Hemorrhoidal disease is the most common proctologic disease and the search for new treatment methods, as well as an in-depth understanding of the mechanisms underlying effects of well-known agents on disease pathogenesis still remain relevant. There have been long recognized the effects of the E.coli bacterial culture suspension (BCS) as a therapeutic means eliciting decreased exudation during inflammation, wound healing, tissue regeneration, and stimulated immunity. Here, based on recent findings related to innate and adaptive immune cells, we set out to present mechanisms accounting for some effects coupled to commensal bacteria, particularly inactivated E.coli BCS, which are important for understanding pathogenesis-related action of drug Posterisan and Posterisan forte, and outline their broad application in therapy of hemorrhoids. Based on the analysis, it was concluded that such effects are mediated via multi-pronged and complementary interactions between diverse human receptors expressed in the anorectal region cells and microbial components: NOD ligands, metabolites, enzymes, heat shock proteins and nucleic acids, which lead to production of pro-inflammatory cytokines by anodermal colonocytes, innate and adaptive immune cells, neurons in the submucosal plexus covered by transitional zone epithelium, and hemorrhoid plexus endothelium. Based on current concepts, it may be plausible that E.coli BCS-derived biologically active components contained in drug Posterisan are capable of exerting both positive local and systemic effects, which extend our understanding and substantiate its use in hemorrhoidal disease. The effectiveness of using Posterisan and Posterisan forte is corroborated by their indications in real-life clinical practice, both as a conservative therapy as well as after surgical interventions.