Microbiota and Immunity—Consequences of Gut Colonization: Comparison
View Latest Version
Please note this is a comparison between Version 2 by Conner Chen and Version 1 by Melissa Stephanie Kartjito.

Microbiota of the gut heavily affects the development and maturation of the immune system, especially in the development of tolerance towards ingested antigens in the gut. The tolerance is developed to ensure that non-harmful antigens do not trigger an inflammatory response in the gut—with the suggestion that failure in developing tolerance will result in inflammatory-related diseases in the gut later in life.

  • gut microbiota
  • immunity
  • cognition

1. Introduction

The first 1000 days of life are crucial moments in human development that provide a unique opportunity to shape lifelong health conditions. During this early period, the establishment of gut microbiota is influenced by a complex interaction between maternal health, nutrition, metabolic status, and various other internal and external factors. It is widely believed that the maturation of the gut microbiota is completed before the third year of life [1]. Through recent understanding of the gut–brain axis, this period of rapid gut microbiota establishment would be crucial to the development of the brain and subsequent cognitive function.
Recently, the immune system has been identified as one of the possible main bridges which connect the gut–brain axis [2]. The association between intestinal inflammatory disorder and behavioral and neuropsychological problems has been established to a certain extent. Conversely, issues in the spine and brain have also manifested with gastrointestinal complications [3]. Studies have tried to explain such a phenomenon through several theories, one of them being that the leakage of microbiota through a breach in gut integrity may result in chronic inflammation that would release systemic inflammatory cytokines, affecting the central nervous system (CNS) causing changes in behavior, mood, and stress level [4]. Analysis has also revealed that certain microbes, such as Enterobacteriaceae, are more likely to induce a systemic inflammatory response. On the other hand, bacteria such as Lactobacillus secrete acid, which can create an environment in the gut that is less favorable for pro-inflammatory microbes, leading to a somewhat anti-inflammatory condition [5].
The immune system and nervous system are also the two primary regulators of homeostasis in the body, communicating and relying on each other to ensure a normal functioning organism. Components of the immune system, particularly microglia, play a crucial role in the development and activity of the nervous system; the microglia have been known to constantly monitor synapses in the parenchyma of the central nervous system and affect its development early in life [6]. Therefore, a properly functioning immune system in a child is critical for the development of cognitive functions and neurogenesis.
Considering the intricate relationship between gut microbiota, immunity, and cognition, it can be assumed that disruption in the gut microbiota may lead to changes in the immune system’s effectiveness that will cause impairment in the central nervous system and cognitive functions. Conversely, maintaining and supporting a healthy microbiota may contribute to the proper development of the immune system and cognitive functions. This assumption, however obvious, still needs to be analyzed further.

2. Microbiota and Immunity—Consequences of Gut Colonization

Microbiota of the gut heavily affects the development and maturation of the immune system, especially in the development of tolerance towards ingested antigens in the gut. The tolerance is developed to ensure that non-harmful antigens do not trigger an inflammatory response in the gut—with the suggestion that failure in developing tolerance will result in inflammatory-related diseases in the gut later in life.

