Intestinal epithelium impairment in cystic fibrosis: What consequences in clinical practice?

Abstract

Cystic fibrosis (CF) results from the loss of function of the CF transmembrane conductance regulator protein, which is expressed at the apical membrane of various epithelia, including the digestive tract, and involved in chloride and bicarbonate transport. While modulators can improve pulmonary function, digestive symptoms remain a concern for patients with CF. Against this backdrop, it seems important to provide a current overview of research on intestinal inflammation in CF and a detailed analysis of the impact of this inflammation on each intestinal barrier compartment. It would also be useful to offer a description of the consequences of intestinal inflammation on associated complications, such as digestive cancers, and a comprehensive assessment of CF treatments and their impact on digestive manifestations. The different compartments of the intestinal barrier are impaired in CF (gut microbiota, mucus layer, intestinal epithelium, and immune cells), leading to chronic inflammation. This may explain the risk of colorectal cancer.

Key Words: Cystic fibrosis; Intestinal permeability; Microbiota; Mucus layer; Intestinal stem cells

Core Tip: Several reviews in the literature consider the role of and impact on the intestines in cystic fibrosis (CF) pathophysiology. The focus of such studies are, however, the gut-lung axis, the intestinal microbiota, the mucus layer, or electrolyte transport. This is the first review to take into account all aspects of the intestinal barrier (microbiota, mucus layer, intestinal epithelium, and immune system) that are altered in CF and may be involved in intestinal inflammation or colorectal cancer. The present review should therefore contribute to knowledge of intestinal pathophysiology in CF and inform the management of patients with gastrointestinal manifestations of CF.

INTRODUCTION

Cystic fibrosis (CF) is an autosomal recessive genetic disorder that affects > 105000 people worldwide[1]. CF results from the loss of function of the protein encoded by the CF transmembrane conductance regulator (CFTR) gene located on chromosome 7. More than 2000 CFTR variants have been reported, resulting in a number of different impacts on disease severity[2]. Mutations have been categorized as severe (class I: Defective synthesis; class II: Defective trafficking; class III: Impaired gating) and mild (class IV: Defective conductance; class V: Reduced synthesis; class VI: Reduced half-life at the membrane)[2,3]. The most common variant is Phe508del; a class II mutation that leads to misfolding events and protein degradation by the proteasome with a complete loss of CFTR function.

The CFTR protein is involved in chloride and bicarbonate transport and is expressed at the apical membrane of various epithelia, including the respiratory tract, sweat glands, and the digestive and urogenital tracts[4]. The CFTR gene is highly expressed in the intestinal tract. mRNA levels follow a cephalo-caudal gradient with high detection in the duodenum and acinar glands and smaller levels in the small and large intestines[5]. In the digestive tract, CFTR channel alterations lead to exocrine pancreatic insufficiency, meconium ileus, acute and chronic pancreatitis, malabsorption, and endocrine pancreatic dysfunction. CFTR is also expressed in cholangiocytes, leading to hepatic inflammation and fibrosis, with multifocal cirrhosis and portal hypertension.

The intestinal tract is a complex interface between the outside environment and organs. Its structural composition involves a monolayer epithelium that features villi and crypts in the small intestine, while the large intestine exhibits crypts only. Various cell types are present, categorized into absorptive lineage (enterocytes) and secretive lineage (goblet cells for mucus secretion, Paneth cells restricted to the small intestine for antimicrobial peptide secretion, enteroendocrine cells secreting hormones, and Tuft cells for antiparasitic defense)[6]. The intestinal barrier function (IBF) displays the ability to tolerate food antigens and beneficial bacteria, combating pathogens through multiple defense mechanisms involving: (1) billions of bacteria producing short-chain fatty acids (SCFAs) and digesting fibers; (2) two mucosal layers, one dense and sterile without bacteria, and another looser layer with bacteria and IgA to bind and eliminate pathogens; (3) monocellular epithelium that forms a physical barrier, regulating nutrient absorption through tight junctions (TJs) (occludins, claudins, etc.); and (4) gut immune system including lymphoid tissue (initiation site for gut immune reactions), lymphocytes, and myeloid cells in the lamina propria, as well as isolated lymphocytes (effector sites)[7]. IgA is secreted to neutralize and eliminate pathogens. T-regulator lymphocytes play a significant role in antigen tolerance and wound healing. Global interactions occur between each part leading to homeostasis. If any alteration occurs, interactions are disrupted, resulting in digestive inflammation. Figure 1 is a simplified and nonexhaustive overview of the main differences between IBF in normal and CF conditions.

