14/ Using bioassay-guided fractionations we identified the key soy phytochemicals responsible: soyasaponins (SSA), which are transformed into soyasapogenols by the gut microbiome. Soyasapogenols activate liver CYP, leading to reduced PI3Ki exposure and loss of tumor control.

13/ We found it was soy, which is abundant in standard rodent chow! It wasn’t the soy protein, but rather the small molecules—phytochemicals—in soy that activated liver CYP in a microbiome-dependent manner.

12/ Next, we asked: what ingredient in chow is responsible for activating drug clearance, leading to the reduced efficacy in chow-fed mice?

11/ The increased drug exposure wasn’t due to suppression of direct drug metabolism by the gut microbiota, but rather to reduced hepatic CYP450-mediated clearance.

10/ We then discovered that the effect was mediated by drug pharmacokinetics—drug exposure was higher in mice fed purified diets or treated with antibiotics.

9/ After we were convinced the results were real and robust, we set out to investigate the mechanism. First, we found that antibiotics that ablate the microbiome also strongly enhance the anticancer activity of the drugs.

8/ To test whether the control diet was the real driver, we ran the experiment shown in the first figure panels of the paper—directly comparing the two high-carb control diets (plus keto). The results were clear: the “secret sauce” boosting PI3Ki efficacy was switching to a purified diet!

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