Cystic fibrosis (CF) is the most common autosomal recessive disease among Caucasians. Over the last 20 years, culture-independent analysis, including next-generation sequencing, has paired with culture-based microbiology, offering deeper insight into CF lung and gut microbiota. The aim of this review is to analyse the features of gut microbiota in patients with CF and its possible role in the progression of the disease, establishing the basis for a potential role in microbe-based therapies. The literature analysis showed that the gut environment in CF patients has unique features due to the characteristics of the disease, such as decreased bicarbonate secretion, increased luminal viscosity, and an acidic small intestinal environment, which, due to the treatment, includes regular antibiotic use or a high-energy and fat-dense diet. As a result, the gut microbial composition appears altered, with reduced richness and diversity. Moreover, the population of pro-inflammatory bacteria is higher, while immunomodulatory genera, such as Bacteroides and Bifidobacterium, are scarcer. The imbalanced gut microbial population has a potential role in the development of systemic inflammation and may influence clinical outcomes, such as respiratory exacerbations, spirometry results, and overall growth. Although a better understanding of the pathophysiology behind the gut–lung axis is needed, these findings support the rationale for considering gut microbiota manipulation as a possible intervention to regulate the severity and progression of the disease.

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