Altered intestinal microbiota composition, antibiotic therapy and intestinal inflammation in children and adolescents with cystic fibrosis

Abstract

The aim of the present study was to evaluate the effect of cystic fibrosis and antibiotic therapy on intestinal microbiota composition and intestinal inflammation in children and adolescents. A cross-sectional controlled study was conducted with 36 children and adolescents: 19 in the cystic fibrosis group (CFG) and 17 in the control group (CG) matched for age and sex. The CFG was subdivided based on the use of antibiotic therapy (CFAB group) and non-use of antibiotic therapy (CFnAB group). The following data were evaluated: colonization, antibiotic therapy, mutation, breastfeeding, use of infant formula, type of delivery, introduction of solid foods, body mass index, fecal calprotectin and intestinal microbiota composition (fluorescence in situ hybridization). Intestinal inflammation evaluated by fecal calprotectin was significantly higher in the CFG (median: 40.80 µg/g, IQR: 19.80–87.10, p = 0.040) and CFAB group (median: 62.95 µg/g, IQR: 21.80–136.62, p = 0.045) compared to the CG (median: 20.15 µg/g, IQR: 16.20–31.00), and the Bacteroides, Firmicutes, Eubacterium rectale and Faecalibacterium prausnitzii were significantly decreased (p < 0.05) in the CFG compared to the CG, whereas the bacteria Clostridium difficile, Escherichia coli and Pseudomonas aeruginosa were significantly increased in the CFG (p < 0.05). The main differences were found between the CG and CFAB group for Eubacterium rectale (p = 0.006), Bifidobacterium (p = 0.017), Escherichia coli (p = 0.030), Firmicutes (p = 0.002), Pseudomonas aeruginosa (p < 0.001) and Clostridium difficile (p = 0.006). The results of this study confirm intestinal inflammation in patients with CF, which may be related to changes in the composition of the intestinal microbiota.

Interactions between the gut microbiome and host gene regulation in cystic fibrosis

“…We found an increase in Actinobacteria, one of the most predominant genera found in the sputum of CF patients [70], but decreased in colon cancer gut microbiome [73]. Furthermore, our observation of a significant decrease in the abundance of Verrucomicrobia, and increase in abundance of Firmicutes and Actinobacteria in CF patients, is consistent with the findings from the fecal microbiome of CF patients [17]. We also found a depletion in butyrate-producing bacteria, such as Ruminococcaceae and Butyricimonas, similar to previously reported depletion in butyrate-producing microbes by Manor et al [14] in their study comparing CF fecal samples from children on varying degrees of fat intake.…”

“…The intestinal microbiota of these animals is also distinguished by lower bacterial community richness, evenness, and diversity, consistent with a major impact of CFTR deficiency on gastrointestinal physiology [11]. Altered fecal microbiome has also been demonstrated in a number of clinical CF cohorts, where it was characterized by decreased microbial diversity, lower temporal microbial community stability, and decreased relative abundances of taxa associated with health, such as Faecalibacterium, Roseburia, Bifidobacterium, Akkermansia, and Clostridium cluster XIVa [12][13][14][15][16][17]. Greater degrees of dysbiosis were noted to correlate with severity of CF disease phenotype, burden of antibiotics, and evidence for intestinal inflammation in diverse pediatric cohorts with varying degree of fat malabsorption.…”

“…Pseudomonas was not identified as a contaminant in our decontam analysis. Interestingly, Pseudomonas aeruginosa, which is a major pathogen in cystic fibrosis lung infection [38,39], has previously been isolated from the fecal samples of patients with cystic fibrosis [17,40]. This suggests that the presence of Pseudomonas in our samples is not due to contamination and could be potentially attributed to the cystic fibrosis condition of our patient cohort.…”

Inflamação intestinal em crianças com fibrose cística

“…Vários trabalhos vêm demonstrando seu aumento em indivíduos com FC em comparação aos controles saudáveis, evidenciando que a inflamação intestinal é um aspecto relacionado à doença (DHALIWAL et al, 2015;ELLEMUNTER et al, 2017;GARG et al, 2017;PARISI et al, 2017). Trabalhos recentemente publicados mostraram por meio do aumento dos níveis de calprotectina fecal e de outros biomarcadores fecais, como piruvato quinase M2, que a inflamação intestinal está presente precocemente nas crianças com FC, já nos primeiros anos de vida (DE FREITAS et al, 2018;GARG et al, 2017GARG et al, , 2018 As pesquisas vêm demonstrando que a CLP é naturalmente elevada nos primeiros 4 anos de vida. Oord e Hornung (2014) sugeriram 3 valores de ponto de corte para avaliar CLP em crianças saudáveis, baseados nos percentis 97,5%: 538 mg/kg (1 a 6 meses), 214 mg/kg (6 meses a 3 anos) e 75 mg/kg (3 a 4 anos).…”

“…ALJASSER; SALH, 2015). Utilizando esse valor de referência, estudos em crianças e adolescentes têm mostrado um aumento desse biomarcador em 47% a 57,3% dos pacientes com FC em comparação a 10% nas crianças saudáveis (DE FREITAS et al, 2018;GARG et al, 2017). Um único estudo mostrou aumento de CLP em apenas 9,7% das crianças com FC estudadas, mas foi utilizada uma ampla faixa etária para comparação, não foram definidos critérios de exclusão e não houve comparação com crianças saudáveis (WIECEK et al, 2017).…”