In both the intestines and liver, tissue function is linked to spatial architecture. Gradients of nutrients, oxygen and gene expression along defined structural axes—the portal-central axis in the liver and the crypt–villus axis in the small intestine—underlie specialized, spatially coordinated metabolic functions. To study spatial variations in metabolism in these tissues, researchers led by Ludwig Princeton’s Laith Samarah and Director Joshua Rabinowitz, together with Princeton computer scientist Ben Raphael, mapped metabolite abundances and pathway activity at high spatial resolution in mice using imaging mass spectrometry (MALDI-IMS), isotope tracing and a deep-learning approach that inferred the metabolic topography of tissues from metabolomic images. They reported in an October issue of Nature that more than 90% of metabolites vary significantly along the portal–central axis in the liver and along the crypt–villus axis in the intestine. Laith, Josh and their colleagues described metabolic activity patterns underlying these concentration gradients. They also traced the metabolic fate of dietary fructose, a major factor in obesity, and showed how, at high doses, the sugar causes profound local disruptions in the levels of ATP—the body’s most basic currency of energy—in the liver. The authors note that fructose intake is associated with cancers of both the liver and intestine, and the technologies developed here should be powerful tools for spatial analysis of tumor metabolism.
Spatial metabolic gradients in the liver and small intestine
Nature, 2025 October 15