Gut microbial arginine biosynthesis mediates the anti-obesity effect of a pasteurized Akkermansia muciniphila 11

<title>Abstract</title> <p> Background <italic>Akkermansia muciniphila</italic> is regarded as a promising next-generation probiotic for metabolic disorders, yet the postbiotic modes of action through which it exerts benefits remain poorly defined. This study explored how pasteurized <italic>A. muciniphila</italic> (pAkk11) might influence host metabolism by remodeling the gut microbial ecosystem. Results In a 12-week intervention involving 61 overweight or obese individuals, pAkk11 intake was accompanied by an 8.0% reduction in body weight and a concurrent rise in serum L-arginine levels; arginine biosynthesis pathways were among those most closely linked to metabolic improvements. In diet-induced obese mice, multi-omics profiling showed that pAkk11 did not increase the abundance of <italic>A. muciniphila</italic> itself but was instead associated with a marked enrichment of <italic>Faecalibaculum rodentium</italic> , a species harboring upregulated arginine synthesis genes <italic>(argC</italic> , <italic>argD</italic> , <italic>argH</italic> ) and correspondingly elevated L-arginine levels. The higher L-arginine availability coincided with evidence of nitric oxide production and AMPK signaling activation in both liver and adipose tissues. These molecular events paralleled a pattern of reduced lipogenesis, reflected by ACC phosphorylation, and enhanced lipolysis, reflected by HSL upregulation, together pointing to a rebalancing of lipid metabolism. Conclusions These observations raise the possibility that pAkk11 may alleviate obesity not through direct colonization, but by ecologically reshaping the gut microbiota to augment microbial arginine synthesis, which in turn engages the host NO–AMPK axis. Such microbial metabolic reprogramming could represent a core postbiotic mechanism and may offer a new conceptual direction for microbiome-targeted strategies in metabolic disease. </p>