Files
Abstract
Type 1 diabetes (T1D), previously referred to as "juvenile diabetes", is alarmingly increasing in young adults. The associations of high soy consumption and risk of T1D are uncertain and intricate, which may depend on the window of exposures and its interaction with the other dietary intake, as epidemiological evidences are limited. Two soy isoflavones of particular significance are genistein (GEN) and daidzein (DAZ). The soy intake in adult T1D patients was associated with protected renal function, while the mechanisms of isoflavone protection on T1D are largely unknown. The current study showed adult GEN intake decreased the hyperglycemia in adult male non-obese diabetic (NOD) mice and reduced the incidence of T1D in female NOD mice. The immunomodulatory effect of GEN is sex-specific, in that the male adults demonstrated an anti-inflammatory response whereas the adult female demonstrated a pro-inflammatory response, as shown by cytokine/chemokine and antibody profiles. To further reveal the mechanisms, the 16s ribosomal RNA (rRNA) genes from feces were sequenced to reflect the abundance and diversity of gut microbes, and GEN dosing could affect both the diversity and the abundance of gut microbiota (GMB) in males toward an anti-inflammatory response, while affecting the abundance GMB in females toward a pro-inflammatory response. An alteration of urinary metabolomic profile was also observed in males. As a comparison, in severe combined immunodeficiency (SCID) adult female mice, an alteration of GMB, but no alteration of blood glucose level was found following GEN intake. However, there is evidence that soy milk formula consumption in infants was associated with increased T1D risk. Therefore, we also evaluated the effect of GEN from perinatal exposure. The incidence of T1D in offspring with maternal GEN intake reflected an exacerbation effect in female offspring (in accordance with antibodies, cytokines, chemokines, and splenocyte subpopulations); despite no protection among male offspring with regard to T1D incidence and blood glucose level, an immune-modulation toward anti-inflammatory was found. The GMB in the three-month feces from female offspring showed a clear separation and an increase of pro-inflammatory microbes, but not in one-month feces. DAZ intake could also modulating immune homeostasis by increasing T cell numbers and modulating immune system as well. Taken together, our studies on T1D have identified that isoflavones, especially GEN, have a strong sex-specific and exposure window-specific effect in NOD mice that was associated with GMB-related immunomodulation.