BioMed Research International

BioMed Research International / 2019 / Article
Special Issue

Interplay between Immune Cells and their Microenvironment Niches

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Review Article | Open Access

Volume 2019 |Article ID 6764919 | 8 pages |

Interactions between Intestinal Microflora/Probiotics and the Immune System

Academic Editor: Zenghui Teng
Received28 Jun 2019
Revised24 Oct 2019
Accepted04 Nov 2019
Published20 Nov 2019


The digestive tract is home to millions of microorganisms and is the main and most important part of bacterial colonization. On one hand, the abundant bacterial community in intestinal tissues may pose potential health challenges such as inflammation and sepsis in cases of opportunistic invasion. Thus, the immune system has evolved and adapted to maintain the symbiotic relationship between host and microbiota. On the other hand, the intestinal microflora also exerts an immunoregulatory function to maintain host immune homeostasis, which cannot be neglected. In addition, the interaction of either microbiota or probiotics with immune system in regard to therapeutic applications is an area of great interest, and novel therapeutic strategies remain to be investigated. The review will elucidate interactions between intestinal microflora/probiotics and the immune system as well as novel therapeutic strategies.

1. Intestinal Immune System

Gut associated lymphoid tissue (GALT) is composed of the epithelium, lamina propria, and muscular layer [1]. Enterocytes constitute most of the intestinal epithelial cells and are able to absorb sugar, amino acid, and many other nutrients. Some enterocytes express Toll-like receptors (TLRs) and will secrete a series of proinflammatory chemokines (IL-8), cytokines (IL-1, IL-6, IL-7, IL-11, and TNF), and growth factors (SCF and G-CSF) when encountering with pathogens or toxins. These molecules will recruit peripheral neutrophils and mast cells to intestinal subepithelial regions and accelerate activation and differentiation of local lymphocytes. For instance, IL-7 and SCF secreted by intestinal epithelial cells can act synergistically to activate γδ intestinal intraepithelial lymphocytes (iIELs). Then, activated γδ–iIEL can also secrete cytokines and chemokines to activate αβ–iIEL, thus initiating a more robust adaptive immune response [24]. Between intestinal epithelial cells are enteroendocrine cells, paneth cells, and goblet cells. When a pathogen invades the body, paneth cells release certain antibacterial molecules such as defensins into villi in the small intestine lumen while goblet cells secrete mucus to the intestinal surface, which is helpful for maintaining the intestinal barrier [5, 6]. Intraepithelial αβT and γδT lymphocytes, NK cells, and NKT cells can also be gathered among intestinal epithelial cells. Intestinal intraepithelial lymphocytes (iIELs) are a unique cluster of cells which reside in intestinal mucosal epithelium and have two different cell sources. Approximately 40 percent of iIELs are thymus-dependent αβ T cells and their phenotype is similar to peripheral T cells. About 60 percent of iIELs are thymus-independent γδ T cells. γδ T cells are innate immune cells with strong cytotoxicity as well as the capacity to secrete various cytokines. Therefore, iIEL plays a vital role in immunosurveillance and cell-mediated mucosal immunity [79].

Lamina propria contains a large number of macrophages and neutrophils as well as a small number of NKT cells, mast cells, and immature dendritic cells. A certain number of mature αβ T cells and B cells as well as few γδ T cells also reside in the lamina propria [10, 11]. Lymphocytes in the lamina propria usually congregate together to form intestinal follicle, which contains germinal centers populated by B cells and follicular dendritic cells, topped by immature dendritic cells, macrophages, CD4+T cells, and mature B cells [12, 13]. Located in one side of intestinal follicle that is close to the intestinal luminal are specialized phagocytic cells named M cells, which can transport antigens across the epithelium to the side of basement membrane via transcytosis. Consequently, the antigens interact with the local immune cells and initiate mucosal immune responses where B cells differentiate into IgA secreting plasma cells [1416]. The elements of intestinal mucosal immunity are summarized in Table 1.

StructuresConstitutionEffect and mechanism

LumenCommensal bacteriaCompetitively inhibit pathogenic bacteria
Produce antimicrobial substances
MucusTraps pathogens
Prevents access to epithelial layer
Contains secretory immunoglobulin A
GlycocalyxProvides physical barrier

Epithelial layerEnterocytesConnected by tight junctions
Surface TLRs induce secretion of proinflammatory chemokines, cytokines, and growth factors
Capture some antigens
Goblet cellsSecrete mucus
Paneth cellsProduce defensins and antibiotic substances
Enteroendocrine cellsProduce neuroendocrine mediators
γδiIELsPromote αβiIEL activation through cytokine and chemokine secretion
Produce antimicrobial effectors and protect against pathogens
Prevent inflammation-induced epithelium damage
M cellsCapture and transport antigen

Lamina propriaαβT cells, B cells, DCs, and other APCsInitiate adaptive immune responses in lymphoid follicles
Treg cellsSuppress activation and effector function of immune cells

