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Gut Microbiome Study in Infants Identifies Alterations That May Contribute to Celiac Disease

NEW YORK – Researchers in Italy and the US and investigators from the Celiac Disease Genomic Environmental Microbiome and Metabolomic Study examined the gut microbiomes of 20 infants in order to identify alterations in the microbiota, functional pathways, and metabolome that could contribute to the onset of celiac disease.

In a paper published on Monday in the Proceedings of the National Academy of Sciences, the researchers noted that the incidence of chronic inflammatory autoimmune conditions, such as celiac disease, is increasing. Celiac disease is the only autoimmune condition for which the trigger — gluten — is known, but its etiology and pathogenesis remain incompletely defined.

For this study, the investigators prospectively examined the trajectory of the gut microbiota starting 18 months before the onset of celiac disease in 10 infants who developed the condition and 10 infants who did not, and they identified several differences between the two cohorts before disease onset.

"The findings indicate notable changes in the microbiome of infants with celiac disease very early in disease onset and progression," co-corresponding author and University of Maryland researcher Rita Colwell said in an email. "It is an early step toward treatment and prevention but a significant finding."

When they performed a cross-sectional analysis at disease onset, the researchers identified an altered abundance of six microbial strains and several metabolites between the 10 cases and 10 controls, but they saw no change in microbial species or pathway abundance.

Conversely, a longitudinal analysis revealed several microbial species, strains, pathways, and metabolites occurring in increased abundance before the onset of disease that had previously been linked to other autoimmune and inflammatory conditions (such as Dialister invisus, Parabacteroides species, Lachnospiraceae, tryptophan metabolism, and metabolites serine and threonine). The analysis also showed that other microbial species, which are known to have anti-inflammatory effects, decreased in abundance before disease onset (such as Streptococcus thermophilus, Faecalibacterium prausnitzii, and Clostridium clostridioforme).

Additionally, the investigators uncovered previously unreported microbes, pathways, and metabolites (such as Porphyromonas species, high mannose-type N-glycan biosynthesis, and serine) that point to celiac disease-specific biomarkers.

In one interesting observation, the researchers detected six strains of Bifidobacterium longum at significantly increased abundance in healthy controls at three months. These findings agreed with previously published reports showing increased abundance of B. longum in control subjects compared with those who later developed celiac disease. B. longum has been shown to increase production of IL-10 and to decrease inflammatory cytokines and the CD4-positive T-cell immune response in animal models with gliadin-induced enteropathy, which further supports its possible role in protection against chronic immune conditions.

Further, the researchers detected an increased abundance of nine strains of Bifidobacterium breve at nine months, a common probiotic for infants that has been linked to protection against necrotizing enterocolitis and the development of allergic diseases, as well as decreased inflammation in celiac disease.

The researchers also observed associations between some metabolites and functional pathways. For example, they identified a positive association between 3-hydroxyphenylacetic acid and the ubiquinone and other terpenoid-quinone biosynthesis pathway. Both the metabolite and the pathway were found to be decreased in infants with celiac disease at three, six, and nine months before disease onset. Importantly, ubiquinone has been reported to be an antioxidant and to modulate the innate immune response.

"Following babies at risk of celiac disease since birth, we have shown with this paper that longitudinal analysis in which [the genome, environment, microbiome, and metabolome] are followed over time allow us to monitor the 'march' from genetic predisposition to clinical outcome, something that cannot be done in classic cross-sectional case-control studies," co-corresponding author Alessio Fasano, a researcher at the MassGeneral Hospital for Children and the European Biomedical Research Institute of Salerno, said in an email.

"Thanks to this longitudinal analysis, we were able to identify specific microbiome and metabolomic 'signatures' that distinguish children that eventually will go on to develop celiac disease from those that will remain healthy, months before the onset of the disease," Fasano added.

He also concurred with Colwell that the findings offer the potential for finding therapeutic targets that would prevent the switch from genetic predisposition to actual onset of disease, and further said, "Our celiac disease model can pave the way to the intervention for other chronic inflammatory diseases by exploiting the microbiome as a therapeutic target."