Berberine consistently lowers fasting glucose, but its effect on postprandial excursions remains unmeasured in humans. We hypothesize that berberine reduces postprandial glucose spikes by inhibiting intestinal SGLT1‑mediated glucose absorption through an AMPK‑independent pathway, and that the magnitude of this effect varies with an individual’s baseline gut microbiota composition, specifically the abundance of bile‑acid‑transforming bacteria.

Mechanistic rationale Berberine activates AMPK in liver and muscle, increasing glucose uptake and suppressing gluconeogenesis Berberine activates AMPK. However, several studies report AMPK‑independent glucose consumption, suggesting parallel mechanisms AMPK‑independent pathways. In vitro work shows berberine can bind to and inhibit SGLT1, the transporter responsible for luminal glucose uptake in the intestine SGLT1 inhibition. Inhibition of SGLT1 would blunt postprandial glucose appearance independent of hepatic AMPK activity. Furthermore, berberine alters gut microbiota, increasing bile‑acid‑deconjugating taxa such as Lactobacillus and Bifidobacterium Microbiota shifts. These bacteria transform primary bile acids into secondary bile acids that can modulate SGLT1 expression via FXR‑TGR5 signaling, providing a mechanistic link between microbiota composition and transporter activity.

Predictions

1. In individuals with high baseline abundance of bile‑acid‑deconjugating bacteria, berberine will produce a greater reduction in postprandial glucose peaks (measured as time‑above‑range >140 mg/dL) than in those with low abundance, despite similar fasting glucose changes.
2. The reduction in postprandial excursions will occur without a proportional change in fasting insulin or HOMA‑IR, indicating an AMPK‑independent contribution.
3. Combining berberine with metformin will yield additive improvements in time‑in‑range, reflecting complementary hepatic (AMPK‑dependent) and intestinal (SGLT1‑dependent) actions.

Experimental design A double‑blind, crossover trial with 40 prediabetic participants will receive berberine 500 mg TID or placebo for 4 weeks, separated by a 4‑week washout. Continuous glucose monitoring will capture fasting glucose, postprandial glucose area under the curve, coefficient of variation, and time‑in‑range. Stool samples collected at baseline and week 4 will undergo 16S rRNA sequencing to quantify bile‑acid‑deconjugating taxa. Fasting insulin, HOMA‑IR, and HbA1c will be measured to assess hepatic effects.

Statistical analysis Primary outcome: change in postprandial time‑above‑range. Secondary outcomes: fasting glucose change, HbA1c shift, insulin sensitivity. Interaction effects will be tested using linear models with microbiota abundance as a moderator. A significant interaction (p<0.05) supporting greater postprandial improvement in high‑abundance subjects would confirm the hypothesis. Lack of interaction or absent postprandial effect despite fasting changes would falsify the proposed AMPK‑independent SGLT1 mechanism.

Implications Confirming this hypothesis would explain interindividual variability in berberine response, guide personalized supplementation based on microbiome profiling, and reveal a novel intestinal target that complements existing AMPK‑focused therapies.