The intestine is a unique organ which is in close contact with microorganisms. Most microbes are destroyed and killed by the harsh gastric acid environment, but a few can still make it through the intestine. The intestinal surface is covered with a large number of finger-like projections called microvilli (also named brush border), whose primary function is the absorption of nutrients. Brush border is wrapped up by a molecule called glycocalyx [17]. Since glycocalyx is a negatively charged and mucoid glycoprotein complex, microvilli could prevent the invasion of pathogenic bacteria. Besides, apical tight junctions of intestinal epithelial cells also ensure that pathogens do not pass through the intestine [18]. A vast population of immune cells reside within these and the underlying structures. As the most crucial intestinal sentinels, Peyer’s patches are composed of B-cell follicles, interfollicular regions, macrophages, and dendritic cells [19]. A key function of Peyer’s patch is sampling of particulate antigens, mostly bacteria and food through a specialized phagocytic cells called M cells, which can transport material from the lumen to subepithelial dome [20]. Then, local dendritic cells are able to sample antigens and present them to immune effector cells [21]. Nevertheless, intestinal tolerance is mainly mediated by CD4+ Treg cells in the context of uptake of food antigens. These Treg cells secrete IL-10 and TGF-β which exerts suppressive effects on immune cells within the lamina propria. However, a breakdown in the process of immune hemostasis will lead to gut pathology such as food allergy and inflammatory bowel disease [22, 23]. Intestinal barriers including mucin, antimicrobial peptides, and secretory IgA prevent the direct contact between the microorganisms and gut epithelial layer. Barrier destructions can contribute to bacteria influx, activation of epithelium, and inflammatory responses [24]. Proinflammatory antigen-presenting macrophages and dendritic cells are activated and release inflammatory cytokines such as IL-6, IL-12, and IL-23. Th1 and Th17 effector T-cell subsets are polarized and produce inflammatory cytokines such as TNF-α, IFN-γ, and IL-17 [25]. In addition, neutrophils are recruited and undergo dramatic form of cell destruction called NETosis, with the production of neutrophil extracellular traps (NETs) and tissue injuries [26].

2. Intestinal Microflora and Probiotics

There are a large number of microorganisms in the intestine, which are mainly distributed in the colon. It is estimated that over 40 trillion bacteria (including Archaebacteria) inhabit in the colon of adults, with a small proportion of fungus and Protista. In general, each individual carries an average of 600,000 intestinal microbial genes [27, 28]. In terms of bacterial strains, there is a distinct diversity among individuals. Each individual has his unique intestinal microflora, which is determined by host genotype, initial colonization through vertical transmission at birth, and dietary habits [2932]. In healthy adults, the composition of bacterial flora in feces is stable regardless of time. Bacteroidetes and Firmicutes are two main bacteria in human intestinal ecosystem, accounting for over 90 percent of all microorganisms. The remains are Actinobacteria, Proteobacteria, Verrucomicrobia, and Fusobacteria [33, 34]. Probiotics are microorganisms that may be beneficial to health when consumed in adequate amounts [35]. Lactobacillus and Bifidobacteria are most commonly applied probiotics in clinical practice. Yeast Saccharomyces boulardii and Bacillus species are also widely used [36, 37]. The function of probiotics is closely related to the species of microorganisms that colonize within the intestine. The interaction between probiotics and host cells as well as intestinal flora is a key factor which influences the host health. Probiotics have an impact on intestinal ecosystem by regulating gut mucosal immunity, by having interactions with commensal microflora or potentially harmful pathogens, by producing metabolites (such as short-chain fatty acids and bile acids), and by acting on host cells through signaling pathways (Table 2). These mechanisms can contribute to the inhibition and elimination of potential pathogens, improvement of intestinal microenvironment, strengthening the intestinal barrier, attenuation of inflammation, and enhancement of antigen-specific immune response [38, 39].


Immunologic functions
Stimulate intestinal antigen-presenting cells such as macrophages or dendritic cells and increase immunoglobulin A (IgA) secretion
Regulate lymphocyte polarization and cytokine profiles
Induce tolerance to food antigens

Nonimmunologic functions
Digest food and inhibitory compete with pathogens for nutrition and adhesion
Alter local PH to create an unfavorable microenvironment for pathogens
Generate bacteriocins to inhibit pathogens
Scavenge superoxide radicals
Promote epithelial antimicrobial peptides production and enhance intestinal barrier function

Disturbed intestinal immune niche is a contributory cause for the digestive diseases such as inflammatory bowel disease (IBD), functional dyspepsia, gastroesophageal reflux disease, and nonalcoholic fatty liver disease. IBD patients are characterized by an increase in potentially aggressive gut microbial strains as well as decreased regulatory species [4042]. Aggressive gut microbial strains activate inflammatory response by inducing Th1 and Th17 effector cells while decreased regulatory species inhibit the generation and function of regulatory cells including regulatory T cells (Treg), B cells (Breg), macrophages, dendritic cells (DCs), and innate lymphoid cells (ILCs). This has further resulted in elevated levels of TNF-α and inflammasome and reduced levels of IL-10, TGF-β, and IL-35 [43]. Therefore, dysbiosis of the intestinal flora has contributed to dysfunctional immune system and the chronic inflammation in IBD.

3. Immune Regulation by Microflora and Probiotics

3.1. Promoting the Balance of Th1, Th2, Th17, and Treg Cells

Actually, intestinal microorganism can elicit diverse signals and induce CD4+T-cell differentiation. Invasive bacteria such as ectopic colonization of Klebsiella species can induce DCs phagocytosis and release of proinflammatory cytokines (IL-6, IL-12, and TNF), which is closely associated with Th1 polarization. Bacteroides fragilis is a kind of symbiotic anaerobic bacteria which colonizes in human lower digestive tract. Polysaccharide A (PSA) in its outer membrane can be recognized by T-cell surface molecule TLR2, which induces differentiation of CD4+T cells into Treg cells. Here, the Treg cells secrete molecules such as IL-10 and TGF-β which exert a suppressive action on immune cells. Actually, it has been demonstrated that administration of PSA or intestinal Bacteroides fragilis colonization can prevent intestinal inflammatory diseases in mice models [4446]. In addition, segmented filamentous bacteria can be presented to T cells by dendritic cells and contribute to the synthesis of Th17 cells in lamina propria of small intestine, thus playing a vital role in antibacterial immune response [47, 48]. Parasites, for instance, Heligmosomoides polygyrus, can contribute to a Th2 immune response. The parasite can bind to tuft cells and secret high amounts of IL-25, which then acts upon dendritic cells. Dendritic cells produce IL-4 and TGF-β and induce CD4+ T differentiation into Th2 subset, with upregulated levels of IL-4 and GATA3 transcription factor. The immunomodulatory effects of various probiotics are listed in Table 3.

