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Infants with cystic fibrosis have altered fecal functional capacities with potential clinical and metabolic consequences.
Eng, A, Hayden, HS, Pope, CE, Brittnacher, MJ, Vo, AT, Weiss, EJ, Hager, KR, Leung, DH, Heltshe, SL, Raftery, D, et al
BMC microbiology. 2021;(1):247
Abstract
BACKGROUND Infants with cystic fibrosis (CF) suffer from gastrointestinal (GI) complications, including pancreatic insufficiency and intestinal inflammation, which have been associated with impaired nutrition and growth. Recent evidence identified altered fecal microbiota taxonomic compositions in infants with CF relative to healthy infants that were characterized by differences in the abundances of taxa associated with GI health and nutrition. Furthermore, these taxonomic differences were more pronounced in low length infants with CF, suggesting a potential link to linear growth failure. We hypothesized that these differences would entail shifts in the microbiome's functional capacities that could contribute to inflammation and nutritional failure in infants with CF. RESULTS To test this hypothesis, we compared fecal microbial metagenomic content between healthy infants and infants with CF, supplemented with an analysis of fecal metabolomes in infants with CF. We identified notable differences in CF fecal microbial functional capacities, including metabolic and environmental response functions, compared to healthy infants that intensified during the first year of life. A machine learning-based longitudinal metagenomic age analysis of healthy and CF fecal metagenomic functional profiles further demonstrated that these differences are characterized by a CF-associated delay in the development of these functional capacities. Moreover, we found metagenomic differences in functions related to metabolism among infants with CF that were associated with diet and antibiotic exposure, and identified several taxa as potential drivers of these functional differences. An integrated metagenomic and metabolomic analysis further revealed that abundances of several fecal GI metabolites important for nutrient absorption, including three bile acids, correlated with specific microbes in infants with CF. CONCLUSIONS Our results highlight several metagenomic and metabolomic factors, including bile acids and other microbial metabolites, that may impact nutrition, growth, and GI health in infants with CF. These factors could serve as promising avenues for novel microbiome-based therapeutics to improve health outcomes in these infants.
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Assessment of Neonatal Intensive Care Unit Practices and Preterm Newborn Gut Microbiota and 2-Year Neurodevelopmental Outcomes.
Rozé, JC, Ancel, PY, Marchand-Martin, L, Rousseau, C, Montassier, E, Monot, C, Le Roux, K, Butin, M, Resche-Rigon, M, Aires, J, et al
JAMA network open. 2020;(9):e2018119
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Abstract
IMPORTANCE In very preterm newborns, gut microbiota is highly variable with major dysbiosis. Its association with short-term health is widely studied, but the association with long-term outcomes remains unknown. OBJECTIVE To investigate in preterm newborns the associations among practice strategies in neonatal intensive care units (NICUs), gut microbiota, and outcomes at 2 years. DESIGN, SETTING, AND PARTICIPANTS EPIFLORE is a prospective observational cohort study that includes a stool sample collection during the fourth week after birth. Preterm newborns of less than 32 weeks of gestational age (GA) born in 2011 were included from 24 NICUs as part of the French nationwide population-based cohort, EPIPAGE 2. Data were collected from May 2011 to December 2011 and analyzed from September 2016 to December 2018. EXPOSURES Eight NICU strategies concerning sedation, ventilation, skin-to-skin practice, antibiotherapy, ductus arteriosus, and breastfeeding were assessed. A NICU was considered favorable to a practice if the percentage of that practice in the NICU was more than the expected percentage. MAIN OUTCOMES AND MEASURES Gut microbiota was analyzed by 16S ribosomal RNA gene sequencing and characterized by a clustering-based method. The 2-year outcome was defined by death or neurodevelopmental delay using a Global Ages and Stages questionnaire score. RESULTS Of 577 newborns included in the study, the mean (SD) GA was 28.3 (2.0) weeks, and 303 (52.5%) were male. Collected gut microbiota was grouped into 5 discrete clusters. A sixth cluster included nonamplifiable samples owing to low bacterial load. Cluster 4 (driven by Enterococcus [n = 63]), cluster 5 (driven by Staphylococcus [n = 52]), and cluster 6 (n = 93) were significantly associated with