Genetic Variation of Enzyme hCAZYme May Affect IBS Response to Low-Carb Diet

Mauro D’Amato, PhD

Credit: CicbioGune

A new study discovered people with irritable bowel syndrome (IBS) who have a genetic variation of a human carbohydrate-active enzyme (hCAZYme) are more likely to experience symptom relief from a carbohydrate-reduced diet.¹

“These findings suggest that genetic variations in hCAZyme enzymes, which play a key role in digesting carbohydrates, could become critical markers for designing personalized dietary treatments for IBS,” said lead investigator Mauro D’Amato, PhD, from Ikerbasque Research Professor from the Gastrointestinal Genetics Research group at CIC bioGUNE and LUM University in Italy. “The ability to predict which patients respond best to a carbohydrate-reduced diet has the potential to strongly impact IBS management, leading to better adherence and improved outcomes.”

Several risk factors contribute to IBS, including psychological stressors, gut dysbiosis, epithelial barrier dysfunction, and mucosal immunity. However, another risk factor, dietary triggers, has led UK England and Wales NICE guidelines to recommend avoiding carbohydrates as the first-line approach.

For many, limiting carbohydrates, particularly fermentable oligosaccharides, disaccharides, monosaccharides, and polyols, have therapeutic effects on IBS symptoms. Another recent study found that 2 4-week dietary interventions reduced the severity of IBS symptoms.² Although some patients with IBS find relief in a low-carb diet, not all do.¹

Research indicates that IBS symptoms may be caused by an inability to digest carbohydrates due to an inefficient enzymatic breakdown of polysaccharides. The process of polysaccharide breakdown involves the action of several hCAZymes. Investigators sought to investigate how genetic variation in hCAZymes genes influenced the response to a carbohydrate-reduced diet.

The DOMINO study evaluated hCAZy polymorphism in 196 patients who tried a low-carb diet and 54 who took medication. Investigators detected 60 missense hCAZyme variants, with 49 rare ones and 11 common variants.

The team targeted the sequencing of 6 genes of interest: AMY2B, LCT, MGAM, MGAM2, SI, and TREH. Based on computational predictions of the functional effects of these amino acid changes, 25 hCAZyme variants were classified as hypomorphic, or dysfunctional, and 35 were classified as benign.

Among participants on a low-carb diet, the number of hypomorphic hCAZyme genes positively correlated with treatment response rate (odds ratio [OR], 1.51; 95% confidence interval [CI], 0.99 – 2.32; P = .03). The low-carb diet reached a 100% success rate in the group of IBS patients who carried defective variants in 3 hCAZyme.

Additionally, greater severity of IBS symptoms was often correlated with the number of defected hCAZyme genes.

In the IBS-D group (n = 55), hCAZyme carriers were 6 times more likely to respond to the diet than non-carriers (OR, 6.33; 95% CI, 1.83 – 24.77; P = .002) as assessed on the IBS symptom severity at the global and individual level. The same was not found among participants on medication.

Investigators found SI hypomorphic variants, especially the Val15Phe variant, were the most common hCAZyme variants. When the cohort was stratified into SI hypomorphic carriers and non-carriers, they observed no significant association with the response to a low-carb diet. However, SI hypomorphic variants were more common in those who responded to the low-carb diet (P = .044).

When the team excluded SI carriers from the analysis, it showed how hCAZyme carriers responded better than non-carriers (P = .06).

“These data needs to be further validated by future studies,” said investigator Maura Corsetti, MD, PhD, from Nottingham University Hospitals NHS Trust and the University of Nottingham, in the UK. “If confirmed, this approach open the way to personalized dietary and treatment strategies.”

References

1. ^{Zamfir-Taranu A, Löscher BS, Carbone F, et al. Functional variation in human CAZyme genes in relation to the efficacy of a carbohydrate-restricted diet in IBS patients. Clin Gastroenterol Hepatol. Published online October 7, 2024. doi:10.1016/j.cgh.2024.09.004}
2. ^{Nybacka S, Törnblom H, Josefsson A, et al. A low FODMAP diet plus traditional dietary advice versus a low-carbohydrate diet versus pharmacological treatment in irritable bowel syndrome (CARIBS): a single-centre, single-blind, randomised controlled trial [published correction appears in Lancet Gastroenterol Hepatol. 2024 Jun;9(6):e9. doi: 10.1016/S2468-1253(24)00122-5]. Lancet Gastroenterol Hepatol. 2024;9(6):507-520. doi:10.1016/S2468-1253(24)00045-1}