Feeding the estrobolome with sweet prebiotics?

Background: Sweeteners are widely consumed, yet their effects on the gut microbiota remain incompletely characterized, while their potential influence on the estrobolome has received little direct investigation. Although many sweeteners are absorbed in the small intestine, a variable fraction reaches the colon, where it interacts with the gut microbiota. Some sweeteners may also meet the definition of a prebiotic when they are selectively utilized by host microorganisms and such utilization confers a demonstrated health benefit. Because the estrobolome encompasses microbial genes encoding estrogen-metabolizing enzymes, including β-glucuronidases and sulfatases, sweetener-induced changes in gut microbial composition or function could plausibly influence enterohepatic estrogen metabolism and systemic estrogen availability. Methods: This narrative review synthesizes current evidence on the effects of different sweeteners on the gut microbiota and examines their potential implications for the estrobolome. We summarize the consensus definition of prebiotics, the classification, metabolism, and colonic availability of major sweeteners, and review the biological basis of the estrobolome, with particular emphasis on microbial estrogen metabolism. Results: Experimental and human studies indicate that individual sweeteners can modify gut microbial composition and metabolic activity, but the direction and magnitude of these effects vary substantially according to the compound, dose, study model, and host context. However, direct studies evaluating the impact of sweeteners on estrobolome function are lacking, and potential effects currently remain inferential, based largely on reported changes in microbial taxa known or presumed to harbor genes encoding estrogen-metabolizing enzymes rather than on direct measurements of gene expression or enzymatic activity. Conclusion: Current evidence provides a biological basis for considering sweeteners as potential modulators of the estrobolome, although evidence directly linking individual sweeteners to changes in estrobolome function remains lacking. Well-designed multi-omic clinical studies integrating dietary exposure, gut microbiota composition, estrobolome function, estrogen metabolism, and clinically relevant outcomes are needed to establish the physiological and clinical relevance of this relationship and determine whether it can ultimately inform personalized nutritional strategies.