Figure 1 Description of the intestinal barrier components and their involvement in cystic fibrosis. SCFAs: Short-chain fatty acids; CFTR: Cystic fibrosis transmembrane conductance regulator; LPS: Lipopolysaccharides; SIBO: Small intestinal bacterial overgrowth; Treg: Regulatory T cell; Th: T helper cell; E. coli: Escherichia coli.

While digestive involvement in CF has a less significant impact on disease prognosis compared to pulmonary involvement, it plays a critical role in disease severity by influencing the gut-lung axis, exacerbating lung disease through malnutrition and, most importantly, making a substantial contribution to morbidity[8]. When the CFTR gene is mutated, fluid secretion into the intestinal lumen is of low volume and bicarbonates are deficient, leading to a weakly hydrated luminal microenvironment and the thickening and accumulation of mucus; this, in turn, promotes local bacterial development and dysbiosis, chronic inflammation, and immune dysfunction. Motility is also affected, leading to increased transit time and increased retention of luminal content[9].

Innovative treatments for CF, such as CFTR protein modulators, have been available for several years[10]. These treatments have profoundly modified the progression of the disease and enhanced respiratory function. However, despite their impact on the respiratory system, clinical digestive symptoms remain common[11]. While modulator therapy improves fecal calprotectin (FC)[12] and nutritional status[13], gastrointestinal symptoms remain a concern[11]. Alongside increasing food intake and enhancing exocrine pancreatic function, improving the nutritional status of patients with CF is probably secondary to achieving better lung function with decreased pulmonary exacerbations[13]. Notably, one review reported that ~20% of CF patients with exocrine pancreatic insufficiency acquired pancreatic sufficiency following modulator treatment[14]. Improvements in fecal elastase seem to be negatively correlated with the patient’s age at modulator initiation[15]. Finally, in the last decade, research has reported an increased risk of colorectal cancer (CRC)[16].

The objectives of this review are to provide: (1) a current overview of intestinal inflammation in CF and a detailed analysis of the impact of this inflammation on each intestinal barrier compartment; (2) a description of the consequences of this intestinal inflammation on associated complications such as digestive cancers; and (3) a comprehensive assessment of CF treatments and their impact on digestive manifestations.

METHODOLOGY

Literature search

A narrative review was performed by searching PubMed using the following terms: “cystic fibrosis” and [(“intestinal inflammation” or “intestinal permeability” or “intestinal epithelial cell” or “intestinal microbiota” or “colorectal cancer”) and “modulators”)], from 1970 to June 30, 2025. Literature published in any language other than English was excluded.

Literature selection

As this was a narrative review, C. Carlé selected the appropriate articles, first by deeming whether their titles and abstracts were in line with the aims of this review, and then by reading the texts in their entirety.

IBF IN CF

Intestinal microbiota

The gut microbiota plays a fundamental role in nutrition, immunity, metabolism, inflammation, and cancer. Structural and functional modifications of the digestive tract in CF disease (e.g., malabsorption, mucus modification, hydro-electrolyte imbalance, dysmotility, inflammation, and frequent use of antibiotics or proton pump inhibitors) likely play a crucial role in dysbiosis. Many studies have analyzed the link between microbiota and CF disease. Dysbiosis seems to be linked to a distinctive microbiota and to occur early in life in CF patients[17]. It seems to be a multifactorial event that combines the consequences of: (1) CFTR dysfunction itself; (2) digestive inflammation; and (3) disease management, involving diet and medications (pancreatic enzyme supplementation, and frequent use of antibiotics affecting microbiota composition and functionality). In a study of children with CF from birth through the age of 4 years, Price et al[18] showed a delayed microbiome maturation, a decrease in protective strains, and a negative impact of preterm birth and early antibiotic exposure on microbiota structure. To optimize the nutritional status of children with CF, the guidelines recommended that their calorie intake be increased to 110%-200% of the reference guide for the general population[19]. A lipid-rich diet could modify the type of Escherichia coli (E. coli), as shown by Matamouros et al[20].

