Evolving Therapy for Celiac Disease

Abstract

Gluten is known to be the main triggering factor for celiac disease (CeD), an immune-mediated disorder. CeD is therefore managed using a strict and lifelong gluten-free diet (GFD), the only effective treatment available currently. However, the GFD is restrictive. Hence, efforts are being made to explore alternative therapies. Based on their mechanisms of action on various molecular targets involved in the pathogenesis of CeD, these therapies may be classified into one of the following five broad approaches. The first approach focuses on decreasing the immunogenic content of gluten, using strategies like genetically modified wheat, intra-intestinal gluten digestion using glutenases, microwave thermal treatment of hydrated wheat kernels, and gluten pretreatment with either bacterial/ fungal derived endopeptidases or microbial transglutaminase. The second approach involves sequestering gluten in the gut lumen before it is digested into immunogenic peptides and absorbed, using binder drugs like polymer p(HEMA-co-SS), single chain fragment variable (scFv), and anti- gluten antibody AGY. The third approach aims to prevent uptake of digested gluten through intestinal epithelial tight junctions, using a zonulin antagonist. The fourth approach involves tissue transglutaminase (tTG) inhibitors to prevent the enhancement of immunogenicity of digested gluten by the intestinal tTG enzyme. The fifth approach seeks to prevent downstream immune activation after uptake of gluten immunogenic peptides through the intestinal mucosal epithelial layer. Examples include HLA-DQ2 blockers that prevent presentation of gluten derived- antigens by dendritic cells to T cells, immune- tolerizing therapies like the vaccine Nexvax2 and TIMP-Glia, cathepsin inhibitors, immunosuppressants like corticosteroids, azathioprine etc., and anti-cytokine agents targeting TNF-α and interleukin-15. Apart from these approaches, research is being done to evaluate the effectiveness of probiotics/prebiotics, helminth therapy using Necator americanus , low FODMAP diet, and pancreatic enzyme supplementation in CeD symptom control; however, the mechanisms by which they play a beneficial role in CeD are yet to be clearly established. Overall, although many therapies being explored are still in the pre-clinical phase, some like the zonulin antagonist, immune tolerizing therapies and glutenases have reached phase II/III clinical trials. While these potential options appear exciting, currently they may at best be used to supplement rather than supplant the GFD.

Serum cytokines elevated during gluten-mediated cytokine release in coeliac disease

“…Various repurposed or developmental compounds might be considered for specific unmet clinical needs or as short-term adjuncts with antigen-specific immunotherapy; for example, antagonists of IFN-γ such as salicylates [43], IL-6 [44], TNF-α antagonists, IL-17 [45] or CCL2/CCR2 blockade by natural compounds [46]. At present, IL-15 is the only target tested as anticytokine therapy in coeliac disease [18], but our findings do not support a quantitatively important role for IL-15 during acute, systemic gluten-mediated cytokine release.…”

Pathogenesis of Celiac Disease and Other Gluten Related Disorders in Wheat and Strategies for Mitigating Them

“…Following a life-long gluten-free diet is very difficult for CD patients. As a result, different strategies and therapies have been being discovered and explored to reduce the potential toxicity of gluten in CD (137). CD epitopes present in wheat can be lowered through various molecular biology, biotechnology, plant breeding, microbial, enzymatic, nano-technology, chemical, and pharmaceutical approaches (137)(138)(139)(140)(141)(142).…”

Nutraceuticals as modulators of gut microbiota: Role in therapy

“…These contrast with what is often referred to as the "Western diet" which involves high intakes of red meat, processed meat, pre-packaged foods, butter, fried foods, high-fat dairy products, eggs, refined grains, potatoes, corn, corn syrup and high-sugar drinks. The plant-based diets are thought to provide protection against a number of chronic diseases, including cardiovascular disease, through various mechanisms, including the antioxidant effects of plant polyphenols (Pandey & Rizvi, 2009) Of the aforementioned diets, the low FODMAP diet has gained a significant foothold in the management of irritable bowel syndrome (IBS; Dionne et al, 2018) and may also be of benefit to some affected by inflammatory bowel disease (Colombel, Shin, & Gibson, 2019) and celiac disease (Yoosuf, 2019). Given the prebiotic effects of oligosaccharides (discussed later) on important components of the normal microbiome, such as lactobacilli and bifidobacteria, as well as their metabolic products, such as short-chain fatty acids (SCFAs), the longterm effects of the low FODMAP diet were of some concern.…”