2.1. Effects on Innate Immunity Development

The intestinal mucosa, along with the membrane, acts as the first line of defense against pathogens that invade the gastrointestinal tract. This barrier is made up of a thick extracellular layer and a thinner yet complex inner layer. The inner layer is made up of intestinal epithelial cells (IECs), goblet cells, and various membrane-bound mucins and glycolipids attached to IECs. The extracellular layer is made up of mucus that contains antimicrobial peptides (AMPs), secreted IgA (sIgA), and secreted mucin. The secreted mucin provides a principal energy source for gut microbiota, as well as a protective barrier toward pathogen invasion [7]. AMPs are proteins that confer protective effects against pathogenic bacteria, certain fungal species, protozoa, and viruses. Well-known AMPs that play a major role in gut immune defense are the α- and β-defensin produced by Paneth cells [8]. Meanwhile, sIgA antibodies modulate the microbial colonization of the epithelium and prevent the adsorption of pathogenic microbes [9]. It is evident from current studies that gut microbiota significantly influences the development and homeostasis of barrier components. For instance, the production of secreted mucins is modulated by gut microbiota. Factors such as the presence of pathogenic bacteria and poor diet can disrupt the process of mucin glycosylation, which is crucial for physiological protection and cellular communication, including signal transduction and cell-to-cell adhesion [10,11][10][11]. The absence of physiological commensal gut microbes and the presence of pathogenic species such as B. hyodysenteriae and Helicobacter suis can alter the normal glycosylation process, contributing to the development of inflammatory diseases such as IBD, Crohn’s disease, and colorectal cancer [12,13,14][12][13][14]. Certain microbes are also known to support the production of antimicrobial peptides (AMPs). Vaishnava et al. demonstrated that Paneth cells can detect enteric bacteria via MyD88 signaling, a crucial step for bacterial-induced secretion of AMPs, thus protecting against the penetration of pathogenic bacteria such as Salmonella sp. [15]. In addition to the microbes themselves, various biologically active metabolites secreted by gut microbiota are known to modulate immunity and maintain immune homeostasis. Short-chain fatty acids (SCFAs) such as acetate, butyrate, and propionate, which account for 90–95% of all colonic SCFAs, are produced by the fermentation of dietary fiber by commensal microbiota [16]. These SCFAs regulate adaptive immunity by binding to various G protein-coupled receptors (GPCRs). The three SCFAs can interact with GPR43, a receptor that recognizes a wide range of SCFAs. The interaction of acetate with the GPR43 pathway positively influences intestinal IgA response, with retinoic acid, a metabolite of vitamin A, acting as the mediator [17,18][17][18]. Furthermore, SCFAs are known to regulate the colonic regulatory T cell (Treg) pool by inhibiting histone deacetylase, subsequently increasing the acetylation and expression of the Foxp3 gene, a key transcription factor promoting Treg differentiation [19,20][19][20]. Beyond modulating IgA response and Treg differentiation, SCFAs also nourish and promote the proliferation of CD4+ T cells and CD8+ T cells, underscoring the importance of gut microbiota in the systemic response against invading bacterial or viral pathogens. Kespohl et al. demonstrated the low-dose effect of butyrate in amplifying Foxp3 transcription factor and subsequent Treg differentiation, while concurrently producing pro-inflammatory molecules that aid the function of conventional T cells. [19] SCFAs also enhance the functionality of memory CD8+ T cells, presumably through butyrate, which promotes oxidative phosphorylation and fatty acid catabolism as the principal method for CD8+ T cell metabolism [21].

2.2. Effects on Adaptive Immunity Development

The adaptive immune mechanisms serve as a secondary line of defense against invasive pathogens, notable for their specific responses towards these pathogens. Within the gastrointestinal (GI) system, both bacterial components and active metabolites contribute to the development and maintenance of adaptive immune system homeostasis. Certain microbes, such as Bacteroides fragilis and Bacteroides thetaiotaomicron, can penetrate the mucus layer, colonize intestinal epithelial cells (IECs) and colonic crypts, and interact with Mucispirillum schaedleri, which resides in the cecal crypt. These microbes are presented to the immune system’s dendritic cells, allowing a minor population of these commensal microbes to enter and localize within the mesenteric lymph node, thereby stimulating an effective mucosal immune response [22,23,24,25,26,27][22][23][24][25][26][27]. Adaptive humoral immunity within the GI tract primarily operates through secretory Immunoglobulin A (sIgA) antibodies, which are responsive to the commensal gut microbiota. The presence of intestinal plasma cells facilitates the production of sIgA through either T cell-independent or T cell-dependent mechanisms. Notably, most commensal gut microbiota trigger sIgA responses via T cell-independent pathways [21]. Certain unusual commensal bacteria, such as Mucispirillum, interact with antigen-presenting cells to incite adaptive T cell and B cell responses for sIgA production, as these particular microbes lack sites for T cell-independent antigen-induced sIgA [28]. Flagellated commensal bacteria also promote sIgA production, as the protein flagellin can activate Toll-like receptor (TLR) 5 on dendritic cells, which subsequently stimulates naïve B cells to differentiate into plasma cells that produce IgA [29]. Finally, the production of sIgA is influenced by intestinal microorganisms. Gut microbiota affect sIgA production by expressing specific microbe-associated molecular patterns (MAMPs) that activate the polymeric immunoglobulin receptor (pIgR). This leads to a process that enables the transportation of dimeric IgA from plasma cells within the lamina propria, through IECs, to eventually display the sIgA on the apical surface of the intestinal mucosa [30,31][30][31]. Several in vitro studies have shown that certain microbes, such as Bacteroides thetaiotaomicron, stimulate increased pIgR expression, while E. coli is known to produce a highly potent, long-lived sIgA response in germ-free mice colonized with non-dividing E. coli. [32,33][32][33]. The sIgA response is adaptive to the current state of gut microbiota. For instance, introducing new microbes to mice previously colonized with E. coli results in a decrease in the sIgA response to the original E. coli colonizer [31].

