<p><i>Akkermansia muciniphila</i> is a prominent member of the intestinal microbiota that has the unique ability to subsist on the mucin <i>O</i>-glycans that form a protective barrier between the host and the gut microbiome. Numerous studies highlight its positive role in metabolic regulation and mucosal barrier maintenance, leading to propositions that <i>A. muciniphila</i> could be used as a next-generation probiotic. However, other work indicates that the effects of <i>A. muciniphila</i> vary depending on nutrition, host genetics and the interaction with surrounding microbes. Furthermore, strain-specific differences in the ability to modulate intestinal barrier function and antimicrobial resistance profiles remain underexplored. Here, by focusing on potential sources of this variation, we provide a nuanced discussion on the complex role of <i>A. muciniphila</i> in human health. With <i>A. muciniphila</i> as an example, we argue that a microbe’s specific environment must be considered to enable critical evaluation of next-generation probiotics.</p>