Molecular Nutrition & Food Research

Association Between Sulfur Microbial Diet With All‐Cause, Cardiovascular Disease, and Cancer Mortality: A Population‐Based Cohort Study

ABSTRACTThis study aimed to determine the associations between sulfur microbial diet (SMD) and all‐cause, cardiovascular disease, and cancer mortality. A total of 91 891 adults were included from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. To evaluate adherence to this dietary pattern, the SMD score was calculated with higher scores indicating greater compliance. The hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using the Cox proportional hazards regression. After a median follow‐up of 15.0 years, 20 706 all‐cause deaths were noted. The participants in the highest quartile of the SMD score had an enhanced risk of death from all causes (HR: 1.12, 95% CI: 1.07, 1.17) and cancer (HR: 1.15, 95% CI: 1.06, 1.24) than those in the lowest quartile. Dose–response analysis indicated a nonlinear association between the SMD score and both all‐cause and cancer mortality. Subgroup analyses demonstrated a significant positive association between the SMD score and all‐cause mortality in participants aged 65 years and older. Higher adherence to the SMD is linked to increased risks of all‐cause and cancer mortality in the US population. These study findings suggest that intestinal sulfur‐metabolizing bacteria may play a role in the association between diet and health outcomes.

From Gut to Hormones: Unraveling the Role of Gut Microbiota in (Phyto)Estrogen Modulation in Health and Disease

AbstractThe human gut microbiota regulates estrogen metabolism through the “estrobolome,” the collection of bacterial genes that encode enzymes like β‐glucuronidases and β‐glucosidases. These enzymes deconjugate and reactivate estrogen, influencing circulating levels. The estrobolome mediates the enterohepatic circulation and bioavailability of estrogen. Alterations in gut microbiota composition and estrobolome function have been associated with estrogen‐related diseases like breast cancer, enometrial cancer, and polycystic ovarian syndrome (PCOS). This is likely due to dysregulated estrogen signaling partly contributed by the microbial impacts on estrogen metabolism. Dietary phytoestrogens also undergo bacterial metabolism into active metabolites like equol, which binds estrogen receptors and exhibits higher estrogenic potency than its precursor daidzein. However, the ability to produce equol varies across populations, depending on the presence of specific gut microbes. Characterizing the estrobolome and equol‐producing genes across populations can provide microbiome‐based biomarkers. Further research is needed to investigate specific components of the estrobolome, phytoestrogen‐microbiota interactions, and mechanisms linking dysbiosis to estrogen‐related pathology. However, current evidence suggests that the gut microbiota is an integral regulator of estrogen status with clinical relevance to women's health and hormonal disorders.

3′‐Hydroxypterostilbene Potently Suppresses Tumor Growth via Inhibiting the Activation of the JAK2/STAT3 Pathway in Ovarian Clear Cell Carcinoma

ScopeOvarian clear cell carcinoma (OCCC) is a subtype of epithelial ovarian cancer (EOC) that is associated with higher interleukin‐6 (IL‐6) levels, and suppression of the Janus kinase 2/Signal transducer and activator of transription 3 (JAK2/STAT3) pathway may contribute to the suppression of this cancer. This study aims to compare the anti‐cancer effect of pterostilbene (PSB) and 2’‐ and 3’‐hydroxypterostilbene (2HPSB and 3HPSB, respectively) on the JAK2/STAT3 pathway.Methods and resultsIn vitro experiments with the OCCC cell line TOV21G and a xenograft nude mouse model are used to achieve the study aims. The results showed that 3HPSB has the greatest anti‐proliferative and pro‐apoptotic effects of the three compounds studied. Activation of the JAK2/STAT3 pathway and the nuclear translocation of STAT3 are effectively inhibited by 3HPSB and PSB. Both 3HPSB and PSB can effectively suppress tumor growth, which is mediated by the inhibition of JAK2/STAT3 phosphorylation.ConclusionThis is the first study to compare the efficacy of PSB, 3HPSB, and the newly identified compound 2HPSB regarding ovarian cancer. Moreover, targeting JAK2/STAT3 is shown to be a potentially effective strategy for OCCC treatment. This study is expected to provide new insights into the potential of the abovementioned phytochemicals for development as adjuvants for cancer treatment in the future.