Literature (PMID)Probiotic strainsMechanism and immunologic effects

15940144, 11751960Lactobacillus reuteriPromote IL-10 secretion by Treg cells
Lactobacillus casei
17521319, 16297146Bifidobacterium bifidumPromote IL-10 secretion by mature DCs
15585777Lactobacillus rhamnosusInhibit T-cell proliferation
Decrease IL-2 and IL-4 secretion by mature DCs
15654823Bifidobacterium longumPromote IL-10 secretion by DCs
21740462E. coli strain, Nissle 1917Increase FoxP3+ Treg cells
19300508, 18804867Lactobacillus casei, DN-114 001Increase FoxP3+ Treg cells
Promote IL-10 and TGF-β secretion
18670628Bifidobacterium infantis 35, 624Increase FoxP3+ Treg cells
Inhibit TNF-α and IL-6 secretion
19029003Lactobacillus reuteri (ATCC 23272)Increase FoxP3+ Treg cells
16522473Bifidobacterium breveActivate TLR2 and promote maturation of DCs
Increase IL-10 secretion

3.2. Regulation of Intestinal Related Gene Expression

Previous reports have demonstrated that expression of multiple intestinal genes is regulated by probiotics. For instance, Escherichia coli and Lactobacillus rhamnosus can upregulate mucin expression in intestinal cells to enhance intestinal mucosal barrier. Probiotics can also regulate gene expression of enterocytes and dendritic cells. It has been demonstrated that probiotic VSL#3 in certain concentrations (107 organisms/mL) could alter the DC phenotypes by the upregulation of costimulatory molecule (CD80, CD86, and CD40) expression [49].

3.3. Regulation of Immune Response through Microbial Metabolites

Probiotics can produce a series of metabolites by digesting different foods and impact the immune response within the body.

3.3.1. Short-Chain Fatty Acids

Short-chain fatty acid (SCFA) is fatty acid with carbon chain length of 1–6 carbon atoms. It is produced through fermentation of fibres by probiotics. Intestinal SCFA mainly includes acetate, propionate, and butyrate. SCFA can exert its immunoregulatory function as both extracellular and intracellular signaling molecules [50, 51]. Extracellularly, SCFA can act as ligands for cell surface G protein coupled receptors such as GPR41, GPR43, and GPR109a and regulate immune function indirectly. SCFA can bind to GPR43 in the surface of neutrophils and eosinophils to alleviate intestinal inflammation. GPR109a, which is expressed in colon epithelial cells and innate immune cells, can specifically bind to butyrate and induce differentiation of Treg cells [52, 53]. Intracellularly, SCFA can inhibit histone deacetylases (HDAC) and regulate gene transcription to exert immunoregulatory functions. For example, SCFA can promote acetylation of FoxP3 and synthesis of colon FoxP3+Treg cells to enhance their immunosuppressive function. Butyrate can suppress HDAC activity of macrophages in intestinal lamina propria and inhibit their secretion of inflammatory mediators such as nitric oxide, IL-6, and IL-12 [54, 55]. In addition, SCFA can also promote Tfh-cell production, B-cell differentiation, and antibody synthesis, as evidenced by latest reports [56].

SCFA also plays a crucial role in homing of T cells. Retinol, the main component of vitamin A, can be oxidized into retinaldehyde by retinol dehydrogenase. Retinal can be further oxidized to retinoic acid (RA) in vivo through an enzyme called Aldh1a. SCFA, the metabolites of probiotics, increases the activity of Aldh1a and promotes the conversion of intestine absorbed vitamin A into RA. Dendritic cells in intestinal Peyer’s patch (PP) and mesenteric lymph nodes (MLN) express Aldh1a1 and Aldh1a2, respectively, and therefore produce RA locally. When an antigen is presented to T cells by CD103+ dendritic cells in MLD, the local RA induces expression of α4 in T-cell surfaces, which then binds with β7 to form α4β7 integrin. The α4β7 integrin can combine with MadCAM-1 molecule of high endothelial vein (HEV) surface. Meanwhile, RA also induces CCR9 expression in T-cell surface, which binds to CCL25 in intestinal epithelial cells [57, 58]. Therefore, probiotics can promote homing of T cells to intestinal mucosa.

3.3.2. Amino Acid Metabolites

Certain essential amino acids are produced as metabolites of probiotics. Particularly, tryptophan (Trp) is closely related to the immune system. Trp can be decomposed into various metabolites by microflora. In the gut, indolic acid derivatives, including indole-3-acetic acid (IAA), indole-3-aldehyde (IAld), indole acryloyl glycine (IAcrGly), indole lactic acid, and indole acrylic acid (IAcrA), originate from Trp catabolism. Specifically, intestinal bacteria, such as Bacteroides, Clostridia, and E. coli, can decompose Trp to tryptamine and indole pyruvic acid, which are then turned into IAA, indole propionic acid, and indole lactic acid. IAA can combine with glutamine to synthesize indolyl acetyl glutamine in the liver or converted to IAld through aerobic oxidation by peroxidase catalyzation. Indolyl propionic acid can also be further transformed to IAcrA and combine with glycine to produce IAcrGly in the liver or kidney [59]. Indole is the most effective product among various bacterial Trp metabolites. It can also attenuate TNF-α-induced activation of NF-κB and reduce expression of the proinflammatory chemokine IL-8 as well as the adhesive capacity of pathogenic E. coli to HCT-8 cells [60]. In addition, both indole and its derivatives (IAld, IAA, and tryptamine) can activate intestinal innate lymphoid cells (ILCs) and regulate local IL-22 synthesis by sensitizing AhR to maintain intestinal mucosal homeostasis [6163]. Besides, indole has been confirmed to strengthen intestinal epithelial barrier by fortifying tight junctions between cells through the pregnane X receptor (PXR) [64].

