The Impact of Highly Effective CFTR Modulators on Growth and Nutrition Status

Abstract

Patients with cystic fibrosis (CF) are at increased risk of malnutrition and growth failure due to multiple factors as a result of suboptimal or absent function of the CFTR chloride channel protein. Dysfunctional CFTR contributes to increased energy expenditure, exocrine pancreatic insufficiency causing impaired dietary macronutrient digestion and absorption, intestinal dysbiosis, and impaired bile acid homeostasis. Poor nutritional status as a result of these mechanisms is associated with decreased lung function, worse clinical outcomes, and ultimately, increased mortality. Nutritional interventions addressing these mechanisms, such as pancreatic enzyme-replacement therapy and enteral caloric supplementation, have improved nutritional status and, by association, clinical outcomes. In the last decade, the advent of medications targeting defective CFTR proteins has revolutionized the care of patients with CF by reducing the overall impact of CFTR dysfunction. Below, we summarize the effects of highly effective CFTR modulators on nutritional status overall as well as specific factors including bile acid metabolism, pancreatic function, energy expenditure, and intestinal dysbiosis. The future of CF nutrition care will require a paradigm shift away from focusing on methods addressing CFTR dysfunction such as excess calorie provision and toward an individualized, holistic approach in the context of specific mutations and CFTR-directed therapy.

What Do We Know about the Microbiome in Cystic Fibrosis? Is There a Role for Probiotics and Prebiotics?

“…While patients who are overweight or obese are reported to have better lung function than their normal weight or underweight counterparts in some studies, this finding may be confounded by the fact that these patients are also more likely to be pancreatic sufficient and have milder disease genotypes [ 118 , 119 , 120 , 121 , 122 ]. Additionally, weight gain and increased BMI, fat mass, and fat-free mass are reported outcomes of CFTR modulator therapies that need to be taken into account as modulator therapies gradually become the cornerstone of CF treatment [ 123 , 124 , 125 , 126 ]. Importantly, both high-fat diets and obesity may exacerbate existing alterations in gut microbial composition and chronic intestinal inflammation, with important clinical implications for individuals with CF [ 81 , 82 , 83 , 127 , 128 ] ( Figure 1 ).…”

Association of Body Mass Index With Clinical Outcomes in Patients With Cystic Fibrosis

“…59 The continuous spread of modulators that aim to diminish the influence of CFTR dysfunction has been shown to have beneficial effect on body composition. 60 In addition to weight gain, the proportion of FFM is increasing, which is associated with the reduction of REE.…”

Correlates of Pancreatic Enzyme Replacement Therapy Intake in Adults with Cystic Fibrosis: Results of a Cross-Sectional Study

“…However, emerging data in young children treated with CFTR modulators suggest some degree of recovery of the exocrine pancreatic function [ 24 , 25 , 26 ]. Modulators have also shown beneficial effects on intestinal microbiome and epithelia function [ 27 , 28 ]. Thus, it is likely that the future needs of PERT will change in the era of triple CFTR modulator therapy.…”