Several species are classically described as exhibiting increased prevalence, such as E. coli, Fusobacterium spp., Streptococcus spp., Veillonella spp., Enterococcus faecalis, and Enterococcus faecium. The relative abundance of commensal strains, mostly described as having beneficial roles on the digestive tract, are also decreased in CF patients, such as Bifidobacterium spp., Akkermansia spp., Faecalibacterium prausnitzii, Roseburia spp.[21], and Clostridium spp.[22] (Table 1).

Table 1 Gut microbiota dysbiosis reported in patients with cystic fibrosis in the literature.

Cystic fibrosis patients
Species level	Increase	Actinomyces odontolyticus[56]
		Anaerococcus unclassified[56]
		Citrobacter unclassified[39,56]
		Clostridium difficile[39,48,56]
		Clostridium perfringens[39,48,56]
		Enterobacter cloacae[56]
		Enterobacter unclassified[56]
		Enterococcus faecalis[39,40,56]
		Enterococcus faecium[39,40,56]
		Escherichia coli[35,37,39,40,56] more abundant in case of severe CF and in presence of F508del mutations[37]
		Faecalictena gnavus[39]
		Finegoldia magna[56]
		Fusobacterium[39,40,48,55] associated with colorectal or pancreatic cancers[48,55]
		Klebsiella pneumoniae[39,56]
		Klebsiella unclassified[39,56]
		Megasphaera micronuciformis[56]
		Pseudomonas aeruginosa[39]
		Rothia muciaginosa[56]
		Shigella[39]
		Streptococcus mitis[39,44,48,56]
		Veillonella atypica[39,40,48,55,56] associated with colorectal or pancreatic cancers[48,55]
		Veillonella dispar[39,40,48,55,56] associated with colorectal or pancreatic cancers[48,55]
		Veillonella parvula[39,40,48,55,56] associated with colorectal or pancreatic cancers[48,55]
		Veillonella unclassified[39,40,48,55,56] associated with colorectal or pancreatic cancers[48,55]
	Decrease	Agathobacter rectalis[39]
		Akkermansia[39,40]
		Bifidobacterium[39,40]
		Faecalibacterium prausnitzii[37,39,40] more reduced in case of severe CF and in presence of F508del mutations[37]
		Roseburia[39,40]
		Ruminococcus bromii[39]
		Clostridium[39,40]

CF: Cystic fibrosis.

Changes in the composition of the microbiota directly affect the functionality of the gut. Some strains of E. coli are known to increase paracellular permeability by modulating TJ protein expression such as claudin 2 in Crohn’s disease[23]. The E. coli strain was greater in stool collected at a distance from any antibiotic treatment in children with CF[24]. Another study confirmed microbiota differences with reduced diversity, and increased E. coli strain on ileal biopsies from mice and patients with CF[25]. The preferential development of this strain could be linked to the mucosal microenvironment in CF patients, enriched in luminal fat, making the digestive tract an ideal and nutritious environment for these strains. More specifically, these strains feed on glycerol, found in higher abundance in the digestive tract of patients with CF[20].

E. faecalis and E. faecium are classically described as pathogenic and frequently present resistance to first-line antibiotics, thus complicating the management of patients[26]. Beyond the altered frequency of strains, microbiota modifications have a strong impact on digestive tract functionality by, for example, altering the mucus layer via the secretion of enzymes and proteins (sialidases, fucosidases, proteases, etc.), leading to microbial invasion, higher presentation of pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs), inflammation, strong stimulation, and activation of the immune system downstream[27].

