Gut-to-liver Pathway Uncovered: New Hope for Obesity adn Diabetes Treatment
Table of Contents
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Wikipedia‑style Context
The concept that gut‑derived metabolites travel via the portal vein to directly influence liver physiology dates back to the early 20th century, when the anatomical importance of the hepatic portal system was first described by Porter (1912).However,it was not until the advent of germ‑free animal models in the 1960s-70s that researchers began to appreciate the metabolic dialogue between intestinal microbes and the liver. Early experiments showed that germ‑free mice were protected against diet‑induced obesity, implicating the microbiota in energy balance (Bäckhed et al., 2005).
The 2000s ushered in high‑throughput sequencing and metabolomics, providing the tools to catalog microbial metabolites in the portal blood. Landmark studies identified short‑chain fatty acids (acetate, propionate, butyrate) as key signalling molecules that activate hepatic G‑protein‑coupled receptors (GPR41/43) and modulate gluconeogenesis (Krautkramer et al., 2016). Parallel work on bile‑acid transformations revealed that microbiota‑derived secondary bile acids act on the farnesoid‑X‑receptor (FXR) and the Takeda G‑protein‑coupled receptor 5 (TGR5), reshaping hepatic lipid metabolism and insulin sensitivity (Sun et al., 2014).
more recent investigations have broadened the catalogue of portal‑vein metabolites to include trimethylamine‑N‑oxide (TMAO), phenylacetic acid, indole‑propionic acid, and various aromatic amino‑acid derivatives. Using targeted portal‑vein metabolomics, Wang et al. (2022) demonstrated that phenylacetic acid suppresses hepatic phosphoenolpyruvate carboxykinase (PEPCK) expression, thereby reducing gluconeogenesis. Kim et al. (2023) showed that indole‑propionic acid enhances hepatic insulin signaling via the AMPK pathway. The cumulative evidence positions the gut‑liver axis as a therapeutic frontier for obesity and type 2 diabetes, with microbial metabolites serving both as biomarkers and drug targets.
In 2024 a multi‑institutional consortium (Harvard T.H. Chan, University of Copenhagen, and the European Molecular Biology Laboratory) published a complete portal‑vein metabolomic atlas that linked specific microbial pathways to altered hepatic lipid handling and systemic insulin resistance. This work not only confirmed earlier findings but also uncovered novel targets-such as microbial‑derived lactate‑derived oxaloacetate and bile‑acid‑conjugates-that can be modulated through diet, probiotics, or small‑molecule inhibitors.