A Cascade of Microbiota-Leaky Gut-Inflammation- Is it a Key Player in Metabolic Disorders?

This review addresses critical gaps in knowledge and provides a literature overview of the molecular pathways connecting gut microbiota dysbiosis to increased intestinal permeability (commonly referred to as "leaky gut") and its contribution to metabolic disorders. Restoring a healthy gut microbiota holds significant potential for enhancing intestinal barrier function and metabolic health. These interventions offer promising therapeutic avenues for addressing leaky gut and its associated pathologies in metabolic syndrome.

In metabolic disorders such as obesity and type 2 diabetes (T2D), beneficial microbes such as those producing short-chain fatty acids (SCFAs) and other key metabolites like taurine, spermidine, glutamine, and indole derivatives are reduced. Concurrently, microbes that degrade toxic metabolites such as ethanolamine also decline, while proinflammatory, lipopolysaccharide (LPS)-enriched microbes increase. These microbial shifts place a higher burden on intestinal epithelial cells, which are in closest proximity to the gut lumen, inducing detrimental changes that compromise the structural and functional integrity of the intestinal barrier. Such changes include exacerbation of tight junction protein (TJP)s dysfunction, particularly through mechanisms such as destabilization of zona occludens (Zo)-1 mRNA or post-translational modifications. Emerging therapeutic strategies including ketogenic and Mediterranean diets, as well as probiotics, prebiotics, synbiotics, and postbiotics have demonstrated efficacy in restoring beneficial microbial populations, enhancing TJP expression and function, supporting gut barrier integrity, reducing leaky gut and inflammation, and ultimately improving metabolic disorders. This review summarizes the mechanisms by which gut microbiota contribute to the development of leaky gut and inflammation associated with metabolic syndrome. It also explores strategies for restoring gut microbiota balance and functionality by promoting beneficial microbes, increasing the production of beneficial metabolites, clearing toxic metabolites, and reducing the proportion of proinflammatory microbes. These approaches can alleviate the burden on intestinal epithelial cells, reduce leaky gut and inflammation, and improve metabolic health.