Some reduced beneficial strains are known to play a crucial role in SCFA production (Table 1). SCFAs, largely represented by acetate, butyrate, and propionate, play a major role in digestive health by acting as energy substrates for colonocytes and hepatocytes, as signaling molecules, epigenetic regulators, and regulatory T-cell promoters[28]. Metabolomic analysis of the stools of CF patients revealed that propionate and butyrate (but not acetate) were reduced, probably as a consequence of: (1) decreased SCFA strain producers; and (2) increased activity in the catabolic pathways for butyrate and propionate[29]. Conversely, another study showed that only valerate and hexanoate, which are other SCFAs, were reduced in the colon of CF patients, but not propionate and butyrate[30]. SCFAs maintain epithelium integrity and permeability[31], and we could hypothesize that decreased SCFAs in CF patients contribute to greater intestinal permeability (IP), in turn leading to increased antigen presentation, immune system activation, and chronic inflammation.

The microbiota is also essential for bile acid metabolism. Malabsorption and steatorrhea are frequent CF manifestations, leading to malnutrition and metabolic disorders. Bile acids are mainly absorbed by enterocytes at the distal ileum, within the enterohepatic cycle of bile acids, and around 5% of the bile acid pool is lost in stools each day[32]. The microbiota is responsible for transforming primary bile acids into secondary bile acids. The latter play a central role in metabolism and inflammation, but they also indirectly affect SCFA production by supporting SCFA-producing bacteria, reducing bile acid toxicity and modulating host-microbiome interactions[33]. In CFTR knockout (KO) mice and CF patients, several bacteria metabolizing biliary acids are depleted in the small intestine, such as those of the bacillota phylum, leading to lower secondary bile acid production[34].

In conclusion, the microbiota is altered in CF patients. However, it is unclear whether the changes in the microbiota occur before the gut becomes inflamed or if such changes are a consequence of digestive inflammation. The role of the microbiota in the severity of digestive symptoms[27] and in the development of associated digestive disorders such as CRC is still unknown.

Mucus alteration

In CF, the mucus layer is altered in both respiratory and digestive tracts, as bicarbonates and water are essential for mucus polymerization and secretion. The CFTR channel is also responsible for water regulation, allowing mucus to flow and therefore regulating thickness. CFTR mutation, as described above, leads to an increase in mucus thickening[27], which is associated with the development of small intestine bacterial overgrowth and slow intestinal transit in mice[35].

Alterations of intestinal epithelium cells

Architectural modifications of the gastrointestinal tract are observed in CF patients. Using capsule endoscopy, Werlin et al[36] demonstrated a number of pathological changes with villi loss, areas of ulceration, and inflammatory edema in the jejunum and ileum of CF patients. Other studies confirmed these findings, reporting modifications of intestinal architecture with excessive mucus, increased goblet cells, shortening of villi, increased cellularity, and edema of the lamina propria in some small bowel biopsies[37,38]. In the ileum of CFTR KO mice, cellular distribution was affected with the result that there were more stem cells and goblet cells (mucus secretion), fewer Paneth cells (antimicrobial peptides secretion), and fewer enteroendocrine cells compared to wild-type mice. The authors confirmed a similar cellular repartition on an ileal biopsy of a CF patient. Enterocytes also presented abnormal distribution in both models[25]. Similar results were found by Scull et al[39], who reported increased goblet cells in the small intestine of different CFTR KO mouse models. Beyond the altered quantitative expression of these different cell types, the antimicrobial activity (-defensin and lysosome secretion) was altered because secreted granules were poorly dissolved within the intestinal lumen[40]. Modulation of expression and functionality of epithelial cell populations in CF induce abnormalities in nutrient absorption, increased mucus secretion, decreased and altered antibacterial factor secretion, and modification of intestinal motility, thus restricting the regulation of the composition of the microbiota. One hypothesis that could explain this modification of cellular expression also anchors itself on the microbiota, particularly E. coli, which has been shown to promote the expression of epithelial differentiation factors[41].

