The Interplay between the Gut and Ketogenic Diets in Health and Disease

Abstract The gut plays a central role in translating dietary signals into systemic health effects, making it a key mediator of the ketogenic diet (KD), a high fat, low carbohydrate regimen. This review synthesizes current knowledge on the interaction between the KD and the gut, emphasizing gut‐mediated mechanisms as an interface between dietary interventions and systemic health outcomes, spanning gastrointestinal to neurological health. Topics address gut physiology (gut digestion and absorption, epithelial nutrient sensing, gut motility), intestinal immunity (covering innate, adaptive, and antiviral responses), and extracellular to intracellular processes (i.e. mitochondrial function, stem cell fate, and intestinal circadian rhythm). Special focus is given to the gut microbiome, including both bacterial and fungal communities and how the KD modulates them in conditions such as epilepsy, obesity, traumatic brain injury, and multiple sclerosis. Innovative methods for tailoring the KD, including the use of alternative formulations, ketone esters, and microbiome‐focused interventions such as prebiotics and probiotics are examined. Strategies to maximize the diet's benefits while reducing potential side effects are considered. Together, these insights herein offer a comprehensive framework for understanding the interactions between the KD and the gut, a prerequisite for optimizing the overall health benefits of metabolism‐based treatments.