Estrobolome and Hepatocellular Adenomas-Connecting the Dots of the Gut Microbial β-Glucuronidase Pathway as a Metabolic Link

Abstract

Hepatocellular adenomas are benign endothelial tumors of the liver, mostly associated with female individual users of estrogen-containing medications. However, the precise factors underlying the selective development of hepatic adenomas in certain females remain elusive. Additionally, the conventional profile of individuals prone to hepatic adenoma is changing. Notably, male patients exhibit a higher risk of malignant progression of hepatocellular adenomas, and there are instances where hepatic adenomas have no identifiable cause. In this paper, we theorize the role of the human gastrointestinal microbiota, specifically, of bacterial species producing β-glucuronidase enzymes, in the development of hepatic adenomas through the estrogen recycling pathway. Furthermore, we aim to address some of the existing gaps in our knowledge of pathophysiological pathways which are not yet subject to research or need to be studied further. As microbial β-glucuronidases proteins recycle estrogen and facilitate the conversion of inactive estrogen into its active form, this process results in elevated levels of unbound plasmatic estrogen, leading to extended exposure to estrogen. We suggest that an imbalance in the estrobolome could contribute to sex hormone disease evolution and, consequently, to the advancement of hepatocellular adenomas, which are estrogen related.

Keywords: GUS; HCA; estrogen; fatty liver; gut microbiota; hepatic adenoma; hepatocellular adenoma; liver; steatohepatitis; β-glucuronidase enzymes.

Figure 1

Gut bacterial triggers and the liver immunological response (created in BioRender.com). The components of the gut bacterial envelope are triggers for the hepatic immune response. The LPS are the components of the external layer of the wall of Gram-negative bacteria, while PGN are the components of the rigid layer of Gram-positive bacteria (alongside LTA) and of the internal wall of Gram-negative bacteria. The LPS, PGN, LTA, and bacterial DNA-endosome enter into the portal circulation, bypassing the intestinal barrier. In the liver, these components are ligands for TLR receptors and promote the pro-inflammatory response by macrophage activation and cytokine release. The consequence is hepatic inflammation and steatosis. TLR—Toll-like receptor; PGN—peptidoglycan; LTA—lipoteichoic acid; LPS—lipopolysaccharide.