Immune system

Histological modifications have been described in CF patients. Raia et al[42] demonstrated increased lamina propria immune cells and altered expression of markers of cell adhesion, inflammation, and a shift towards inflammatory cytokine secretion profile. In whole gut lavage, pediatric CF patients had higher levels of interleukin (IL)-1β and chemokine CXC ligand-8; two inflammatory mediators involved in the attraction of neutrophils and macrophages[43]. In CFTR KO mice, inflammatory cytokines such as tumor necrosis factor (TNF)-α were increased and anti-inflammatory cytokines such as IL-10 were decreased[44]. These changes are of particular interest since these cytokines have been described to modulate the IP, which is increased in CFTR KO mice[44]. Therefore, while TNF-α enhances IP by upregulating myosin light chain kinase expression[45], IL-10 reduces permeability by improving TJs. We could speculate that a similar mechanism may occur in CF patients.

CFTR protein is widely expressed by leukocytes including neutrophils; it is involved in antimicrobial defense and, more broadly, in innate immunity. These cells exhibit an abnormal oxidative response with impaired hypochlorous acid (HOCl) production, as the CFTR mutation directly affects chlorine transfer into phagosomes. Consequently, bacterial species like Pseudomonas aeruginosa, which require significant amounts of HOCl if they are to be eradicated, tend to thrive in CF patients and contribute to the development of chronic lung infections[46]. Despite immune defense dysfunction, these cells are widely recruited and activated in alveolar spaces and produce large amounts of inflammatory cytokines (IL-1β, IL-6, IL-8, and TNF-α), prostaglandins, leukotrienes, reactive oxygen species, and proteases, leading to a deleterious environment and tissue alterations[47]. In the digestive tract of CFTR KO mice, increased neutrophils were also observed near lymph nodes and in the lamina propria[48]. In CF patients, excessive NETosis (a physiologically programmed neutrophil cell death characterized by the release of neutrophil extracellular traps composed of chromatin, histones, and antimicrobial proteins, which immobilize and neutralize pathogens, while also being involved in various diseases) has been demonstrated[27]. Studies have demonstrated increased neutrophil elastase levels[43] and FC levels in children with CF, as noted above.

Other immune cells types, such as monocytes, dendritic cells, and macrophages, are also altered as they express the CFTR gene[49]. In Phe508del mice, peritoneal macrophages showed a proinflammatory phenotype after in vitro stimulation, including higher IL-1β secretion and lower IL-10 secretion[49]. Toll-like receptor (TLR) signaling, involved in bacterial motif detection, also seems to be altered in CFTR KO mice, with an excessive response to lipopolysaccharide-induced stimuli. Research on humans has focused on macrophages derived from blood monocytes. Here, proinflammatory cytokines were increased in CF macrophage supernatants (TNF-α and IL-6). Macrophages exhibited a lower expression of TLR5, which is involved in flagellin recognition, and the adaptative immune response was also affected while CD11b expression was decreased and phagocytosis impaired. As a result, infections were poorly restricted and an excessive inflammatory response was observed[50]. Other abnormalities have been described, including the alteration of lipids, fatty acids, and ceramides, leading to dysfunctional inflammatory response and altered phagocytosis. As a result, infection management is severely impaired.

With regard to adaptive immunity, an imbalance between T helper (Th) 1/Th2 cell responses seems to occur in CF patients, with variable profiles depending on the stage of the disease. While a Th2-polarized profile with a moderate immune response is initially present, a shift is observed towards a Th1 profile that involves Th17 cells, innate lymphoid cells (ILC1 and ILC3), M1 macrophages, and natural killer cells, resulting in decreased pathogen clearance, increased IP, extravasation of leukocytes, excessive NETosis, increased PAMP/DAMP pathways, and inflammasome activation[27]. By contrast, other studies demonstrated a shift towards a Th2 response with a significant production of IL-10, which would limit the production of interferon-γ and, consequently, macrophage activation alongside polarization towards a M1 profile. In this context, pathogens such as P. aeruginosa in the lungs would be eliminated less efficiently[51]. More investigations are needed that explore the impact of T lymphocytes in digestive immunity.

The humoral response has been only weakly characterized, with histological evidence of increased deposits of immunoglobulins in the intestinal lumen[48]. Falchuk and Taussig[52] have demonstrated increased number of IgA-secreting plasma cells in the jejunum in humans, suggesting an increased local production of IgA.