Gut commensal Ruminococcus gnavus and Firmicutes C. sporogenes have the capacity to decarboxylate Trp to tryptamine [65]. Since tryptamine exerts inhibitory effect against IDO1, it is regarded as a potential target in immune escape [66]. Skatole has been reported to inhibit CYP11A1, leading to decreased synthesis of pregnenolone, glucocorticoids, and sex steroids [67]. In the intestine, formation of endogenous steroid hormones, for instance, the anti-inflammatory glucocorticoid cortisol, is essential for the maintenance of intestinal homeostasis [68]. Therefore, skatole has been reported to play a vital role in the pathogenesis of inflammatory bowel disease (IBD).

3.3.3. Bile Acids

Bile acids are mainly converted from cholesterol in hepatocytes and undergo a series of metabolic processes mediated by intestinal microflora in the intestine. With the help of probiotics, primary bile acids, namely, cholic acid and chenodeoxycholic acid, convert to deoxycholic acid and lithocholic acid, respectively [69, 70]. Since intestinal macrophages, dendritic cells, and natural killer T cells express bile acids receptors such as GPBAR1 and FXR, intestinal bile acids can bind to these receptors and suppress NLRP3 mediated inflammatory response to maintain immune homeostasis [71, 72]. In addition, bile acids also regulate chemokine CXCL16 expression on liver sinusoidal endothelial cells (LSECs) and the accumulation of CXCR6+ hepatic NKT cells, which exhibit activated phenotypes and inhibit liver tumor growth [73].

3.3.4. Vitamins

Intestinal microflora has the capacity to synthesize vitamins and is their important source, especially for vitamin B [74]. As is known to all, vitamins play a vital role in regulating the immune system. Vitamin B1 is a key cofactor of tricarboxylic acid cycle. A decrease in vitamin B1 levels results in reduction of naive B cells residing in intestinal Peyer’s patch, thus influencing intestinal immune function [75]. As a cofactor of sphingosine-1-phosphate (S1P) lyase, vitamin B6 is involved in the degradation of S1P. Therefore, it plays a fundamental role in maintaining S1P concentration gradient and promoting intestinal lymphocytes migration to periphery [7680]. Besides, vitamin B also acts as a ligand for immune cells. The interaction is mediated by major histocompatibility complex MHC class I related proteins, which bind to vitamin B2, leading to the activation of mucosal-associated invariant T cells (MAITs) as well as secretion of IL-17 and IFN-γ. From this perspective, vitamin B2 has exerted the function of immune surveillance [81, 82].

At present, the immunoregulatory mechanism of probiotics is still not entirely clear regardless of its great variety and extensive clinical application. It requires further studies to investigate the in vivo process of probiotics through oral administration or enema therapy including the residence time, colonization, and reproduction, impact on original intestinal flora, and microbial interactions. And it is worthwhile to have a focus on the interaction of either microbiota or probiotics with immune system in regard to novel therapeutic applications. Apart from anti-TNF agents and immunomodulators, probiotics, prebiotics, and fecal microbial transplantation have been applied empirically in IBD. In addition, multiple novel strategies have already done in preclinical and clinical trials through targeting certain microbial organisms and altering mucosal immune niches. These strategies include blocking fimH to inhibit AIEC mucosal attachment, introduction of bacteriophages to eliminate pathobionts, and applying CRISPER-CAS editing to generate specific bacteriocins [8385]. Hopefully, these approaches will be more effective which can be applied in a personalized manner in the future.

Conflicts of Interest

The authors declare that they have no conflicts of interest.

Authors’ Contributions

Chen-xing Zhang and Hui-yu Wang are co-first authors and contributed equally to the work.


