## 2 Overview of the Human Gut Microbiota
### Composition and Functional Organisation of the Human Gut Microbiota
#### 2.2.2 Regulation of Immune Response and Protection Against Pathogenic Organisms  
The microbiota also plays a crucial role in the induction, formation, and function of the host's immune system. In turn, the immune system, composed of innate and adaptive components, develops mechanisms to maintain its symbiotic interaction with the microbiota, promoting its tolerance to beneficial commensal microorganisms and generating protective responses against pathogens [67]. Considering that the intestine is the most extensive interface between the external environment and the human body, the strategy adopted to ensure the continuity of this interaction is the maintenance of a stable and semi-permeable physical barrier that regulates host-microbe interactions [22]. Additionally, the intestinal epithelial barrier must maintain a balance between selective permeability for the passage of nutrients, electrolytes, and water from the intestinal lumen to the systemic circulation via intercellular or transcellular transport and protection against harmful components from the external environment, which are ultimately eliminated in faeces [22; 68]. This barrier comprises multiple layers, including the mucus layer (which traps pathogens), the epithelial cell monolayer (sealed by tight junctions regulating paracellular permeability, which allow for the selective absorption of nutrients, electrolytes, and water,while preventing the translocation of both commensal and pathogenic microorganisms and harmful antigens), and the underlying immune elements (such as secretory immunoglobulin A (IgA), dendritic cells, and macrophages) that coordinate immune defence while maintaining immune homeostasis [69; 70; 71]. Various stimuli, such as microbial metabolites (e.g., SCFAs), dietary components, cytokines, and pattern recognition receptor signalling, modulate the function of this barrier. These stimuli contribute to the maintenance of barrier integrity, defined as the structural and functional cohesion of the epithelial and mucosal interface, by promoting epithelial cell renewal, upregulating the expression of tight-junction proteins, stimulating mucus secretion, and modulating immune tolerance, without compromising its semi-permeable nature, which refers to selective molecular trafficking while preventing microbial translocation [22; 68; 72; 73]. The mucus layer, secreted primarily by Globet cells, consists of a physical barrier that harbours beneficial commensal microorganisms, such as _Bacteroides_ spp., _Faecalibacterium prausnitzii_, and _Akkernansia muciniphila_, and contains defence proteins with immune-regulatory functions, including antimicrobial peptides (AMPs) and secretory IgA, which are secreted primarily by Paneth cells and plasma cells, respectively [74; 75]. Beneath this layer lies a continuous and polarised monolayer of intestinal epithelial cells, under which the lamina propria contains immune cells such as T cells, B cells, macrophages, and dendritic cells, which provide both innate and adaptive immune responses that reinforce intestinal defence [68; 76]. A schematic representation of the intestinal barrier, including the mucus layer, epithelial cell monolayer, and immune cell populations in the lamina propria, is provided in Figure 2 to illustrate these components and their spatial organisation. On the other hand, microbiota-derived SCFAs regulate immune cells by binding to G-protein-coupled receptors (GPCRs) and by altering gene expression through the reduction in histone deacetylase activity. Although the intestinal epithelial barrier separates microbes from the immune cells in the lamina propria, SCFAs, being small and soluble, can diffuse through epithelial cells via passive diffusion or be transported by specific monocarboxylate  
Figure 2: Intestinal barrier structure. The barrier includes a mucus layer, with commensal bacteria, immunoglobulin A antibodies (IgA) and antimicrobial peptides (AMPs), epithelial cells with tight junctions, and immune cells in the lamina propria.