Beyond Bacteria and Fungi: Cystic Fibrosis and Possible Association with Intestinal Parasitic Diseases

1. Introduction

Cystic fibrosis (CF) is among the most common life-shortening genetic disorders in Europe, affecting approximately 30% of live births [1]. Recently, global mapping data have identified CF in many countries across Asia and Africa [2,3]. The disease results from mutations in the CFTR gene, located on chromosome 7. This gene encodes a chloride channel regulated by cyclic AMP (cAMP)-dependent phosphorylation, which is highly expressed on the apical surface of lung and intestinal epithelial cells, pancreatic ductal cells, cholangiocytes, and the reproductive tract [4,5,6]. Dysfunction of CFTR in the lungs leads to dehydrated mucus, impaired mucociliary clearance, chronic bacterial colonisation such as Pseudomonas aeruginosa, and progressive tissue damage [6]. In the gastrointestinal (GI) tract, CF symptoms include meconium ileus, pancreatic insufficiency, malabsorption, distal intestinal obstruction syndrome (DIOS), and changes in intestinal microbiota [7,8,9,10,11]. The bidirectional communication within the gut–lung axis in cystic fibrosis (CF) presents a complex pathophysiological paradigm, as the microbial ecosystems of both anatomical sites are fundamentally compromised by the same underlying aetiology, which is the loss of CFTR protein function. Although the resulting dysbiosis in the gastrointestinal and respiratory tracts develops somewhat independently—driven by distinct, organ-specific microenvironments characterized by highly viscous mucus and hyperinflammation—the two microbiomes remain highly interconnected [12]. Most notably, the composition of the pulmonary microbiome is heavily influenced by the intestinal microbiome through the systemic exchange of microbial metabolites [13]. In the context of CF, the gut–lung axis is further impaired by a marked reduction in microbial populations capable of synthesizing short-chain fatty acids (SCFAs) [14,15]. Because SCFAs possess critical immunomodulatory properties, this intestinal dysbiosis is directly correlated with defects in pulmonary immune homeostasis [16,17]. The profound interdependence of these mucosal microbiotas has been corroborated in vivo using a murine model of CF; specifically, Bazett and his colleagues [16] demonstrated that antibiotic-induced disruption of the intestinal microbiota precipitates pulmonary hyper-reactivity. Consequently, the depletion of gut microbial diversity and its associated functional capacity—often a result of recurrent antibiotic therapies initiated in early childhood—may be a significant exacerbating factor in the progression of pulmonary disease among patients with CF [17].

Despite extensive research on bacterial and fungal infections in CF [18], the relationship between CF and parasitic infections, particularly protozoa and helminths, remains poorly comprehended and underreported. Parasitic diseases, including intestinal protozoa and soil-transmitted helminths, affect over 18% of people worldwide, mainly in tropical and subtropical regions [19]. Due to the limited number of comprehensive studies on CF and intestinal parasite co-infections, this review adopts a narrative, non-systematic approach. Intestinal parasitic infections discussed in this review are those which meet one or more of the following criteria: (i) reported or plausible clinical relevance to CF patients; (ii) the availability of peer-reviewed publications that enable meaningful synthesis of clinical or pathophysiological insights; and (iii) the representation of pathogens that are clinically significant or likely to influence the course of disease in CF. It is worth noting that the global burden of parasitic infections, especially in low- and middle-income countries, may lead to underdiagnosis of CF, whilst CF-parasitic comorbidity is rarely addressed in high-income countries with advanced hygiene standards. With increased global mobility and longer life expectancy among CF patients due to modern treatments like CFTR modulators, clinicians now encounter CF patients in regions where parasitic infections are prevalent and receive referrals from these areas [20,21,22]. This review focuses on clinically significant infections worldwide to provide a balanced, comprehensive, and evidence-based overview of current knowledge, while highlighting gaps and areas for further research.

