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Kartjito, M.S.; Yosia, M.; Wasito, E.; Soloan, G.; Agussalim, A.F.; Basrowi, R.W. Microbiota and Immunity—Consequences of Gut Colonization. Encyclopedia. Available online: (accessed on 30 November 2023).
Kartjito MS, Yosia M, Wasito E, Soloan G, Agussalim AF, Basrowi RW. Microbiota and Immunity—Consequences of Gut Colonization. Encyclopedia. Available at: Accessed November 30, 2023.
Kartjito, Melissa Stephanie, Mikhael Yosia, Erika Wasito, Garry Soloan, Achmad Furqan Agussalim, Ray Wagiu Basrowi. "Microbiota and Immunity—Consequences of Gut Colonization" Encyclopedia, (accessed November 30, 2023).
Kartjito, M.S., Yosia, M., Wasito, E., Soloan, G., Agussalim, A.F., & Basrowi, R.W.(2023, July 03). Microbiota and Immunity—Consequences of Gut Colonization. In Encyclopedia.
Kartjito, Melissa Stephanie, et al. "Microbiota and Immunity—Consequences of Gut Colonization." Encyclopedia. Web. 03 July, 2023.
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.

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]. 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].
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].
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]. 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].
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]. 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]. 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].


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