  1. E. M. Brown, M. Sadarangani, and B. B. Finlay, “The role of the immune system in governing host-microbe interactions in the intestine,” Nature Immunology, vol. 14, no. 7, pp. 660–667, 2013. View at: Publisher Site | Google Scholar
  2. E. C. Lavelle, C. Murphy, L. A. O’Neill, and E. M. Creagh, “The role of TLRs, NLRs, and RLRs in mucosal innate immunity and homeostasis,” Mucosal Immunology, vol. 3, no. 1, pp. 17–28, 2010. View at: Publisher Site | Google Scholar
  3. D. P. Hoytema van Konijnenburg, B. S. Reis, V. A. Pedicord et al., “Cell crosstalk mediates a dynamic response to infection,” Cell, vol. 171, no. 4, pp. 783–794, 2017. View at: Google Scholar
  4. A. Montalban-Arques, M. Chaparro, J. P. Gisbert, and D. Bernardo, “The innate immune system in the gastrointestinal tract: role of intraepithelial lymphocytes and lamina propria innate lymphoid cells in intestinal inflammation,” Inflammatory Bowel Diseases, vol. 24, no. 8, pp. 1649–1659, 2018. View at: Publisher Site | Google Scholar
  5. M. E. V. Johansson, M. Phillipson, J. Petersson, A. Velcich, L. Holm, and G. C. Hansson, “The inner of the two Muc2 mucin-dependent mucus layers in colon is devoid of bacteria,” Proceedings of the National Academy of Sciences, vol. 105, no. 39, pp. 15064–15069, 2008. View at: Publisher Site | Google Scholar
  6. C. L. Bevins and N. H. Salzman, “Paneth cells, antimicrobial peptides and maintenance of intestinal homeostasis,” Nature Reviews Microbiology, vol. 9, no. 5, pp. 356–368, 2011. View at: Publisher Site | Google Scholar
  7. N. Cerf-Bensussan and D. Guy-Grand, “Intestinal intraepithelial lymphocytes,” Gastroenterology Clinics of North America, vol. 20, no. 3, pp. 549–576, 1991. View at: Google Scholar
  8. L. Van Kaer and D. Olivares-Villagómez, “Development, homeostasis, and functions of intestinal intraepithelial lymphocytes,” The Journal of Immunology, vol. 200, no. 7, pp. 2235–2244, 2018. View at: Publisher Site | Google Scholar
  9. Y. Qiu and H. Yang, “Effects of intraepithelial lymphocyte-derived cytokines on intestinal mucosal barrier function,” Journal of Interferon & Cytokine Research, vol. 33, no. 10, pp. 551–562, 2013. View at: Publisher Site | Google Scholar
  10. A. M. Mowat and W. W. Agace, “Regional specialization within the intestinal immune system,” Nature Reviews Immunology, vol. 14, no. 10, pp. 667–685, 2014. View at: Publisher Site | Google Scholar
  11. O. Pabst and G. Bernhardt, “The puzzle of intestinal lamina propria dendritic cells and macrophages,” European Journal of Immunology, vol. 40, no. 8, pp. 2107–2111, 2010. View at: Publisher Site | Google Scholar
  12. T. W. Spahn and T. Kucharzik, “Modulating the intestinal immune system: the role of lymphotoxin and GALT organs,” Gut, vol. 53, no. 3, pp. 456–465, 2004. View at: Publisher Site | Google Scholar
  13. M. Buettner and M. Lochner, “Development and function of secondary and tertiary lymphoid organs in the small intestine and the colon,” Frontiers in Immunology, vol. 7, p. 342, 2016. View at: Publisher Site | Google Scholar
  14. H. Ohno, “Intestinal M cells,” Journal of Biochemistry, vol. 159, no. 2, pp. 151–160, 2016. View at: Publisher Site | Google Scholar
  15. N. A. Mabbott, D. S. Donaldson, H. Ohno, I. R. Williams, and A. Mahajan, “Microfold (M) cells: important immunosurveillance posts in the intestinal epithelium,” Mucosal Immunology, vol. 6, no. 4, pp. 666–677, 2013. View at: Publisher Site | Google Scholar
  16. D. Rios, M. B. Wood, J. Li, B. Chassaing, A. T. Gewirtz, and I. R. Williams, “Antigen sampling by intestinal M cells is the principal pathway initiating mucosal IgA production to commensal enteric bacteria,” Mucosal Immunology, vol. 9, no. 4, pp. 907–916, 2016. View at: Publisher Site | Google Scholar
  17. S. W. Crawley, M. S. Mooseker, and M. J. Tyska, “Shaping the intestinal brush border,” The Journal of Cell Biology, vol. 207, no. 4, pp. 441–451, 2014. View at: Publisher Site | Google Scholar
  18. D. Delacour, J. Salomon, S. Robine, and D. Louvard, “Plasticity of the brush border—the yin and yang of intestinal homeostasis,” Nature Reviews Gastroenterology & Hepatology, vol. 13, no. 3, pp. 161–174, 2016. View at: Publisher Site | Google Scholar
  19. C. Jung, J.-P. Hugot, and F. barreau, “Peyer’s patches: the immune sensors of the intestine,” International Journal of Inflammation, vol. 2010, Article ID 823710, 12 pages, 2010. View at: Publisher Site | Google Scholar
  20. A. Reboldi and J. G. Cyster, “Peyer’s patches: organizing B cell responses at the intestinal frontier,” Immunological Reviews, vol. 271, no. 1, pp. 230–245, 2016. View at: Publisher Site | Google Scholar
  21. C. Da Silva, C. Wagner, J. Bonnardel, J. P. Gorvel, and H. Lelouard, “The peyer’s patch mononuclear phagocyte system at steady state and during infection,” Frontiers in Immunology, vol. 8, p. 1254, 2017. View at: Publisher Site | Google Scholar
  22. O. J. Harrison and F. M. Powrie, “Regulatory T cells and immune tolerance in the intestine,” Cold Spring Harbor Perspectives in Biology, vol. 5, no. 8, Article ID a021022, 2013. View at: Publisher Site | Google Scholar