lower mean (SD) GA (26.7 [1.8] weeks and 26.8 [1.9] weeks, respectively) and cluster 3 (driven by Escherichia/Shigella [n = 61]) with higher mean (SD) GA (29.4 [1.6] weeks; P = .001). Cluster 3 was considered the reference. After adjustment for confounders, no assisted ventilation at day 1 was associated with a decreased risk of belonging to cluster 5 or cluster 6 (adjusted odds ratio [AOR], 0.21 [95% CI, 0.06-0.78] and 0.19 [95% CI, 0.06-0.62], respectively) when sedation (AOR, 10.55 [95% CI, 2.28-48.87] and 4.62 [1.32-16.18], respectively) and low volume of enteral nutrition (AOR, 10.48 [95% CI, 2.48-44.29] and 7.28 [95% CI, 2.03-26.18], respectively) was associated with an increased risk. Skin-to-skin practice was associated with a decreased risk of being in cluster 5 (AOR, 0.14 [95% CI, 0.04-0.48]). Moreover, clusters 4, 5, 6 were significantly associated with 2-year nonoptimal outcome (AOR, 6.17 [95% CI, 1.46-26.0]; AOR, 4.53 [95% CI, 1.02-20.1]; and AOR, 5.42 [95% CI, 1.36-21.6], respectively). CONCLUSIONS AND RELEVANCE Gut microbiota of very preterm newborns at week 4 is associated with NICU practices and 2-year outcomes. Microbiota could be a noninvasive biomarker of immaturity.
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Fecal dysbiosis in infants with cystic fibrosis is associated with early linear growth failure.
Hayden, HS, Eng, A, Pope, CE, Brittnacher, MJ, Vo, AT, Weiss, EJ, Hager, KR, Martin, BD, Leung, DH, Heltshe, SL, et al
Nature medicine. 2020;(2):215-221
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Abstract
Most infants with cystic fibrosis (CF) have pancreatic exocrine insufficiency that results in nutrient malabsorption and requires oral pancreatic enzyme replacement. Newborn screening for CF has enabled earlier diagnosis, nutritional intervention and enzyme replacement for these infants, allowing most infants with CF to achieve their weight goals by 12 months of age1. Nevertheless, most infants with CF continue to have poor linear growth during their first year of life1. Although this early linear growth failure is associated with worse long-term respiratory function and survival2,3, the determinants of body length in infants with CF have not been defined. Several characteristics of the CF gastrointestinal (GI) tract, including inflammation, maldigestion and malabsorption, may promote intestinal dysbiosis4,5. As GI microbiome activities are known to affect endocrine functions6,7, the intestinal microbiome of infants with CF may also impact growth. We identified an early, progressive fecal dysbiosis that distinguished infants with CF and low length from infants with CF and normal length. This dysbiosis included altered abundances of taxa that perform functions that are important for GI health, nutrient harvest and growth hormone signaling, including decreased abundance of Bacteroidetes and increased abundance of Proteobacteria. Thus, the GI microbiota represent a potential therapeutic target for the correction of low linear growth in infants with CF.
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Gut Microbiota in Children With Cystic Fibrosis: A Taxonomic and Functional Dysbiosis.
Coffey, MJ, Nielsen, S, Wemheuer, B, Kaakoush, NO, Garg, M, Needham, B, Pickford, R, Jaffe, A, Thomas, T, Ooi, CY
Scientific reports. 2019;(1):18593
Abstract
Intestinal dysbiosis has been observed in children with cystic fibrosis (CF), yet the functional consequences are poorly understood. We investigated the functional capacity of intestinal microbiota and inflammation in children with CF. Stool samples were collected from 27 children with CF and 27 age and gender matched healthy controls (HC) (aged 0.8-18 years). Microbial communities were investigated by iTag sequencing of 16S rRNA genes and functional profiles predicted using Tax4Fun. Inflammation was measured by faecal calprotectin and M2-pyruvate kinase. Paediatric CF gastrointestinal microbiota demonstrated lower richness and diversity compared to HC. CF samples exhibited a marked taxonomic and inferred functional dysbiosis when compared to HC. In children with CF, we predicted an enrichment of genes involved in short-chain fatty acid (SCFA), antioxidant and nutrient metabolism (relevant for growth and nutrition) in CF. The notion of pro-inflammatory GI microbiota in children with CF is supported by positive correlations between intestinal inflammatory markers and both genera and functional pathways. We also observed an association between intestinal genera and both growth z-scores and FEV1%. These taxonomic and functional changes provide insights into gastrointestinal disease in children with CF and future gastrointestinal therapeutics for CF should explore the aforementioned pathways and microbial changes.
