Abstract
Non-celiac gluten sensitivity (NCGS) is an emerging diagnosis, and its symptoms overlap with irritable bowel syndrome (IBS). The gut microbiome is likely to play a role in the pathogenesis of NCGS. We analyzed the gut microbiome in patients with NCGS and in patients with IBS, using shotgun metagenomics and metabolomics of fecal samples. Analyses of taxonomic and functional microbial diversity revealed a higher abundance of methanogenic archaea, such as Methanobrevibacter filiformis, Methanobrevibacter boviskoreani, Methanosphaera stadtmanae, and a higher fold change in urea, uridine 5-monophosphate, and adenosine monophosphate in patients with NCGS compared to patients with IBS, who showed higher fold changes in metabolites gamma-aminobutyric acid and lactic acid. Furthermore, pangenome and metabolome analyses revealed disease-specific gene clusters, as well as genomic and metabolic features differentiating NCGS from IBS. While patients with NCGS did not show lower potential for gluten degradation, a lower synthetic potential for fructan beta-fructosidase was found in them. The present study provides an extensive analysis of taxonomic, genomic, and metabolic features that may play a role in the pathogenesis and symptom development in patients with NCGS. IMPORTANCE: Non-celiac gluten sensitivity (NCGS) is an emerging diagnosis with symptoms that overlap with irritable bowel syndrome (IBS). Using shotgun metagenomics and metabolomics, we report deeper insights into the microbiome profile, including viral and archaeal diversity, lower fructan degradation potential, the differential abundance of metabolites, and genomic features of gut bacteria in patients with NCGS. Understanding the microbiome associated with this disorder may shed light on the possible role of the microbiome in the pathophysiology of NCGS.