Sorbitol, a poorly absorbable sweetener, is catabolized by gut microbiota, mainly Clostridia. Lee et al. now elucidate the pathophysiology of sorbitol intolerance and highlight a role for Clostridia and butyrate, a short-chain fatty acid metabolite.

Stable engraftment of Escherichia coli strain Nissle 1917, a probiotic that catabolizes sorbitol, restored caecal SDH activity in mice and protected them from diarrhoea. Inocculation of Anaerostipes caccae, an abundant component of the human gut microbiome that belongs to Clostridia and uses sorbitol as a carbon source, also protected against sorbitol intolerance, even despite transient gut colonization. The protective effect of A. caccae involved both endogenous sorbitol catabolism early after inoculation and butyrate-dependent promotion of gut re-colonization by diverse Clostridia species, which took over sorbitol catabolism upon A. caccae clearance. A. caccae-derived or exogenous butyrate activated the transcription factor PPARγ in host intestinal epithelium. PPARγ activation restored the hypoxic microenvironment that is required by the anaerobic Clostridia and that is perturbed by a high-fat diet. Prophylactic administration of the PPARγ agonist 5-ASA protected mice from prolonged sorbitol intolerance. “While current guidelines for the diagnosis and treatment of intolerance to sugar alcohols or other FODMAPs emphasize on eliminating the causative dietary ingredients, our study provides an entirely new starting point for strategies to diagnose, prevent, and manage sorbitol intolerance,” notes Lee. Further research by the group will “examine how the consumption of artificial sweeteners, such as sorbitol, may exacerbate intestinal inflammation in the context of dysbiosis,” adds Lee.