Given the increased IP and immune dysregulation in CF, the risk of associated autoimmune enteropathies, particularly celiac disease, warrants attention[53,54]. Serial serological screening for celiac disease should be considered in CF patients with unexplained malabsorption or failure to thrive, as the symptomatic overlap between the two conditions poses a significant diagnostic challenge.

IP alteration

IP is characterized by transcellular and paracellular permeabilities. Transcellular permeability enables the selective passage of amino acids, fatty acids, and sugars through epithelial cells. Paracellular permeability allows water absorption and the passage of electrolytes and small molecules between two epithelial cells linked together by TJs composed of transmembrane proteins involved in opening or closing (occludins, claudins, etc.) and cytosolic proteins (zonula occludens 1-3 etc.).

De Lisle et al[55] demonstrated an increased IP in CFTR KO mice by measuring rhodamine dextran blood levels. After antibiotic treatment, IP seemed to be partially restored, as a sign of the strong involvement of bacterial overgrowth on IP. Other authors have presented similar results by demonstrating increased permeability of the terminal ileum and the proximal colon in CF mice. Using an using chamber a classical experiment used to evaluate tissular permeability tissue resistance was shown to be decreased by 30%-40% in the terminal ileum and proximal colon of CF mice[48]. Changes in CFTR KO mice TJs were also observed. Genes encoding claudins 1, 7, and 8 were weakly expressed compared to control mice; and claudin 2, which promotes the opening of TJs, showed increased gene and protein expression. In the intestinal villi, all proteins that produce the TJs were mislocated on the basal cell side[44].

By performing lactulose-rhamnose ingestion tests in children with CF, Leclercq-Foucart et al[56] demonstrated increased paracellular permeability of the intestinal mucosa. Hallberg et al[57] correlated CFTR mutations and IP by demonstrating that homozygous or heterozygous Phe508del patients had a higher IP on lactulose/L-rhamnose excretion tests than other patients with mutated CFTR. Therefore, increased IP allows presentation of more bacterial antigens and induces an inflammatory immune response. On a systemic level, del Campo et al[58] demonstrated an increased lipopolysaccharide passage into the plasma of CF patients, compared to controls. The integrity of the intestinal epithelium is affected in CF. However, although the malfunction of CFTR likely plays a central role in the altered epithelial homeostasis, we cannot exclude the role of gut microbiota dysbiosis and/or an abnormal immune response.

In conclusion, an excessive immune response is clearly described in the gut mucosa of CF patients. However, we have not yet identified the involvement of gut microbiota dysbosis or of the increased IP in excessive immune responses.

INTESTINAL INFLAMMATION AND CRC

Inflammation

Strong microenvironmental alterations, whether indirectly caused by CFTR mutations or by frequent use of antibiotics or a modified diet (high-fat diet, low-fiber intake, etc.), lead to significant chronic inflammation. FC, released by neutrophils, is a biological marker that is used to diagnose and monitor inflammation in inflammatory bowel diseases (IBDs). FC levels are increased in children with CF, who exhibit exocrine pancreatic insufficiency compared to healthy subjects, but they are lower than in children with IBD[59]. FC levels are related to pancreatic function, with normal levels in patients with pancreatic sufficiency patients but increased levels in patients with exocrine pancreatic insufficiency[36]. There is no clear association between age and FC levels[60]. A recent meta-analysis questioned the usefulness of FC in CF patients and demonstrated that this parameter could be valuable for monitoring digestive disorders[61]. FC may reflect systemic inflammation, as another study has demonstrated decreased FC levels after antibiotic treatment for pulmonary exacerbation[62]. Although FC is an easily accessible tool for evaluating digestive inflammation, greater standardization across age and pancreatic status is needed in CF for FC to be used in clinical practice.

Digestive cancer and CF

CF significantly affects quality of life and life expectancy. The most harmful extra-digestive complications are those that affect the airways[63]. This section focuses on the consequences of chronic intestinal inflammation resulting from an abnormal IBF.

