Letter: Supporting the Role of Enzyme Therapy in Management of Coeliac Disease

Abstract

I appreciate the opportunity to comment on the review article by Bonner et al. [1].

The article rightly highlights the duodenum as the site where enzymatic interaction with gluten will be most beneficial. The caricain-based supplement was the first technology proposing the small intestine as the site of enzyme activity through extensive in vitro studies and clinical trials. The product formulation involves the combination of an acid-resistant coating and superdisintegrant excipients to ensure rapid release of the enzyme in the duodenum, post gastric emptying. There it neutralises partially digested gluten immunogenic peptides (GIPs) in conjunction with brush border peptidases before symptoms and immune activation occur.

Caricain (EC 3.4.22.30) is a well-characterised cysteine endopeptidase derived from Carica papaya which cleaves proline-rich motifs in gluten [2]. It offers a high degree of protection against the toxic action of gliadin on rat liver lysosomes [3], mimicking pathological alterations to lysosomes seen in the mucosa of the small intestine [4]. Caricain rapidly digests GIPs in pepsin trypsin-treated gliadin [5] and also extensively hydrolyses Wheat ⍺-Amylase Trypsin Inhibitors (ATIs) [6]. Unlike exopeptidases (DPPIV), which inefficiently degrade gluten [5, 7] caricain rapidly degrades GIPs into non-immunogenic fragments, including the 33-mer, under physiologically relevant conditions (pH 3–7) and is stable to the action of gastric proteases, trypsin, and pepsin [5].

Missing from the review of Bonner et al. are two important peer-reviewed reports of randomised, double-blind, placebo-controlled clinical studies published in an international searchable journal. The first study evaluated caricain's efficacy in dermatitis herpetiformis. Despite a substantial gluten challenge (6 g/day for 14 days), supplementation with caricain demonstrated significant protective effects with an 81% reduction in skin lesion area (19.5 to 3.7 cm²; p = 0.02), 71% decrease in new lesions, and 38% decline in pruritus compared to placebo [8]. The second study investigated the effects of caricain supplementation in patients with coeliac disease in remission undergoing a controlled gluten challenge for 42 days. Overall symptom scores and five individual symptoms (well-being, fatigue, nausea/vomiting, stomach pain and cramps, at day 14) favoured caricain over placebo (p < 0.01 for each). Dropouts occurred almost exclusively in the group randomised to placebo, due to the clinical effects of the gluten challenge; those randomised to caricain tolerated the challenge well [9]. Indeed, the large, statistically significant effects were secured even with a small sample size. The observed protective effects support caricain's intended role to mitigate the effects of inadvertent gluten exposure.

Enzyme therapies like caricain offer protection against gluten before it triggers immune responses. The mechanism is localised to the gastrointestinal lumen, with no direct effects on the immune system or intestinal healing. This distinction is critical to avoid misclassification as disease-modifying treatments.

The authors are to be commended for bringing attention to the benefits of enzyme therapy in the management of coeliac disease, which these studies support.

Finlay Macrae: conceptualization, writing – original draft, writing – review and editing, methodology, project administration.

This article is linked to Bonner et al. paper. To view this article, visit https://onlinelibrary.wiley.com/doi/10.1111/apt.70014 and https://onlinelibrary.wiley.com/doi/10.1111/apt.70205.