Introduced as a novel term in 2023 by the American Heart Association, cardiovascular-kidney-metabolic syndrome (CKM) is defined by the co-occurrence of metabolic, cardiovascular, and kidney illnesses that share pathophysiological linkages. The gut microbiome of a healthy adult contains approximately 100 trillion bacteria, ten times the number of human cells. This complex system of microorganisms has a key role in several physiological processes, such as inflammation, immunological response, and metabolism, all essential for developing CKM. The primary physiopathological mechanism that links these pathologies is the occurrence of dysbiosis, by increasing the Firmicutes/Bacteroides ratio, decreasing the diversity of the microbiota, and increasing the abundance of some pathogenic species. These lead to increased production of trimethylamine-N-oxide (TMAO), p-cresol sulfate, and indoxyl sulfate, with a role in increasing intestinal permeability, oxidative stress, chronic inflammation, metabolic abnormalities, and alterations in the composition of microorganisms. Understanding these mechanisms helps find new therapeutic targets and develop new therapies.