References

  1. Wernroth, M.-L.; Peura, S.; Hedman, A.M.; Hetty, S.; Vicenzi, S.; Kennedy, B.; Fall, K.; Svennblad, B.; Andolf, E.; Pershagen, G.; et al. Development of gut microbiota during the first 2 years of life. Sci. Rep. 2022, 12, 9080.
  2. Cryan, J.F.; O’Riordan, K.J.; Cowan, C.S.; Sandhu, K.V.; Bastiaanssen, T.F.; Boehme, M.; Codagnone, M.G.; Cussotto, S.; Fulling, C.; Golubeva, A.V.; et al. The Microbiota-Gut-Brain Axis. Physiol. Rev. 2019, 99, 1877–2013.
  3. Casella, G.; Tontini, G.E.; Bassotti, G.; Pastorelli, L.; Villanacci, V.; Spina, L.; Baldini, V.; Vecchi, M. Neurological disorders and inflammatory bowel diseases. World J. Gastroenterol. 2014, 20, 8764–8782.
  4. Camilleri, M. Leaky gut: Mechanisms, measurement and clinical implications in humans. Gut 2019, 68, 1516–1526.
  5. Milani, C.; Duranti, S.; Bottacini, F.; Casey, E.; Turroni, F.; Mahony, J.; Belzer, C.; Delgado Palacio, S.; Arboleya Montes, S.; Mancabelli, L.; et al. The First Microbial Colonizers of the Human Gut: Composition, Activities, and Health Implications of the Infant Gut Microbiota. Microbiol. Mol. Biol. Rev. 2017, 81, e00036-17.
  6. Schafer, D.P.; Stevens, B. Microglia Function in Central Nervous System Development and Plasticity. Cold Spring Harb. Perspect. Biol. 2015, 7, a020545.
  7. McGuckin, M.A.; Lindén, S.K.; Sutton, P.; Florin, T.H. Mucin dynamics and enteric pathogens. Nat. Rev. Genet. 2011, 9, 265–278.
  8. Bevins, C.L.; Salzman, N.H. Paneth cells, antimicrobial peptides and maintenance of intestinal homeostasis. Nat. Rev. Genet. 2011, 9, 356–368.
  9. Cerutti, A.; Rescigno, M. The Biology of Intestinal Immunoglobulin A Responses. Immunity 2008, 28, 740–750.
  10. Wagner, C.; Wheeler, K.; Ribbeck, K. Mucins and Their Role in Shaping the Functions of Mucus Barriers. Annu. Rev. Cell Dev. Biol. 2018, 34, 189–215.
  11. Goto, Y.; Uematsu, S.; Kiyono, H. Epithelial glycosylation in gut homeostasis and inflammation. Nat. Immunol. 2016, 17, 1244–1251.
  12. Johansson, M.E.; Jakobsson, H.E.; Holmén-Larsson, J.; Schütte, A.; Ermund, A.; Rodríguez-Piñeiro, A.M.; Arike, L.; Wising, C.; Svensson, F.; Bäckhed, F.; et al. Normalization of Host Intestinal Mucus Layers Requires Long-Term Microbial Colonization. Cell Host Microbe 2015, 18, 582–592.
  13. Padra, M.; Adamczyk, B.; Flahou, B.; Erhardsson, M.; Chahal, G.; Smet, A.; Jin, C.; Thorell, A.; Ducatelle, R.; Haesebrouck, F.; et al. Helicobacter suis infection alters glycosylation and decreases the pathogen growth inhibiting effect and binding avidity of gastric mucins. Mucosal Immunol. 2019, 12, 784–794.
  14. Venkatakrishnan, V.; Quintana-Hayashi, M.P.; Mahu, M.; Haesebrouck, F.; Pasmans, F.; Lindén, S.K. Brachyspira hyodysenteriae Infection Regulates Mucin Glycosylation Synthesis Inducing an Increased Expression of Core-2 O-Glycans in Porcine Colon. J. Proteome Res. 2017, 16, 1728–1742.
  15. Vaishnava, S.; Behrendt, C.L.; Ismail, A.S.; Eckmann, L.; Hooper, L.V. Paneth cells directly sense gut commensals and maintain homeostasis at the intestinal host-microbial interface. Proc. Natl. Acad. Sci. USA 2008, 105, 20858–20863.
  16. Kespohl, M.; Vachharajani, N.; Luu, M.; Harb, H.; Pautz, S.; Wolff, S.; Sillner, N.; Walker, A.; Schmitt-Kopplin, P.; Boettger, T.; et al. The Microbial Metabolite Butyrate Induces Expression of Th1-Associated Factors in CD4+ T Cells. Front. Immunol. 2017, 8, 1036.
  17. Wu, W.; Sun, M.; Chen, F.; Cao, A.; Liu, H.; Zhao, Y.; Huang, X.; Xiao, Y.; Yao, S.; Zhao, Q.; et al. Microbiota metabolite short-chain fatty acid acetate promotes intestinal IgA response to microbiota which is mediated by GPR43. Mucosal Immunol. 2017, 10, 946–956.
