Gut Microbes in Celiac Disease

CeD affects approximately 1% of the global population.  While CeD was once thought to be more prevalent in those of European descent, recent studies have shown a similar prevalence in the Asian population as well [2]. However, prevalence may be lower in the Mexican-American (0.23%), other Hispanic (0.38%) and non-Hispanic black American (0.22%) populations, which may be related to genetic or environmental causes. Far more research is needed in this area, as celiac disease research in these groups has been historically understudied [3].

Traditionally, CeD onset has been linked to T-cell activation by gliadin, the protein in gluten. This activation stimulates the intestinal lamina to trigger an inflammatory response from the adaptive immune system. Recent studies, however, have highlighted the potential role of gut microbiota in the pathogenesis of CeD.

The gut microbiota and celiac disease

Patients with CeD show a different gut microbiota composition compared to healthy individuals, with a decrease in the number of beneficial bacteria such as Faecalibacterium prausnitzii and Bifidobacterium longum [1]. 

Notably, alterations in the gut microbiota may appear even before the clinical manifestation of CeD [3]. Research among children at risk for CeD showed certain bacteria and their associated metabolites, which are linked to inflammatory and autoimmune processes, increase in numbers prior to disease onset. At the same time, bacteria with anti-inflammatory properties decrease, possibly contributing to the development of gluten intolerance and the onset of CeD [4]. 

Hypotheses on potential biomarkers for celiac disease

Alterations in gut microbiota and their byproducts could potentially serve as CeD-specific biomarkers [1]. An increase in the strains of microorganisms linked to inflammation and autoimmunity could indicate risk for gluten intolerance during the preclinical stage of CeD before physical symptoms present.

The role of antimicrobial peptides (AMPs) is also being investigated in the context of CeD. AMPs secreted by intestinal wall cells activate innate immune mechanisms to regulate interactions between commensal microbes and host tissues, exert antimicrobial activity against pathogens, and shape the composition of the microbiome [5]. 

In particular, β-defensin 2, produced by gastrointestinal mucosa epitheliocytes, has been suggested as a potential marker of inflammation [1]. Fecal calprotectin (FC) and bactericidal/permeability-increasing protein (BPI) are also of interest for their potential role in CeD. FC is a protein being assessed as a potential biomarker of disease progression in inflammation-related GI conditions [5]. BPI exhibits anti-inflammatory activity to neutralize lipopolysaccharides (LPS), which are associated with altered gastrointestinal function [6]. However, many questions about AMPs remain, including details on their involvement in malabsorption-based intestinal diseases.

Current research on CeD biomarkers

Traditional assessment and monitoring for CeD includes genetic evaluation, evaluation of immunoglobulin A tissue transglutaminase (IgA tTG) antibodies and specific endomysial antibodies (EMA), and small intestine inflammation and villous atrophy. More robust prognostic biomarkers could provide deeper insight into CeD risk, onset, progression and monitoring. 

A recent study sought to understand the role of gut microbiota and AMPs in the early stages of CeD. Researchers evaluated the levels of fecal β-defensin-2, FC, and anti-BPI antibodies in children with active CeD and compared levels with those in healthy controls. Their hypothesis was that gliadin fragmentation influences T-cell recognition of dominant gliadin epitopes and creates a pro-inflammatory environment for subsequent T-cell activation and tissue destruction.

Study Aim

To assess the levels of fecal β-defensin-2, fecal calprotectin (FC) and antibodies against bactericidal/permeabilizing protein (BPI) in the serum of children with active CeD and compare them with those of healthy controls (HC).

Method

In this study, 76 children with newly diagnosed CeD (mean age: 6.1 ± 1.2 years) and 32 HC (mean age: 6.2 ± 3.8 years) were examined. The level of fecal β-defensin-2 and CF levels in coprofiltrates, and the level of anti-BPI antibodies in blood serum were evaluated. The correlation relationships between the parameters were evaluated using a Pearson correlation coefficient.

Results

The fecal concentration of β-defensin-2 was higher in the CeD group than in the HC group, reaching 99.6 ± 15.5 ng/mL and 64.0 ± 2.4 ng/mL, respectively (p < 0 .02). The FC level in children with CeD was 35.4 ± 8.1 μg/g, while in the control group it was 19.1 ± 1.1 μg/g (p < 0.05), which represents a slight increase. The concentration of anti-BPI antibodies in the CeD and HC groups was 35.9 ± 10.1 U/mL and 5.2 ± 3.2 U/mL, respectively (p < 0.002). There was a strong and direct correlation between fecal β-defensin-2 and FC (r = 0.69), as well as a direct but weak relationship between fecal β-defensin-2 and anti-BPI antibodies (r = 0 ,35).

Conclusion

The data from the study reinforce that fecal β-defensin-2 and anti-BPI antibodies are increased in patients with active CeD and each has a distinct functional role in the protection of the intestinal mucosa. Though more research is needed, these findings indicate AMPs may be relevant biomarkers as part of epithelial innate immunity in the gut. These findings provide important context on the role of the innate immune response in the development of CeD.