2. Pathophysiological Basis of Cystic Fibrosis and Mucosal Immunity

Over 2,500 CFTR variants have been classified into six functional groups. Mutations in classes I–III and VI typically result in little to no functional protein at the cell surface and are associated with severe disease, whereas classes IV and V retain partial channel activity and generally produce milder clinical phenotypes [16]. Under physiological conditions, CFTR regulates chloride and bicarbonate levels through Na⁺-derived Cl^-/HCO3^- and H⁺ ions transport across epithelial membranes, thereby maintaining fluid balance and optimal luminal pH (Figure 1). It also modulates pH changes induced by glucose metabolism in pancreatic islet β-cells [16,17]. CFTR dysfunction results in the most prevalent pulmonary disease observed in adulthood and impacts intestinal function across the individual’s entire lifespan [23]. It also modulates pH changes induced by glucose metabolism in pancreatic islet β-cells [23,24]. Mutated CFTR mediates CF, the most common lung disease in adulthood, which affects the intestine throughout a patient’s lifetime [25]. In the lungs, CFTR mutations mechanistically cause intracellular chloride accumulation and increased sodium absorption, water withdrawal from the airway surface, dehydration of the liquid layer, and mucus thickening [26,27,28]. This impairs mucociliary clearance, facilitating chronic pathogen colonisation and recurrent pulmonary exacerbations [29]. CF is associated with a dysregulated immune profile characterized by excessive neutrophilic inflammation, elevated pro-inflammatory cytokines [30,31], and a shift toward Th2- and Th17-mediated responses, particularly during exacerbations and direct bacterial (P. aeruginosa) infection [32]. Some studies have also revealed altered macrophage responses, impaired dendritic cell function, and reduced T-regulatory (Treg) cell activity in cystic fibrosis models [31,32]. These immune deviations may influence the host responses to intestinal parasitic infections in CF patients. In the gastrointestinal tract, CFTR gene expression on the apical surface of epithelial cells plays a vital role in regulating water and salt flow into the lumen, thereby maintaining the balance between absorption and secretion of intestinal fluids [33]. CFTR mutations have been suggested to lead to reduced luminal hydration, impaired bicarbonate secretion, altered Cl^- secretion, intestinal pH, and mucus concentration [25,34,35,36,37]; similar to their aforementioned impacts on the pulmonary airways. As a consequence, gut microbiome disturbance, bacterial overgrowth, and alterations in host defence against enteric pathogens were suggested [38,39]

3. Pathobiological Basis of Major Human Intestinal Protozoa and Mucosal Immunity

Protozoan parasites exemplify a significant threat to human health, frequently colonising the gastrointestinal tract and resulting in severe clinical manifestations. Among the most clinically relevant species are Giardia lamblia, Entamoeba histolytica, and Cryptosporidium parvum, each associated with distinct pathogenic mechanisms [40]. While both C. parvum and G. lamblia inhabit the small intestine—specifically the duodenum, jejunum, and ileum—and are recognised as the leading etiologies of chronic diarrhoea (cryptosporidiosis and giardiasis, respectively) [41] , E. histolytica exhibits a distinct pathogenic profile [39]. This organism primarily colonises the large intestine and can penetrate the colonic mucosa [42]. Such invasion facilitates systemic dissemination to extraintestinal sites, most notably the liver, potentially leading to fatal amebiasis [42,43]. The three protozoa share common symptoms such as persistent diarrhea, abdominal pain and severe malabsorption [41,44]. Their foundational pathophysiology is driven by disease mechanisms that actively increase intestinal permeability and trigger chloride secretion [45].

At the cellular level, pathogen attachment and colonization induce host epithelial apoptosis, the physical rupture of critical epithelial tight junctions [46], and the shortening of brush-border microvilli [44,47], which directly causes deficiencies in disaccharidases and other essential digestive enzymes [48,49,50]. Molecularly, these parasites utilize virulence factors such as cysteine proteases, which degrade host immunoglobulins and chemokines, deplete protective intestinal mucus and drive microbiome dysbiosis to support their survival [51,52]. The host defense system is triggered to combat these parasitic protozoa, through activation of innate and adaptive immune pathways, beginning with the localized activation of CD8+ lymphocytes [53], and the stimulation of tuft cells by parasite-excreted metabolites [54]. This cascades into an adaptive immune response mediated by IL-6-producing dendritic and mast cells [55], alongside CD4⁺ T-cells that release pro-inflammatory cytokines such as IL-17 and TNF-alpha [56]. Ultimately, the pathogen’s proliferation is suppressed through clearance mechanisms, including the mucosal release of cytotoxic secretory IgA [57], and nitric oxide (NO) generated by both epithelial and immune cells [58,59,60], while localized mast cell degranulation enhances intestinal peristalsis to physically expel the pathogens [39].