  23. K. S. Kim, S. W. Hong, D. Han et al., “Dietary antigens limit mucosal immunity by inducing regulatory T cells in the small intestine,” Science, vol. 351, no. 6275, pp. 858–863, 2016. View at: Publisher Site | Google Scholar
  24. F. Haussner, S. Chakraborty, R. Halbgebauer, and M. Huber-Lang, “Challenge to the intestinal mucosa during sepsis,” Frontiers in Immunology, vol. 10, p. 891, 2019. View at: Publisher Site | Google Scholar
  25. K. R. Groschwitz and S. P. Hogan, “Intestinal barrier function: molecular regulation and disease pathogenesis,” Journal of Allergy and Clinical Immunology, vol. 124, no. 1, pp. 3–20, 2009. View at: Publisher Site | Google Scholar
  26. L. Vong, C. W. Yeung, L. J. Pinnell, and P. M. Sherman, “Adherent-invasive Escherichia coli exacerbates antibiotic-associated intestinal dysbiosis and neutrophil extracellular trap activation,” Inflammatory Bowel Diseases, vol. 22, no. 1, pp. 42–54, 2016. View at: Publisher Site | Google Scholar
  27. R. Sender, S. Fuchs, and R. Milo, “Revised estimates for the number of human and bacteria cells in the body,” PLoS Biology, vol. 14, no. 8, Article ID e1002533, 2016. View at: Publisher Site | Google Scholar
  28. C. A. Lozupone, J. I. Stombaugh, J. I. Gordon, J. K. Jansson, and R. Knight, “Diversity, stability and resilience of the human gut microbiota,” Nature, vol. 489, pp. 220–230, 2012. View at: Publisher Site | Google Scholar
  29. M. A. Conlon and A. Bird, “The impact of diet and lifestyle on gut microbiota and human health,” Nutrients, vol. 7, no. 1, pp. 17–44, 2014. View at: Publisher Site | Google Scholar
  30. A. Spor, O. Koren, and R. Ley, “Unravelling the effects of the environment and host genotype on the gut microbiome,” Nature Reviews Microbiology, vol. 9, no. 4, pp. 279–290, 2011. View at: Publisher Site | Google Scholar
  31. J. K. Goodrich, J. L. Waters, A. C. Poole et al., “Human genetics shape the gut microbiome,” Cell, vol. 159, no. 4, pp. 789–799, 2014. View at: Publisher Site | Google Scholar
  32. D. M. Chu, J. Ma, A. L. Prince, K. M. Antony, M. D. Seferovic, and K. M. Aagaard, “Maturation of the infant microbiome community structure and function across multiple body sites and in relation to mode of delivery,” Nature Medicine, vol. 23, no. 3, pp. 314–326, 2017. View at: Publisher Site | Google Scholar
  33. S. A. Shetty, F. Hugenholtz, L. Lahti, H. Smidt, and W. M. de Vos, “Intestinal microbiome landscaping: insight in community assemblage and implications for microbial modulation strategies,” FEMS Microbiology Reviews, vol. 41, no. 2, pp. 182–199, 2017. View at: Publisher Site | Google Scholar
  34. S. Kim, A. Covington, and E. G. Pamer, “The intestinal microbiota: antibiotics, colonization resistance, and enteric pathogens,” Immunological Reviews, vol. 279, no. 1, pp. 90–105, 2017. View at: Publisher Site | Google Scholar
  35. FAO/WHO, Health and Nutritional Properties of Probiotics in Food including Powder Milk with Live Lactic Acid Bacteria, World Health Organization, Basel, Switzerland, 2001.
  36. O. Simon, “Micro-organisms as feed additives—probiotics,” Advances in Pork Production, vol. 16, pp. 161–167, 2005. View at: Google Scholar
  37. European Food Safety Authority (EFSA), “Scientific Opinion on the update of the list of QPS-recommended biological agents intentionally added to food or feed as notified to EFSA (2017 update),” EFSA Journal, vol. 15, pp. 1–177, 2017. View at: Google Scholar
  38. P. Markowiak and K. Śliżewska, “Effects of probiotics, prebiotics, and synbiotics on human health,” Nutrients, vol. 9, no. 9, p. 1021, 2017. View at: Google Scholar
  39. L. Lin and J. Zhang, “Role of intestinal microbiota and metabolites on gut homeostasis and human diseases,” BMC Immunology, vol. 18, no. 1, p. 2, 2017. View at: Publisher Site | Google Scholar
  40. H. Nagao-Kitamoto and N. Kamada, “Host-microbial cross-talk in inflammatory bowel disease,” Immune Network, vol. 17, no. 1, p. 1, 2017. View at: Publisher Site | Google Scholar
  41. R. B. Sartor and G. D. Wu, “Roles for intestinal bacteria, viruses, and fungi in pathogenesis of inflammatory bowel diseases and therapeutic approaches,” Gastroenterology, vol. 152, no. 2, pp. 327–339.e4, 2017. View at: Publisher Site | Google Scholar
  42. A. D. Kostic, R. J. Xavier, and D. Gevers, “The microbiome in inflammatory bowel disease: current status and the future ahead,” Gastroenterology, vol. 146, no. 6, pp. 1489–1499, 2014. View at: Publisher Site | Google Scholar
  43. Y. Mishima and R. B. Sartor, “Manipulating resident microbiota to enhance regulatory immune function to treat inflammatory bowel diseases,” Journal of Gastroenterology, pp. 1–11, 2019. View at: Publisher Site | Google Scholar
  44. N. K. Surana and D. L. Kasper, “The yin yang of bacterial polysaccharides: lessons learned from B. fragilis PSA,” Immunological Reviews, vol. 245, no. 1, pp. 13–26, 2012. View at: Publisher Site | Google Scholar
