Microbiome signatures of progression toward celiac disease onset in at-risk children in a longitudinal prospective cohort study

Abstract

Other than exposure to gluten and genetic compatibility, the gut microbiome has been suggested to be involved in celiac disease (CD) pathogenesis by mediating interactions between gluten/environmental factors and the host immune system. However, to establish disease progression markers, it is essential to assess alterations in the gut microbiota before disease onset. Here, a prospective metagenomic analysis of the gut microbiota of infants at risk of CD was done to track shifts in the microbiota before CD development. We performed cross-sectional and longitudinal analyses of gut microbiota, functional pathways, and metabolites, starting from 18 mo before CD onset, in 10 infants who developed CD and 10 matched nonaffected infants. Cross-sectional analysis at CD onset identified altered abundance of six microbial strains and several metabolites between cases and controls but no change in microbial species or pathway abundance. Conversely, results of longitudinal analysis revealed several microbial species/strains/pathways/metabolites occurring in increased abundance and detected before CD onset. These had previously been linked to autoimmune and inflammatory conditions (e.g., Dialister invisus, Parabacteroides sp., Lachnospiraceae, tryptophan metabolism, and metabolites serine and threonine). Others occurred in decreased abundance before CD onset and are known to have anti-inflammatory effects (e.g., Streptococcus thermophilus, Faecalibacterium prausnitzii, and Clostridium clostridioforme). Additionally, we uncovered previously unreported microbes/pathways/metabolites (e.g., Porphyromonas sp., high mannose–type N-glycan biosynthesis, and serine) that point to CD-specific biomarkers. Our study establishes a road map for prospective longitudinal study designs to better understand the role of gut microbiota in disease pathogenesis and therapeutic targets to reestablish tolerance and/or prevent autoimmunity.

Dynamics of Gut Microbiome, IgA Response and Plasma Metabolome in Development of Pediatric Celiac Disease

“…Consistent with the previous reports, we showed that the pentose phosphate pathway (PPP) (Raw P=0.0246) was significantly altered in the CD progressors (Leonard et al, 2021); in addition to lysine degradation (Raw P=0.028), and glycolipid metabolism (Raw P=0.0397) pathways.…”

Gut microbiome and health: mechanistic insights

“…The gut microbiome has been associated with several intestinal and extraintestinal disorders 34. Many large studies investigating the gut microbiome and its relevance have been performed in specific gastrointestinal (GI) disorders such as intestinal bowel diseases (IBDs),35 coeliac disease,36 irritable bowel syndrome (IBS),37 colorectal cancer (CRC),38 chronic liver diseases39 40 or pancreatic disorders 41 42. IBDs, prototypic inflammatory disorders of the intestine, are associated with deviating gut microbiome composition and indeed facultative anaerobes outgrow have been reported, especially in the context of active inflammation and metabolite disturbances including BAs, short chain fatty acids (SCFAs) and acylcarnitine pathways 35.…”

“…IBDs, prototypic inflammatory disorders of the intestine, are associated with deviating gut microbiome composition and indeed facultative anaerobes outgrow have been reported, especially in the context of active inflammation and metabolite disturbances including BAs, short chain fatty acids (SCFAs) and acylcarnitine pathways 35. Longitudinal analysis in infants at risk for coeliac disease, another frequent inflammatory intestinal disorder, demonstrated an increased presence of several microbial species such as Dialister invisus, Parabacteroides spp or Lachnospiraceae and certain metabolites such as tryptophan metabolites before disease onset whereas various anti-inflammatory strains such as Faecalibacterium prausnitzii or Clostridium clostridioforme were decreased 36. IBS, a frequent functional disorder of the GI tract, has been associated with IBS subtype-specific changes in the gut microbiome and related metabolites, with purine metabolism being especially affected 37.…”

Wheat/Gluten-Related Disorders and Gluten-Free Diet Misconceptions: A Review

“…Comparing 10 infants who developed CD and 10 infants who did not, the researchers identified complex patterns of increased abundances of proinflammatory species and decreased abundances of protective and anti-inflammatory species at various time points preceding the onset of the disease. They believe these microbiome shifts, coupled with metabolome findings, may represent potential biomarkers of CD development [124]. However, further studies are necessary since the number of patients examined was low.…”