4. Is There a Correlation Between CF and Intestinal parasites?

The symptoms of G. lamblia infection may overlap with GI manifestations of CF [6,7,8,9,10], making diagnosis challenging. G. duodenalis pathophysiology was studied in a human organoid system and proved to down-regulate the CFTR-mediated chloride secretion early [60], which is synergistic with the absence or impairment of CFTR-mediated Cl-/HCO-3 exchanger in CF patients [37]. Therefore, absence or dysfunction of CFTR may theoretically increase the susceptibility and long-term infection of G. lamblia. Several studies [61,62,63]found that the prevalence of giardiasis was higher in patients with CF or chronic pancreatitis than in control groups. A 20-year-old male CF patient, who was on a continuous treatment course of pancreatic enzyme and vitamin supplements, lost weight and underwent severe malabsorption due to an infection with Giardia. These symptoms recovered after a 5-day treatment course of an anti-giardiasis drug [61]. It is indicated that giardiasis reduced the efficacy of supplements in CF patients and worsened malabsorption [61]. It seems that CF treatment with pancreatic enzymes and vitamin supplements [64]is less effective than human duodenal and upper jejunal fluid, which has been shown to kill G. lamblia in vitro [65]. Altogether, altered intestinal pH in CF, along with mucus viscosity and reduced luminal flow, may facilitate Giardia adherence and persistence. In vitro studies suggest that Giardia may exploit host mucins for attachment [60], a mechanism that may be enhanced in CF due to mucin hypersecretion [37]. Giardia was also shown to activate the AKT pathways, destabilising glucose and insulin levels and worsening the “gut-metabolism” cycle [66]. Furthermore, Giardia was experimentally demonstrated to produce specialised thiol proteinases that degrade intestinal tight junctions, causing fluid leakage [66]. Therefore, a co-infection with CF may result in an accelerated “leaky gut” phenotype, further promoting systemic inflammation.

Although Cryptosporidium spp. is one of the most significant pathogens causing waterborne outbreaks [40,45] and is life-threatening to immunocompromised individuals [66,67,68], its prevalence and impact in cystic fibrosis (CF) patients remain relatively underreported. Cryptosporidium spp. are coccidian protozoa that reside intracellularly within a parasitophorous vacuole, located between the cell membrane and the cytoplasm, causing gastroenteric diseases characterised by watery diarrhoea [69,70,71]. Furthermore, Cryptosporidium spp. can cause respiratory infection through transmission by coughing and respiratory secretions via inhalation of aerosolised droplets [72]. In our investigation, we found only one study [73] on Google Scholar indicating co-infection with Cryptosporidium in a CF patient with a bilateral lung transplant. He experienced severe sepsis, renal failure, diarrhoea, and electrolyte disturbance caused by Cryptosporidium [73]. The authors suggested that lung transplant recipients, including those with CF, are at an elevated risk for severe, life-threatening cryptosporidiosis due to the intensive immunosuppressive regimens required to prevent allograft rejection [73]. Interestingly, Cryptosporidium was also shown to express a structure similar to CFTR, a 200-kDa integral protein localised at the host-parasite interface [74]. In this case, we assume that even in the absence or dysfunction of CFTR, the parasite still has a feeder organelle and can disseminate. Despite the severity of amoebic colitis [75], liver cirrhosis [75], and microbiome degradation [76,77,78], we have not found any case report or experimental model describing a comorbidity with CF.

5. Research Gaps

CF is underdiagnosed in low- and middle-income countries (LMICs), where parasitic infections are endemic, and misdiagnosis of CF as “chronic malnutrition” or “recurrent pneumonia” may delay genetic testing (Figure 2). Simultaneously, parasitic infections in undiagnosed CF patients could be fatal. The key research gaps include a lack of documentation on the prevalence of protozoa and helminthic parasitic infections in CF cohorts globally, the impact of parasites on CFTR modulator efficacy and pharmacokinetics, and mechanistic studies of parasite-CFTR interactions using organoid or murine models. Furthermore, there is no evidence regarding the long-term outcomes of co-infection to indicate whether parasitism acts synergistically or antagonistically in CF patients.

6. Conclusion

Parasitic infections constitute an underappreciated aspect of cystic fibrosis (CF) care, particularly in regions where such pathogens are endemic. Incorporating parasitological considerations into diagnostic and management frameworks may enhance clinical outcomes. Accordingly, future research should emphasize mechanistic investigations, strengthened epidemiological surveillance, and the development of region-specific clinical guidelines. Although bacterial and fungal infections predominate in the CF literature, protozoan and helminthic diseases remain underrecognized comorbidities with important global clinical implications. The altered epithelial physiology, immune dysregulation, and gastrointestinal dysfunction characteristic of CF may increase susceptibility to parasitic infections or modulate disease severity. Conversely, chronic parasitic infections may influence CF-associated inflammation and responsiveness to therapy. Case reports underscore diagnostic complexities and potential therapeutic risks, particularly in immunocompromised individuals with helminth infections. As life expectancy in CF continues to improve and global health disparities persist, the integration of parasitology into CF care through targeted screening, clinician education, and focused research is increasingly warranted. Advancing understanding of these interactions may inform novel therapeutic approaches and ultimately improve outcomes for individuals with CF worldwide.