89.
Basso PJ, Câmara NOS, Sales-Campos H. Microbial-based therapies in the treatment of inflammatory bowel disease—an overview of human studies. Front Pharmacol. 2018;9:1571.
Khan KJ, Ullman TA, Ford AC, et al. Antibiotic therapy in inflammatory bowel disease: a systematic review and meta-analysis. Am J Gastroenterol. 2011;106:661–73.
Sartor RB. Review article: the potential mechanisms of action of rifaximin in the management of inflammatory bowel diseases. Aliment Pharmacol Ther. 2016;43(Suppl 1):27–36.
Nitzan O, Elias M, Peretz A, et al. Role of antibiotics for treatment of inflammatory bowel disease. World J Gastroenterol. 2016;22:1078–87.
Zuo T, Ng SC. The Gut microbiota in the pathogenesis and therapeutics of inflammatory bowel disease. Front Microbiol. 2018;9:2247.
Turner D, Levine A, Kolho K-L, et al. Combination of oral antibiotics may be effective in severe pediatric ulcerative colitis: a preliminary report. J Crohns Colitis. 2014;8:1464–70.
Ohkusa T, Kato K, Terao S, et al. Newly developed antibiotic combination therapy for ulcerative colitis: a double-blind placebo-controlled multicenter trial. Am J Gastroenterol. 2010;105:1820–9.
Vangay P, Ward T, Gerber JS, et al. Antibiotics, pediatric dysbiosis, and disease. Cell Host Microbe. 2015;17:553–64.
Gionchetti P, Rizzello F, Venturi A, et al. Oral bacteriotherapy as maintenance treatment in patients with chronic pouchitis: a double-blind, placebo-controlled trial. Gastroenterology. 2000;119:305–9.
Zmora N, Zilberman-Schapira G, Suez J, et al. Personalized Gut mucosal colonization resistance to empiric probiotics is associated with unique host and microbiome features. Cell. 2018;174(1388–1405):e21.
O’Toole PW, Marchesi JR, Hill C. Next-generation probiotics: the spectrum from probiotics to live biotherapeutics. Nat Microbiol. 2017;2:17057.
Sartor RB. Therapeutic manipulation of the enteric microflora in inflammatory bowel diseases: antibiotics, probiotics, and prebiotics. Gastroenterology. 2004;126:1620–33.
Gibson GR, Hutkins R, Sanders ME, et al. Expert consensus document: the International Scientific Association for Probiotics and Prebiotics (ISAPP) consensus statement on the definition and scope of prebiotics. Nat Rev Gastroenterol Hepatol. 2017;14:491–502.
Eom T, Kim YS, Choi CH, et al. Current understanding of microbiota- and dietary-therapies for treating inflammatory bowel disease. J Microbiol. 2018;56:189–98.
Shokryazdan P, Faseleh Jahromi M, Navidshad B, et al. Effects of prebiotics on immune system and cytokine expression. Med Microbiol Immunol. 2017;206:1–9.
Kassam Z, Lee CH, Yuan Y, et al. Fecal Microbiota Transplantation for Clostridium difficile Infection: systematic review and meta-analysis. Am J Gastroenterol. 2013;108:500–8.
Vaughn BP, Rank KM, Khoruts A. Fecal Microbiota Transplantation: current status in treatment of GI and liver disease. Clin Gastroenterol Hepatol. 2019;17:353–61.
Paramsothy S, Kamm MA, Kaakoush NO, et al. Multidonor intensive faecal microbiota transplantation for active ulcerative colitis: a randomised placebo-controlled trial. Lancet (Lond Engl.). 2017;389:1218–28.
Paramsothy S, Nielsen S, Kamm MA, et al. Specific bacteria and metabolites associated with response to fecal microbiota transplantation in patients with ulcerative colitis. Gastroenterology. 2019;156:1440–1454.e2.
Kanai T, Mikami Y, Hayashi A. A breakthrough in probiotics: clostridium butyricum regulates gut homeostasis and anti-inflammatory response in inflammatory bowel disease. J Gastroenterol. 2015;50:928–39.
Delday M, Mulder I, Logan ET, et al. Bacteroides thetaiotaomicron Ameliorates Colon Inflammation in preclinical models of Crohn’s disease. Inflamm Bowel Dis. 2019;25:85–96.
Takahashi K, Nishida A, Fujimoto T, et al. Reduced abundance of butyrate-producing bacteria species in the fecal microbial community in Crohn’s disease. Digestion. 2016;93:59–65.
Ihekweazu FD, Fofanova TY, Queliza K, et al. Bacteroides ovatus ATCC 8483 monotherapy is superior to traditional fecal transplant and multi-strain bacteriotherapy in a murine colitis model. Gut Microb. 2019;10:504–20.
Sivignon A, Bouckaert J, Bernard J, et al. The potential of FimH as a novel therapeutic target for the treatment of Crohn’s disease. Expert Opin Ther Targets. 2017;21:837–47.
Galtier M, De Sordi L, Sivignon A, et al. Bacteriophages targeting adherent invasive Escherichia coli strains as a promising new treatment for Crohn’s disease. J. Crohn’s Colitis. 2017;11:840–7.
Bikard D, Euler CW, Jiang W, et al. Exploiting CRISPR-Cas nucleases to produce sequence-specific antimicrobials. Nat Biotechnol. 2014;32:1146–50.
Vandenbroucke K, de Haard H, Beirnaert E, et al. Orally administered L. lactis secreting an anti-TNF Nanobody demonstrate efficacy in chronic colitis. Mucosal Immunol. 2010;3:49–56.
Zhang B, Liu Y, Lan X, et al. Oral Escherichia coli expressing IL-35 meliorates experimental colitis in mice. J Transl Med. 2018;16:71.
Shigemori S, Shimosato T. Applications of genetically modified immunobiotics with high immunoregulatory capacity for treatment of inflammatory Bowel diseases. Front Immunol. 2017;8:22.
Wang L, **e H, Xu L, et al. rSj16 protects against DSS-induced colitis by inhibiting the PPAR-α signaling pathway. Theranostics. 2017;7:3446–60.
Zhu W, Winter MG, Byndloss MX, et al. Precision editing of the gut microbiota ameliorates colitis. Nature. 2018;553:208–11.
Wallace BD, Wang H, Lane KT, et al. Alleviating cancer drug toxicity by inhibiting a bacterial enzyme. Science. 2010;330:831–5.
Gilbert JA, Blaser MJ, Caporaso JG, et al. Current understanding of the human microbiome. Nat Med. 2018;24:392–400.
Zmora N, Suez J, Elinav E. You are what you eat: diet, health and the gut microbiota. Nat Rev Gastroenterol Hepatol. 2019;16:35–56.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
Dr. Mishima has no financial conflicts of interest to declare. Dr. Sartor receives research preclinical grant support from Janssen, Gusto Global, Vedanta, Seres and BiomX and is on Advisory Boards for Danone/Yakult, Second Genome, BiomX, Biomica and Qu Pharmaceuticals.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
About this article
Cite this article
Mishima, Y., Sartor, R.B. Manipulating resident microbiota to enhance regulatory immune function to treat inflammatory bowel diseases. J Gastroenterol 55, 4–14 (2020). https://doi.org/10.1007/s00535-019-01618-1
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00535-019-01618-1