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Partners of patients with ulcerative colitis exhibit a biologically relevant dysbiosis in fecal microbial metacommunities.
Chen, GL, Zhang, Y, Wang, WY, Ji, XL, Meng, F, Xu, PS, Yang, NM, Ye, FQ, Bo, XC
World journal of gastroenterology. 2017;(25):4624-4631
Abstract
AIM: To investigate alterations in the fecal microbiome using 16S rRNA amplicon sequencing in couples in the same cohabitation environment. METHODS Fecal samples were collected from eight ulcerative colitis (UC) patients and their healthy partners at Lishui People's Hospital, Zhejiang Province, China. DNA was extracted and the variable regions V3 and V4 of the 16S rRNA genes were PCR amplified using a two-step protocol. Clear reads were clustered into operational taxonomic units (OTUs) at the 97% sequence similarity level using UCLUST v1.2.22. The Wilcoxon rank-sum test (R v3.1.2) was used to compare inter-individual differences. Differences with a P value < 0.05 were considered statistically significant. RESULTS Fecal microbial communities were more similar among UC patients than their healthy partners (P = 0.024). UC individuals had a lower relative abundance of bacteria belonging to the Firmicutes, especially Blautia, Clostridium, Coprococcus and Roseburia (P < 0.05). Microbiota dysbiosis was detected in UC patients and their healthy partners. Relevant genera included Akkermansiam, Bacteroides, Escherichia, Lactobacillales, Klebsiella and Parabacteroides. The enriched pathways in fecal samples of UC patients were related to lipid and nucleotide metabolism. Additionally, the pathways involved in membrane transport and metabolism of cofactors and vitamins were more abundant in the healthy partners. CONCLUSION Our results suggested that the microbial composition might be affected in healthy partners cohabiting with UC patients, especially in terms of microbiota dysbiosis.
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Stool microbiota and vaccine responses of infants.
Huda, MN, Lewis, Z, Kalanetra, KM, Rashid, M, Ahmad, SM, Raqib, R, Qadri, F, Underwood, MA, Mills, DA, Stephensen, CB
Pediatrics. 2014;(2):e362-72
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Abstract
OBJECTIVE Oral vaccine efficacy is low in less-developed countries, perhaps due to intestinal dysbiosis. This study determined if stool microbiota composition predicted infant oral and parenteral vaccine responses. METHODS The stool microbiota of 48 Bangladeshi infants was characterized at 6, 11, and 15 weeks of age by amplification and sequencing of the 16S ribosomal RNA gene V4 region and by Bifidobacterium-specific, quantitative polymerase chain reaction. Responses to oral polio virus (OPV), bacille Calmette-Guérin (BCG), tetanus toxoid (TT), and hepatitis B virus vaccines were measured at 15 weeks by using vaccine-specific T-cell proliferation for all vaccines, the delayed-type hypersensitivity skin-test response for BCG, and immunoglobulin G responses using the antibody in lymphocyte supernatant method for OPV, TT, and hepatitis B virus. Thymic index (TI) was measured by ultrasound. RESULTS Actinobacteria (predominantly Bifidobacterium longum subspecies infantis) dominated the stool microbiota, with Proteobacteria and Bacteroidetes increasing by 15 weeks. Actinobacteria abundance was positively associated with T-cell responses to BCG, OPV, and TT; with the delayed-type hypersensitivity response; with immunoglobulin G responses; and with TI. B longum subspecies infantis correlated positively with TI and several vaccine responses. Bacterial diversity and abundance of Enterobacteriales, Pseudomonadales, and Clostridiales were associated with neutrophilia and lower vaccine responses. CONCLUSIONS Bifidobacterium predominance may enhance thymic development and responses to both oral and parenteral vaccines early in infancy, whereas deviation from this pattern, resulting in greater bacterial diversity, may cause systemic inflammation (neutrophilia) and lower vaccine responses. Vaccine responsiveness may be improved by promoting intestinal bifidobacteria and minimizing dysbiosis early in infancy.