Genistein prevention of hyperglycemia and improvement of glucose tolerance in adult non-obese diabetic mice are associated with alterations of gut microbiome and immune homeostasis

Abstract

Although studies have linked soy phytoestrogen 4,7,4-trihydroxyisoflavone genistein (GEN) to reduced type 1 diabetes (T1D) risk, the mechanism of dietary GEN on T1D remains unknown. In our studies, adult non-obese diabetic (NOD) mouse model was employed to investigate the effects of GEN exposure on blood glucose level (BGL), glucose tolerance, gut microbiome, and immune responses. Adult male and female NOD mice were fed with either soy-based or casein-based diet, and received GEN at 20 mg/kg body weight by gavage daily. The BGL and immune responses (represented by serum antibodies, cytokines and chemokines, and histopathology) were monitored, while the fecal gut microbiome was sequenced for 16S ribosomal RNA to reveal any alterations in gut microbial communities. A significantly reduced BGL was found in NOD males fed with soy-based diet on day 98 after initial dosing and an improved glucose tolerance was observed on both diets. In addition, an anti-inflammatory response (suggested by reduced IgG2b and cytokine/chemokine levels, and alterations in the microbial taxonomy) was accompanied by an altered β-diversity in gut microbial species. Among the NOD females exposed to GEN, a later onset of T1D was observed. However, the profiles of gut microbiome, antibodies and cytokines/chemokines were all indicative of pro-inflammation This study demonstrated an association among GEN exposure, gut microbiome alteration, and immune homeostasis in NOD males. Although the mechanisms underlying the protective effects of GEN in NOD mice need to be explored further, the current study suggested a GEN-induced sex-specific effect in inflammatory status and gut microbiome.

Estrogen–gut microbiome axis: Physiological and clinical implications

“…However, the interaction between the gut microbiome and phytoestrogens may not be unidirectional. Non-obese diabetic mice fed with the phytoestrogen genistein, have been shown to have significantly different gut microbial beta-diversity linked to immune homeostasis [7]. Gut microbiota alteration following phytoestrogen consumption may be a factor in the alleviation or causation of cancer.…”

“…Similarly, the host microenvironment of the gut influences the gut microbiome [6]. The gut microbiome has been shown to be influenced by estrogen, however, the gut microbiome also significantly impacts estrogen levels [7,8]. The gut microbiome impacts estrogen levels in the host through the secretion of β-glucuronidase, an enzyme which deconjugates estrogen, enabling it to bind to estrogen receptors and leading to its subsequent physiological downstream effects [9].…”

The “Gut Feeling”: Breaking Down the Role of Gut Microbiome in Multiple Sclerosis

“…Several studies have demonstrated that therapeutic administration of phytoestrogens (genistein and daidzein) ameliorates EAE, which is correlated with a decrease in the production of proinflammatory cytokines and an increase in the production of anti-inflammatory cytokines [159][160][161][162][163][164]. Phytoestrogens are also protective in the nonobese diabetic mouse model of T1D [165] and were associated with shifts in the gut microbiome [166]. A recent study by Berer et al [27] demonstrated that mice transplanted with fecal samples from healthy human controls, which developed a lower frequency of spontaneous EAE than mice transplanted with MS fecal samples, harbored a higher abundance of Adlercreutzia then MS fecaltreated mice.…”

Considering gut microbiota in treatment of type 2 diabetes mellitus

“…Additionally, a range of herbal-derived products including berberine, resveratrol, alliin, capsaicin, betacyanins, and cranberry proanthocyanidins have bioactions and antidiabetic effects potentially mediated by modulation of gut microbiota. [60][61][62][63][64][65][66][67] Galactomannan, pectin, capsaicin, and red pitaya betacyanins altered the proportion of Firmicutes to Bacteroidetes. 62,65,66 Increased fecal butyrate concentration and Roseburia abundance and decreased Bacteroides and Parabacteroides abundances have been reported after intervention by capsaicin in obese diabetic ob/ob mice.…”