Urolithins: The Colon Microbiota Metabolites as Endocrine Modulators: Prospects and Perspectives

Abstract

Selective estrogen receptor modulators (SERMs) have been used in hormone related disorders, and their role in clinical medicine is evolving. Tamoxifen and raloxifen are the most commonly used synthetic SERMs, and their long-term use are known to create side effects. Hence, efforts have been directed to identify molecules which could retain the beneficial effects of estrogen, at the same time produce minimal side effects. Urolithins, the products of colon microbiota from ellagitannin rich foodstuff, have immense health benefits and have been demonstrated to bind to estrogen receptors. This class of compounds holds promise as therapeutic and nutritional supplement in cardiovascular disorders, osteoporosis, muscle health, neurological disorders, and cancers of breast, endometrium, and prostate, or, in essence, most of the hormone/endocrine-dependent diseases. One of our findings from the past decade of research on SERMs and estrogen modulators, showed that pomegranate, one of the indirect but major sources of urolithins, can act as SERM. The prospect of urolithins to act as agonist, antagonist, or SERM will depend on its structure; the estrogen receptor conformational change, availability and abundance of co-activators/co-repressors in the target tissues, and also the presence of other estrogen receptor ligands. Given that, urolithins need to be carefully studied for its SERM activity considering the pleotropic action of estrogen receptors and its numerous roles in physiological systems. In this review, we unveil the possibility of urolithins as a potent SERM, which we are currently investigating, in the hormone dependent tissues.

Keywords: PhytoSERM; estrogen receptor; pomegranate (Punica granatum L.); selective estrogen receptor modulators; urolithin.

Figure 1

The figure depicts various mechanisms by which Urolithin A (UA) is reported to regulate mitochondrial function. Many of these are also known to be modulated via Estrogen Receptor α (ER α). Here, we illustarate pathways that could be mediated by urolithins via ER α and, hence, produce a robust mitochondrial pool maintaining a healthy pool of cells.

Figure 2

Depicts pathways by which urolithins, mainly Urolithin A and Urolithin B, can act in different tissues were U represents either UA or UB. Some of these beneficial effects might be mediated by Estrogen Receptor α (ER α) since these pathways have known to be modulated by Estrogen receptors.