Impact of genistein on the gut microbiome of humanized mice and its role in breast tumor inhibition

Abstract

Since dietary polyphenols can have beneficial effects in prevention and treatment of cancer, we tested the hypothesis that breast cancer patients’ intestinal microbiota is modulated by genistein (GE), an isoflavone found in soy, and that microbial alterations may offset the side effects brought about by chemotherapy. We demonstrated successful humanization of germ-free mice by transplanting fecal samples from breast cancer patients before and after chemotherapy. Mice were then grouped based on chemotherapy status and GE or control diet. We did not find any significant differences between pre-chemotherapy and post-chemotherapy bacterial composition and abundances. Germ-free mice on a GE diet showed differences in microbial composition as compared to mice on control diet. Four weeks after introduction of the customized GE diet, there was distinct clustering of GE-fed mice as compared to the control-fed group. In the gut microbiome of GE-treated humanized mice, there was an increase in abundance of genera Lactococcus and Eubacterium. Phylum Verrucomicrobia showed statistically significant (p = 0.02) differences in abundances between the GE-fed and control-fed groups. There was an increase in bacteria belonging to family Lachnospiraceae and Ruminococcaceae in GE-fed mice. Marked changes were observed in GE catabolism in mice humanized with fecal material from two of three patients’ post-chemotherapy with complete disappearance of 4-ethylphenol and 2-(4-hydroxyphenol) propionic acid conjugates. The post-tumor samples did not show any distinct clustering of the gut microbiota between the two diet groups. There was an increase in latency of about 25% for tumor growth of the humanized mice that were on a GE diet as compared to humanized mice on a control diet. The average tumor size for the GE group was significantly decreased compared to the non-GE group. Collectively, our results suggest that the intestinal microbiota becomes altered with a GE diet before induction of tumor. Our findings indicate that GE modulates the microbiome in humanized mice that may contribute to its effects on increasing the latency of breast tumor and reducing tumor growth.

Genistein stimulates insulin sensitivity through gut microbiota reshaping and skeletal muscle AMPK activation in obese subjects

“…It has also been shown that genistein increases the formation of metabolites derived from the benzoate metabolism. In fact, there is evidence that genistein can be biotransformed by the gut microbiota to 4-ethylphenol 44. In particular, 4-ethylphenylsulfate, a product derived from 4-ethylphenol, is associated with the maximal aerobic capacity in healthy subjects, as well as prediction of lean body mass 24 45.…”

Effect of Added Dietary Betaine and Soluble Fiber on Metabolites and Fecal Microbiome in Dogs with Early Renal Disease

“…The soy flavonoids increased with the test food(s) in this study, including daidzein, genistein, and glycitein, have been associated with a number of positive health attributes, including antioxidant, anticancer, and anti-inflammatory properties [ 39 , 40 , 41 ]. There is also some evidence that genistein can modulate the gut microbiome to reduce tumor growth [ 42 ]. In addition, consumption of soy protein has been shown to slow the decline of estimated GFR and decrease proteinuria in patients with CKD [ 43 ].…”

Effects of Phytoestrogens on the Developing Brain, Gut Microbiota, and Risk for Neurobehavioral Disorders

“…Consumption of soy or exposure to phytoestrogens alters the gut microbiota denizens (14)(15)(16)(17)(18)(19)(20)(21)(22). Most current studies have focused on whether direct or adult exposure affects the gut microbiome, although there is every reason to believe that developmental exposure to such chemicals influences infant gut bacteria populations, which may be even more vulnerable during this initial colonization period than those of adults.…”

“…A similar study found that ingestion of daidzein positively correlated with greater abundance of Asaccharobacter celatus and Slackia isoflavoniconvertens, two equol producing bacteria (13). Other rodent and human studies suggest that genistein (GEN) or soy based foods impacts gut microorganisms (14)(15)(16)(17)(18)(19)(20)(21)(22). Alterations in bacteria residing in the gut or skewing to pathobionts (otherwise considered gut dysbiosis) may result in neurobehavioral changes, giving rise to the term the microbiomegut-brain axis (23)(24)(25)(26).…”