Human gut microbial metabolites are currently the subject of much interest. In a previous work, we have analyzed their structural, physicochemical, and distribution properties, and developed QSAR predictive models for their intestinal permanence. Clarifying the full target space of these molecules could shed light to understand fundamental biological processes that result from the cross-signaling and regulatory pathways established between the microbiome and the host. In addition to the improvement in our comprehension of the role of the microbiome in human health, the knowledge gained can be used in the generation of a new drug and nutraceutic modality of "metabolite-mimetic" molecules. This new modality could benefit from new chemotypes, but additionally, from new targets as they could be directed to proteins encoded by the vast microbial metagenome. It is currently estimated that a total of ~900 proteins (~700 human and ~200 pathogen) are targeted by FDA-approved drugs, while ~3000 are considered druggable out of the 21000 genes in the human genome. In turn, the human gut microbiome has been estimated to contain between 250-to 1000-fold as many genes. As a matter of fact, several drug discovery programs in this area are focused on bacterial proteins as pathogenicity factors, like the E. coli fimbrial adhesin (FimH) for IBD, and the archaeal F420-dependent Mtd, a methane-producing enzyme for the same disease. This is the reason why, in our analysis, we have not focused on just human proteins interacted with bacterial metabolites, as most of the literature does, but we have also considered all possible host-microbe bidirectional communications by including bacterial proteins of typical gut microbiome genera in our dataset. By the same token, we have also taken into account metabolites from the host, xenobiotics, and metabolites from bacteria but modified by host enzymes, or from the host/xenobiotics but modified by bacteria. The later could be useful for instance for drug discovery programs that aim to modulate drug metabolism by the microbiota to enhance already existing drugs, and again we find some examples in the development and use of inhibitors of microbial βglucuronidases and tyrosine decarboxylase to improve the effects of irinotecan and Ldopa, respectively. Our analysis of published interactions has identified 2193 interactions, involving 405 and 128 metabolites, that bind to 451 human and 56 microbial proteins, respectively.