Adherence to Sulfur Microbial Diet and Ovarian Cancer Survival: Evidence from a Prospective Cohort Study

ScopeThe study aims to investigate the role of the sulfur microbial diet in the survival of ovarian cancer (OC).Methods and resultsA prospective cohort study is conducted with 703 patients diagnosed with OC between 2015 and 2020. Diet information is collected using a validated food frequency questionnaire. Deaths are ascertained up to March 31, 2021, via the death registry linkage. During the follow‐up period (median: 37.2 months, interquartile range: 24.7–50.2 months), 130 deaths are observed. A higher sulfur microbial diet score is significantly associated with an increased risk of all‐cause mortality among OC patients (tertile 3 vs tertile 1: HR = 1.93, 95% CI = 1.11–3.35). Each 1‐standard deviation increment in the sulfur microbial diet score increases the all‐cause mortality risk by 33% (95% CI = 1.04–1.71). Stratified analysis shows that significant associations are found in OC patients diagnosed over 50 years of age, with body mass index ≥24  kg m−2, who changed their diet after diagnosis, or without residual lesions.ConclusionsAdherence to the sulfur microbial diet, characterized by high intakes of red meats and processed meats, and low intakes of fruits, vegetables, and whole grains, is associated with poor survival in OC patients.

Gut Bacterial Metabolite Urolithin A Decreases Actin Polymerization and Migration in Cancer Cells

ScopeUrolithin A (UA) is a gut‐derived bacterial metabolite from ellagic acid found in pomegranates, berries, and nuts can downregulate cell proliferation and migration. Cell proliferation and cell motility require actin reorganization, which is under control of ras‐related C3 botulinum toxin substrate 1 (Rac1) and p21 protein‐activated kinase 1 (PAK1). The present study explores whether UA can modify actin cytoskeleton in cancer cells.MethodsThe effect of UA on globular over filamentous actin ratio is determined utilizing Western blotting, immunofluorescence, and flow cytometry. Rac1 and PAK1 levels are measured by quantitative RT‐PCR and immunoblotting. As a result, a 24 h treatment with UA (20 µm) significantly decreased Rac1 and PAK1 transcript levels and activity, depolymerized actin and wound healing. The effect of UA on actin polymerization is mimicked by pharmacological inhibition of Rac1 and PAK1. The effect is also mirrored by knock down using siRNA.ConclusionUA leads to disruption of Rac1 and Pak1 activity with subsequent actin depolymerization and migration. Thus, use of dietary UA in cancer prevention or as adjuvant therapy is promising.

The Potential of Vitamin D and Epigallocatechin Gallate (EGCG) for the Treatment of Uterine Fibroids: Evidence From In Vitro to Clinical Studies

ABSTRACT Uterine fibroids are prevalent benign tumors of the female reproductive tract that cause significant morbidity. Accumulating evidence suggests an association between vitamin D deficiency and uterine fibroid prevalence. Vitamin D, synthesized through sunlight exposure and obtained from fatty fish and fortified foods, regulates key processes, such as cell proliferation and apoptosis. In vitro and in vivo studies have demonstrated the efficacy of vitamin D against uterine fibroids. Clinical evidence further supports its role in fibroid management, as evidenced by a decrease in fibroid incidence, volume, and growth rate. Similarly, EGCG, a major polyphenol in green tea, inhibits cell proliferation and fibrosis while inducing apoptosis. Both in vitro and in vivo studies reveal the potential of EGCG in fibroid treatment, with clinical trials corroborating these findings. Given their complementary mechanisms, a synergistic effect of combined vitamin D and EGCG treatment has been explored. Preliminary clinical evidence indicates promising results, including reduction in fibroid volume, improved surgical outcomes, and enhanced quality of life. This review synthesizes current knowledge of vitamin D and EGCG mechanisms of action, presents preclinical and clinical evidence, and discusses the emerging evidence for their combination therapy as a non‐invasive, cost‐effective treatment strategy for uterine fibroids.