The gut mucosal epithelium plays a crucial role in regulating the interaction between the resident microbiome and the host. The tight control of what passes through this barrier is essential, allowing nutrients and water while restricting harmful microorganisms and antigens. Increased gut permeability, or "leaky gut," is associated with various diseases, including infections, metabolic disorders, inflammatory and autoimmune diseases, and neurological conditions. Factors affecting gut permeability include cytokines, dietary components, and the gut microbiome. This article discusses how the gut microbiome impacts gut epithelial barrier permeability and how this can be harnessed for therapeutic purposes. The intestinal barrier is a complex system that provides a physical separation between the inside and outside of the body. It consists of a mucus layer, an epithelial layer, and immune cells. The epithelial layer, composed of tightly packed cells, regulates nutrient absorption, water transport, and the exclusion of antigens and microorganisms. The interaction between the microbiome, epithelium, and immune system regulates gut permeability. Key elements in barrier permeability include the paracellular and transcellular pathways. The paracellular pathway involves transport through the space between epithelial cells, regulated by intercellular complexes such as desmosomes, adherens junctions, and tight junctions. The transcellular pathway involves the translocation of molecules through epithelial cells. The gut microbiome influences gut permeability through various mechanisms. Microbiome-derived metabolites, such as butyrate and propionate, can improve barrier function by facilitating the assembly of tight junction proteins. Conjugated fatty acids produced by certain bacteria can increase paracellular permeability. Bile acids, polyamines, and structural components like lipopolysaccharide (LPS) and flagellin can also regulate barrier function. Infections and gastrointestinal permeability are closely linked. Enteric pathogens disrupt the intestinal epithelial barrier by altering tight junctions, degrading specific proteins, and activating host cell signaling pathways. Viral and bacterial toxins can degrade tight junction proteins, leading to increased permeability. The activation of host cell signaling pathways and the modulation of the cell cytoskeleton can also contribute to increased permeability. Leaky gut is associated with a wide range of diseases, including inflammatory bowel diseases (IBDs), rheumatic diseases, and metabolic diseases. In IBDs, disrupted expression and function of tight junction proteins are key contributors. Microbiome dysbiosis and altered metabolites can exacerbate disease severity. In rheumatic diseases, gut microbiome dysbiosis and impaired barrier function are hypothesized to facilitate bacterial translocation and systemic inflammation. In metabolic diseases, high-fat diets and hyperglycemia can directly impact epithelial barrier integrity. Therapy-induced epithelial barrier dysfunction, such as radiation enteritis, can be mitigated by correcting microbiome dysbiosis through methods like fecal microbiota transplantation (FMT). The protective effects of certain bacterial metabolitesThe gut mucosal epithelium plays a crucial role in regulating the interaction between the resident microbiome and the host. The tight control of what passes through this barrier is essential, allowing nutrients and water while restricting harmful microorganisms and antigens. Increased gut permeability, or "leaky gut," is associated with various diseases, including infections, metabolic disorders, inflammatory and autoimmune diseases, and neurological conditions. Factors affecting gut permeability include cytokines, dietary components, and the gut microbiome. This article discusses how the gut microbiome impacts gut epithelial barrier permeability and how this can be harnessed for therapeutic purposes. The intestinal barrier is a complex system that provides a physical separation between the inside and outside of the body. It consists of a mucus layer, an epithelial layer, and immune cells. The epithelial layer, composed of tightly packed cells, regulates nutrient absorption, water transport, and the exclusion of antigens and microorganisms. The interaction between the microbiome, epithelium, and immune system regulates gut permeability. Key elements in barrier permeability include the paracellular and transcellular pathways. The paracellular pathway involves transport through the space between epithelial cells, regulated by intercellular complexes such as desmosomes, adherens junctions, and tight junctions. The transcellular pathway involves the translocation of molecules through epithelial cells. The gut microbiome influences gut permeability through various mechanisms. Microbiome-derived metabolites, such as butyrate and propionate, can improve barrier function by facilitating the assembly of tight junction proteins. Conjugated fatty acids produced by certain bacteria can increase paracellular permeability. Bile acids, polyamines, and structural components like lipopolysaccharide (LPS) and flagellin can also regulate barrier function. Infections and gastrointestinal permeability are closely linked. Enteric pathogens disrupt the intestinal epithelial barrier by altering tight junctions, degrading specific proteins, and activating host cell signaling pathways. Viral and bacterial toxins can degrade tight junction proteins, leading to increased permeability. The activation of host cell signaling pathways and the modulation of the cell cytoskeleton can also contribute to increased permeability. Leaky gut is associated with a wide range of diseases, including inflammatory bowel diseases (IBDs), rheumatic diseases, and metabolic diseases. In IBDs, disrupted expression and function of tight junction proteins are key contributors. Microbiome dysbiosis and altered metabolites can exacerbate disease severity. In rheumatic diseases, gut microbiome dysbiosis and impaired barrier function are hypothesized to facilitate bacterial translocation and systemic inflammation. In metabolic diseases, high-fat diets and hyperglycemia can directly impact epithelial barrier integrity. Therapy-induced epithelial barrier dysfunction, such as radiation enteritis, can be mitigated by correcting microbiome dysbiosis through methods like fecal microbiota transplantation (FMT). The protective effects of certain bacterial metabolites