Several digestive cancers (including CRC, pancreatic cancer, esophageal cancer, and liver cancer) are frequently associated with CF. The estimated relative risk for developing pancreatic cancer is 5-10 times higher, and intestinal cancer risk is six times higher in CF patients than in healthy controls[64]. Colonoscopy shows that CF patients have more aggressive polyps: > 50% of individuals in their 40s will have adenomas, and 3% of these patients will develop adenocarcinoma[65]. Between 1990 and 2009, the standardized incidence ratio for CRC was 6.2 in nontransplanted CF patients[16]. Transplanted patients have a higher risk of CRC[66], which is a possible result of their long-term reliance on immunosuppressive treatments[67].

There appears to be a correlation between the type of CFTR mutation and the development of digestive cancer. The risk seems to be higher in patients with a class I, II, or III mutation[68]. Other studies have examined the risk of digestive cancers in heterozygote subjects, identifying an increased incidence of digestive cancers[65,69] and CRC[68].

Pathophysiological mechanisms that promote the development of CRC in CF include the direct role of CFTR mutations and the indirect role of changes to the microbiota. A number of studies have therefore described CFTR as a suppressive tumor protein. If this were the case, CFTR would be a critical regulator of digestive cancer biology and would be involved in other cancers, suggesting a context-dependent mechanism influenced by the cellular environment, signaling pathways, and specific molecular interactions. In CRC tissues, CFTR expression was downregulated and the CFTR promoter was methylated, leading to higher in vitro cell proliferation, migration, and invasion[70]. Another hypothesis relies on the use of new medications such as CFTR modulators that induce late complications, such as the induction of IBD and may lead to CRC[29].

Concerning the gut microbiota, E. coli[71,72] and Fusobacterium spp. are associated with CRC development[73]. An increase of these strains in CF could be linked to altered IBF, leading to chronic inflammation, therefore favoring the development of CRC, as has been described in IBD patients. Thus, one study has shown several similarities between the microbiota of Crohn’s disease patients and that of CF patients[74]. These results emphasize the complex role of microbiota in digestive diseases[75]. Some bacteria, such as E. coli, can be modified in CF with the production of genotoxins, which are involved in CRC development[20]. Similarly, the microbiota might explain the evolution toward CRC in patients with familial adenomatous polyposis who harbor the same mutation of the APC gene[76]. In this study, the bacterial biofilm contains two strains, E. coli and Bacteroides fragilis, producing two genotoxins.

To date, research has not given a more precise explanation of the mechanisms driving the development of CRC in CF. A chronological sequence begins with the diagnosis of CF, before moving to its management and the possible evolution of the disease that can produce a vicious circle with microbiota dysbiosis, inflammation, and IP (Figure 2). These events might promote or be correlated with CRC development[77,78]. However, it is important to perform human studies that are designed in such a way that they enable us to understand the mechanisms and to determine a therapeutic target[79,80].

Figure 2  Schematic representation of the development of intestinal impairment in cystic fibrosis, leading to intestinal inflammation and colorectal cancer.

IMPACT OF CF TREATMENTS ON DIGESTIVE DISORDERS

In recent years, the life expectancy of CF patients has improved, but the management of quality of life continues to present challenges to physicians and patients alike.

Microbiota and nutrition

CF patients require a specific diet because they expend more energy, due to chronic pulmonary inflammation, exocrine pancreatic insufficiency, and associated digestive impairments. In CF, a high-energy, high-fat diet is usually recommended to maintain a good nutritional status. However, these guidelines should be updated for CF patients who are treated with modulators that improve nutritional status[74]. CF patients often need to be supplemented with ursodeoxycolic acid, antacids, pancreatic extracts, and fat-soluble vitamins, and they sometimes require enteral nutrition in cases of severe malnutrition. In a clinical analysis of 19 CF patients, FC levels were positively correlated with takeaway food and negatively with food with grains, wholegrains, core food, and other beneficial proteins. Modulation of some species of the gut microbiota was also associated with the type of diet. This study emphasizes the impact of dietary recommendations on inflammation and dysbiosis, but it also highlights the supposed link between a high-fat diet and CRC[81,82].

