The gastrointestinal tract inner mucus layer, primarily composed of mucins, serves vital functions, including facilitating food movement and providing a barrier against microorganisms and toxins. Akkermansia muciniphila bacteria, thriving on mucins, bolster the gut barrier and outcompete pathogens. Their abundance correlates with mucin content, production of short-chain fatty acids, lowering of intestinal inflammation, and enhances tight junction proteins expression. Metformin medications, used in type 2 diabetes mellitus (T2DM), and metformin’s benefits in T2DM involve modulation of the microbiome, notably increasing Akkermansia muciniphila and short-chain fatty acid (SCFAs) production, aiding glucose balance via gut-liver crosstalk. A relative increase of Akkermansia muciniphila in the gut has a beneficial effect, but its overabundance may thin the mucus layer, compromising the gut barrier function. Excessive Akkermansia muciniphila, possibly from prolonged metformin use, could disrupt the gut barrier and increased lipopolysaccharide challenge, fostering inflammation and potential metformin resistance. Thus, clinically, leveraging metformin-induced microbiome changes warrants caution, especially in chronic T2DM management, due to potential inflammation exacerbation via mucin breakdown, urging contextual evaluation before therapeutic decisions.