  45. E. B. Troy and D. L. Kasper, “Beneficial effects of Bacteroides fragilis polysaccharides on the immune system,” Frontiers in Bioscience, vol. 15, no. 1, pp. 25–34, 2010. View at: Publisher Site | Google Scholar
  46. S. K. Mazmanian, J. L. Round, and D. L. Kasper, “A microbial symbiosis factor prevents intestinal inflammatory disease,” Nature, vol. 453, no. 7195, pp. 620–625, 2008. View at: Publisher Site | Google Scholar
  47. I. I. Ivanov, K. Atarashi, N. Manel et al., “Induction of intestinal Th17 cells by segmented filamentous bacteria,” Cell, vol. 139, no. 3, pp. 485–498, 2009. View at: Publisher Site | Google Scholar
  48. Y. Goto, C. Panea, G. Nakato et al., “Segmented filamentous bacteria antigens presented by intestinal dendritic cells drive mucosal Th17 cell differentiation,” Immunity, vol. 40, no. 4, pp. 594–607, 2014. View at: Publisher Site | Google Scholar
  49. J. Plaza-Diaz, C. Gomez-Llorente, L. Fontana, and A. Gil, “Modulation of immunity and inflammatory gene expression in the gut, in inflammatory diseases of the gut and in the liver by probiotics,” World Journal of Gastroenterology, vol. 20, no. 42, pp. 15632–15649, 2014. View at: Publisher Site | Google Scholar
  50. S. Heinritz, E. Weiss, M. Eklund et al., “Impact of a high-fat or high-fiber diet on intestinal microbiota and metabolic markers in a pig model,” Nutrients, vol. 8, no. 5, p. 317, 2016. View at: Publisher Site | Google Scholar
  51. W. J. Dahl, N. C. Agro, Å. M. Eliasson et al., “Health benefits of fiber fermentation,” Journal of the American College of Nutrition, vol. 36, no. 2, pp. 127–136, 2017. View at: Publisher Site | Google Scholar
  52. M. A. Vinolo, H. G. Rodrigues, R. T. Nachbar, and R. Curi, “Regulation of inflammation by short chain fatty acids,” Nutrients, vol. 3, no. 10, pp. 858–876, 2011. View at: Publisher Site | Google Scholar
  53. N. Arpaia, C. Campbell, X. Fan et al., “Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation,” Nature, vol. 504, no. 7480, pp. 451–455, 2013. View at: Publisher Site | Google Scholar
  54. J. Park, M. Kim, S. G. Kang et al., “Short-chain fatty acids induce both effector and regulatory T cells by suppression of histone deacetylases and regulation of the mTOR-S6K pathway,” Mucosal Immunology, vol. 8, no. 1, pp. 80–93, 2015. View at: Publisher Site | Google Scholar
  55. P. V. Chang, L. Hao, S. Offermanns, and R. Medzhitov, “The microbial metabolite butyrate regulates intestinal macrophage function via histone deacetylase inhibition,” Proceedings of the National Academy of Sciences, vol. 111, no. 6, pp. 2247–2252, 2014. View at: Publisher Site | Google Scholar
  56. M. Kim, Y. Qie, J. Park, and C. H. Kim, “Gut microbial metabolites fuel host antibody responses,” Cell Host & Microbe, vol. 20, no. 2, pp. 202–214, 2016. View at: Publisher Site | Google Scholar
  57. P. Czarnewski, S. Das, S. M. Parigi, and E. J. Villablanca, “Retinoic acid and its role in modulating intestinal innate immunity,” Nutrients, vol. 9, no. 1, p. 68, 2017. View at: Publisher Site | Google Scholar
  58. M. Iwata, “Retinoic acid production by intestinal dendritic cells and its role in T-cell trafficking,” Seminars in Immunology, vol. 21, no. 1, pp. 8–13, 2009. View at: Publisher Site | Google Scholar
  59. J. Gao, K. Xu, H. Liu et al., “Impact of the gut microbiota on intestinal immunity mediated by tryptophan metabolism,” Frontiers in Cellular and Infection Microbiology, vol. 8, p. 13, 2018. View at: Publisher Site | Google Scholar
  60. T. Bansal, R. C. Alaniz, T. K. Wood, and A. Jayaraman, “The bacterial signal indole increases epithelial-cell tight-junction resistance and attenuates indicators of inflammation,” Proceedings of the National Academy of Sciences, vol. 107, no. 1, pp. 228–233, 2010. View at: Publisher Site | Google Scholar
  61. A. Agus, J. Planchais, and H. Sokol, “Gut microbiota regulation of tryptophan metabolism in health and disease,” Cell Host & Microbe, vol. 23, no. 6, pp. 716–724, 2018. View at: Publisher Site | Google Scholar
  62. J. Behnsen and M. Raffatellu, “Keeping the peace: aryl hydrocarbon receptor signaling modulates the mucosal microbiota,” Immunity, vol. 39, no. 2, pp. 206-207, 2013. View at: Publisher Site | Google Scholar
  63. T. Zelante, R. G. Iannitti, C. Cunha et al., “Tryptophan catabolites from microbiota engage aryl hydrocarbon receptor and balance mucosal reactivity via interleukin-22,” Immunity, vol. 39, no. 2, pp. 372–385, 2013. View at: Publisher Site | Google Scholar
  64. Y. Shimada, M. Kinoshita, K. Harada et al., “Commensal bacteria-dependent indole production enhances epithelial barrier function in the colon,” PLoS One, vol. 8, no. 11, Article ID e80604, 2013. View at: Publisher Site | Google Scholar
  65. B. B. Williams, A. H. Van Benschoten, P. Cimermancic et al., “Discovery and characterization of gut microbiota decarboxylases that can produce the neurotransmitter tryptamine,” Cell Host & Microbe, vol. 16, no. 4, pp. 495–503, 2014. View at: Publisher Site | Google Scholar
