Saccharomyces boulardii CNCM I-745 synergizes with the small intestinal microbiota to boost AhR signaling in celiac disease

Celiac disease (CeD) is an immune-mediated condition that leads to small intestinal villous atrophy and is driven by dietary gluten in individuals carrying HLA-DQ2 and DQ8. Microbial factors have been implicated in both the onset of CeD and persistent symptoms (non-responsive CeD) after the gluten-free diet (GFD), through mechanisms including impaired tryptophan metabolism and aryl hydrocarbon receptor (AhR) pathway activation. Although probiotics have been shown to be safe in CeD, there are currently no clinical recommendations for strains that target disease-related mechanisms. We here demonstrate that S. boulardii activated the AhR pathway in gluten-sensitized mice expressing HLA-DQ8, improving gluten-immunopathology. Mechanistically, S. boulardii enhanced the CeD patients' microbiota capacity for AhR activation when duodenal indole-producing commensals, such as Lactobacillus reuteri, were present. Our study provides preclinical evidence that S. boulardii CNCM I-745 targets a microbial deficiency previously described in CeD through modulation of microbial tryptophan metabolism. The findings encourage clinical testing of S. boulardii in CeD to prevent or better treat non-responsive cases.