Complementary treatments are also used, such as those consisting of prebiotics and probiotics. Probiotics have demonstrated multiple beneficial effects: Increased interaction with the microbiome; immune system modulation; production of SCFAs and small molecules (neurotransmitters and hormones); and improved barrier function[83]. The Lactobacillus rhamnosus GG strain has a beneficial impact on weight gain, reduced risk of infection, pulmonary exacerbation, and hospitalization, and reduced abdominal pain. Similar effects were demonstrated with Lactobacillus reuteri (DSM 17938) in a double-blind prospective trial[84]. CF patients exposed to this strain showed lower FC levels and modified microbiota in which there was less γ-Proteobacteria and more Firmicutes. Prebiotics (such as polysaccharides and oligosaccharides) can also be used; they enable the growth of commensal beneficial strains that lead to modulation of the microbiome, increased defense against pathogens, and immunomodulation, etc.[22,83]. Nonetheless, only a few studies have focused on this subject and there is a lack of large-scale in vivo studies. Research to date has examined the in vitro beneficial effects of -glucan[85,86] and pectin[86] combined with probiotic strains on colonic microbiota, and demonstrated dysbiosis modulation and increased metabolic activity.

Antibiotics

de Freitas et al[87] studied the impact of antibiotics on digestive health and inflammation in pediatric CF patients and demonstrated that children treated with antibiotics showed a significant decrease in the Lactobacillus strain as well as strains that produce SCFAs. They also demonstrated, as previously stated, an increase in deleterious strains such as E. coli, Clostridioides difficile, and P. aeruginosa. However, this increase was not linked to antibiotics, and it was also found in CF patients who had not received antibiotics[87]. It is important to note that antibiotic use significantly modifies bacterial resistance, inducing selection pressure. In a study of children and adolescents with CF, Enterobacteria strains found in stools were less sensitive to -lactam antibiotics[22].

CFTR modulators

Small molecules have been approved worldwide for use in CF treatment, thus restoring the quality of life for many patients. Ivacaftor, a CFTR potentiator, has proved its worth in the management of respiratory disorders, with improved lung function and resulting in fewer digestive disorders. Some studies have reported a reduction in FC levels following treatment with CFTR modulators[88], indicating diminished gut inflammation, and we hypothesize that this might reflect a beneficial shift in gut microbiota. More specifically, patients treated with ivacaftor have experienced significant weight gain, decreased FC, a decrease in strains from the Enterobacteria family, and a significant increase in Akkermansia[89], which is known for its beneficial effects on the digestive tract. In another study, ivacaftor led to no significant modifications of the fecal microbiota composition where these followed the use of antibiotics[90]. These results were supported by another study that examined the combination of tezacaftor and ivacaftor and showed negligible effects on the gut microbiome and SCFA composition in CF patients, indicating that this combination does not significantly alter gut microbiota or gastrointestinal symptoms[91]. However, extended therapy with elexacaftor/tezacaftor/ivacaftor has been associated with increased core microbiota diversity and a shift in microbiota composition that more closely resembles that observed in healthy controls, although significant differences remained in CF patients[92].

The gut-lung axis is also a point of interest, as CFTR modulators may influence pulmonary and digestive microbiomes, potentially affecting disease progression[93]. Overall, while some positive changes in gut microbiota have been observed with some CFTR modulators, the full extent of their impact on the gut remains to be fully understood, and further research is needed.

CONCLUSION

Gastrointestinal disorders in CF significantly impact overall health and quality of life. These complications, which include pancreatic insufficiency, malabsorption, distal intestinal obstructive syndrome, and liver disease, remain a substantial burden throughout patients’ lives. While current treatments such as CFTR modulators have reduced the severity of the disease, most digestive symptoms persist, posing considerable challenges in daily life. Despite advances in early diagnosis and nutritional and enzymatic management, these symptoms remain a critical area of unmet need. Thus, several points of the IBF are disrupted in CF. It is important to improve our knowledge of the digestive pathophysiology of CF in order to alleviate many of the symptoms experienced by patients and to prevent the form of chronic inflammation that can lead to CRC.