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Monoglyceride lipase (MGLL) regulates metabolism by catabolizing monoacylglycerols (MAGs), including the endocannabinoid 2-arachidonoyl glycerol (2-AG) and some of its bioactive congeners, to the corresponding free fatty acids. <i>Mgll</i> knockout mice (<i>Mgll</i>^−/−) exhibit elevated tissue levels of MAGs in association with resistance to the metabolic and cardiovascular perturbations induced by a high fat diet (HFD). The gut microbiome and its metabolic function are disrupted in obesity in a manner modulated by 2-arachidonoyl glycerol (2-AG’s) main receptors, the cannabinoid CB1 receptors. We therefore hypothesized that <i>Mgll</i>^−/− mice have an altered microbiome, that responds differently to diet-induced obesity from that of wild-type (WT) mice. We subjected mice to HFD and assessed changes in the microbiomes after 8 and 22 weeks. As expected, <i>Mgll</i>^−/− mice showed decreased adiposity, improved insulin sensitivity, and altered circulating incretin/adipokine levels in response to HFD. <i>Mgll</i>^−/− mice on a chow diet exhibited significantly higher levels of <i>Hydrogenoanaerobacterium</i>, <i>Roseburia</i>, and <i>Ruminococcus</i> than WT mice. The relative abundance of the <i>Lactobacillaceae</i> and <i>Coriobacteriaceae</i> and of the <i>Lactobacillus</i>, <i>Enterorhabdus</i>, <i>Clostridium</i>_<i>XlVa</i>, and <i>Falsiporphyromonas</i> genera was significantly altered by HFD in WT but not <i>Mgll</i>^−/− mice. Differently abundant families were also associated with changes in circulating adipokine and incretin levels in HFD-fed mice. Some gut microbiota family alterations could be reproduced by supplementing 2-AG or MAGs in culturomics experiments carried out with WT mouse fecal samples. We suggest that the altered microbiome of <i>Mgll</i>^−/− mice contributes to their obesity resistant phenotype, and results in part from increased levels of 2-AG and MAGs.