  66. T. Whiteside, “Immune suppression in cancer: effects on immune cells, mechanisms and future therapeutic intervention,” Seminars in Cancer Biology, vol. 16, no. 1, pp. 3–15, 2006. View at: Publisher Site | Google Scholar
  67. A. Mosa, A. Gerber, J. Neunzig, and R. Bernhardt, “Products of gut-microbial tryptophan metabolism inhibit the steroid hormone-synthesizing cytochrome P450 11A1,” Endocrine, vol. 53, no. 2, pp. 610–614, 2016. View at: Publisher Site | Google Scholar
  68. G. Bouguen, L. Dubuquoy, P. Desreumaux, T. Brunner, and B. Bertin, “Intestinal steroidogenesis,” Steroids, vol. 103, pp. 64–71, 2015. View at: Publisher Site | Google Scholar
  69. M. J. Monte, J. J. Marin, A. Antelo, and J. Vazquez-Tato, “Bile acids: chemistry, physiology, and pathophysiology,” World Journal of Gastroenterology, vol. 15, no. 7, pp. 804–816, 2009. View at: Publisher Site | Google Scholar
  70. J. R. Swann, E. J. Want, F. M. Geier et al., “Systemic gut microbial modulation of bile acid metabolism in host tissue compartments,” Proceedings of the National Academy of Sciences, vol. 108, no. Supplement_1, pp. 4523–4530, 2011. View at: Publisher Site | Google Scholar
  71. W. Jia, G. Xie, and W. Jia, “Bile acid-microbiota crosstalk in gastrointestinal inflammation and carcinogenesis,” Nature Reviews Gastroenterology & Hepatology, vol. 15, no. 2, pp. 111–128, 2018. View at: Publisher Site | Google Scholar
  72. C. Guo, S. Xie, Z. Chi et al., “Bile acids control inflammation and metabolic disorder through inhibition of NLRP3 inflammasome,” Immunity, vol. 45, no. 4, pp. 802–816, 2016. View at: Publisher Site | Google Scholar
  73. C. Ma, M. Han, B. Heinrich et al., “Gut microbiome-mediated bile acid metabolism regulates liver cancer via NKT cells,” Science, vol. 360, no. 6391, 2018. View at: Google Scholar
  74. J. G. LeBlanc, C. Milani, G. S. de Giori, F. Sesma, D. van Sinderen, and M. Ventura, “Bacteria as vitamin suppliers to their host: a gut microbiota perspective,” Current Opinion in Biotechnology, vol. 24, no. 2, pp. 160–168, 2013. View at: Publisher Site | Google Scholar
  75. J. Kunisawa, Y. Sugiura, T. Wake et al., “Mode of bioenergetic metabolism during B cell differentiation in the intestine determines the distinct requirement for vitamin B1,” Cell Reports, vol. 13, no. 1, pp. 122–131, 2015. View at: Publisher Site | Google Scholar
  76. J. G. Cyster and S. R. Schwab, “Sphingosine-1-phosphate and lymphocyte egress from lymphoid organs,” Annual Review of Immunology, vol. 30, no. 1, pp. 69–94, 2012. View at: Publisher Site | Google Scholar
  77. J. Kunisawa and H. Kiyono, “Immunological function of sphingosine 1-phosphate in the intestine,” Nutrients, vol. 4, no. 3, pp. 154–166, 2012. View at: Publisher Site | Google Scholar
  78. M. Ikeda, A. Kihara, and Y. Igarashi, “Sphingosine-1-phosphate lyase SPL is an endoplasmic reticulum-resident, integral membrane protein with the pyridoxal 5-phosphate binding domain exposed to the cytosol,” Biochemical and Biophysical Research Communications, vol. 325, no. 1, pp. 338–343, 2004. View at: Publisher Site | Google Scholar
  79. S. R. Schwab, J. P. Pereira, M. Matloubian, Y. Xu, Y. Huang, and J. G. Cyster, “Lymphocyte sequestration through S1P lyase inhibition and disruption of S1P gradients,” Science, vol. 309, no. 5741, pp. 1735–1739, 2005. View at: Publisher Site | Google Scholar
  80. J. Kunisawa, Y. Kurashima, M. Higuchi et al., “Sphingosine 1-phosphate dependence in the regulation of lymphocyte trafficking to the gut epithelium,” The Journal of Experimental Medicine, vol. 204, no. 10, pp. 2335–2348, 2007. View at: Publisher Site | Google Scholar
  81. L. Le Bourhis, L. Guerri, M. Dusseaux, E. Martin, C. Soudais, and O. Lantz, “Mucosal-associated invariant T cells: unconventional development and function,” Trends in Immunology, vol. 32, no. 5, pp. 212–218, 2011. View at: Publisher Site | Google Scholar
  82. L. Kjer-Nielsen, O. Patel, A. J. Corbett et al., “MR1 presents microbial vitamin B metabolites to MAIT cells,” Nature, vol. 491, no. 7426, pp. 717–723, 2012. View at: Publisher Site | Google Scholar
  83. A. Sivignon, J. Bouckaert, J. Bernard, S. G. Gouin, and N. Barnich, “The potential of FimH as a novel therapeutic target for the treatment of Crohn’s disease,” Expert Opinion on Therapeutic Targets, vol. 21, no. 9, pp. 837–847, 2017. View at: Publisher Site | Google Scholar
  84. M. Galtier, L. De Sordi, A. Sivignon et al., “Bacteriophages targeting adherent invasive Escherichia coli strains as a promising new treatment for Crohn’s disease,” Journal of Crohn’s and Colitis, vol. 11, pp. 840–847, 2017. View at: Publisher Site | Google Scholar
  85. D. Bikard, C. W. Euler, W. Jiang et al., “Exploiting CRISPR-cas nucleases to produce sequence-specific antimicrobials,” Nature Biotechnology, vol. 32, no. 11, pp. 1146–1150, 2014. View at: Publisher Site | Google Scholar

Copyright © 2019 Chen-xing Zhang et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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