  18. Macia, L.; Tan, J.; Vieira, A.T.; Leach, K.; Stanley, D.; Luong, S.; Maruya, M.; McKenzie, C.l.; Hijikata, A.; Wong, C.; et al. Metabolite-sensing receptors GPR43 and GPR109A facilitate dietary fibre-induced gut homeostasis through regulation of the inflammasome. Nat. Commun. 2015, 6, 6734.
  19. Elce, A.; Amato, F.; Zarrilli, F.; Calignano, A.; Troncone, R.; Castaldo, G.; Canani, R.B. Butyrate modulating effects on pro-inflammatory pathways in human intestinal epithelial cells. Benef. Microbes 2017, 8, 841–847.
  20. Furusawa, Y.; Obata, Y.; Fukuda, S.; Endo, T.A.; Nakato, G.; Takahashi, D.; Nakanishi, Y.; Uetake, C.; Kato, K.; Kato, T.; et al. Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature 2013, 504, 446–450.
  21. Li, Y.; Ye, Z.; Zhu, J.; Fang, S.; Meng, L.; Zhou, C. Effects of Gut Microbiota on Host Adaptive Immunity Under Immune Homeostasis and Tumor Pathology State. Front. Immunol. 2022, 13, 844335.
  22. Davis, C.P.; Savage, D.C. Habitat, Succession, Attachment, and Morphology of Segmented, Filamentous Microbes Indigenous to the Murine Gastrointestinal Tract. Infect Immun. 1974, 10, 948–956.
  23. Lee, S.M.; Donaldson, G.P.; Mikulski, Z.; Boyajian, S.; Ley, K.; Mazmanian, S.K. Bacterial colonization factors control specificity and stability of the gut microbiota. Nature 2013, 501, 426–429.
  24. Zaborin, A.; Penalver Bernabe, B.; Keskey, R.; Sangwan, N.; Hyoju, S.; Gottel, N.; Gilbert, J.A.; Zaborina, O.; Alverdy, J.C. Spatial Compartmentalization of the Microbiome between the Lumen and Crypts Is Lost in the Murine Cecum following the Process of Surgery, Including Overnight Fasting and Exposure to Antibiotics. mSystems 2020, 5, e00377-20.
  25. Mabbott, N.A.; Donaldson, D.S.; Ohno, H.; Williams, I.R.; Mahajan, A. Microfold (M) cells: Important immunosurveillance posts in the intestinal epithelium. Mucosal Immunol. 2013, 6, 666–677.
  26. Rescigno, M.; Urbano, M.; Valzasina, B.; Francolini, M.; Rotta, G.; Bonasio, R.; Granucci, F.; Kraehenbuhl, J.-P.; Ricciardi-Castagnoli, P. Dendritic cells express tight junction proteins and penetrate gut epithelial monolayers to sample bacteria. Nat. Immunol. 2001, 2, 361–367.
  27. Kraehenbuhl, J.-P.; Corbett, M. Keeping the Gut Microflora at Bay. Science 2004, 303, 1624–1625.
  28. Bunker, J.J.; Flynn, T.M.; Koval, J.C.; Shaw, D.G.; Meisel, M.; McDonald, B.D.; Ishizuka, I.E.; Dent, A.L.; Wilson, P.C.; Jabri, B.; et al. Innate and Adaptive Humoral Responses Coat Distinct Commensal Bacteria with Immunoglobulin A. Immunity 2015, 43, 541–553.
  29. Uematsu, S.; Fujimoto, K.; Jang, M.H.; Yang, B.-G.; Jung, Y.-J.; Nishiyama, M.; Sato, S.; Tsujimura, T.; Yamamoto, M.; Yokota, Y.; et al. Regulation of humoral and cellular gut immunity by lamina propria dendritic cells expressing Toll-like receptor 5. Nat. Immunol. 2008, 9, 769–776.
  30. Macpherson, A.J.; Gatto, D.; Sainsbury, E.; Harriman, G.R.; Hengartner, H.; Zinkernagel, R.M. A Primitive T Cell-Independent Mechanism of Intestinal Mucosal IgA Responses to Commensal Bacteria. Science 2000, 288, 2222–2226.
  31. Johansen, F.-E.; Kaetzel, C.S. Regulation of the polymeric immunoglobulin receptor and IgA transport: New advances in environmental factors that stimulate pIgR expression and its role in mucosal immunity. Mucosal Immunol. 2011, 4, 598–602.
  32. Hapfelmeier, S.; Lawson, M.A.; Slack, E.; Kirundi, J.K.; Stoel, M.; Heikenwalder, M.; Cahenzli, J.; Velykoredko, Y.; Balmer, M.L.; Endt, K.; et al. Reversible Microbial Colonization of Germ-Free Mice Reveals the Dynamics of IgA Immune Responses. Science 2010, 328, 1705–1709.
  33. Hooper, L.V.; Wong, M.H.; Thelin, A.; Hansson, L.; Falk, P.G.; Gordon, J.I. Molecular Analysis of Commensal Host-Microbial Relationships in the Intestine. Science 2001, 291, 881–884.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/)
ScholarVision Creations
Feedback