Impact of Altered Gut Microbiota and Its Metabolites in Cystic Fibrosis
Abstract
:1. Introduction
2. Normal Gastrointestinal Microbiota
2.1. Normal Gut Microbiota Composition
2.2. Factors Affecting Gut Microbiota
2.3. Mutualistic Functions of Gut Microbiota
3. Gut Dysbiosis in Cystic Fibrosis
3.1. Mechanisms of Gut Dysbiosis in CF
3.2. Patterns of Gut Dysbiosis in CF
3.2.1. Decrease in Microbial Diversity
3.2.2. Alteration of Gut Microbial Composition
3.3. Gut Dysbiosis with Altered Proteomics and Metabolomics in CF
4. Impact of Gut Dysbiosis on Cystic Fibrosis Manifestations
4.1. Impact on the Gastrointestinal Tract
4.1.1. Increase Intestinal Inflammation and Barrier Permeability
4.1.2. Alteration of Fat Metabolism
4.1.3. Gut Dysbiosis and Colon Cancer in CF
4.2. Extraintestinal Implications of Gut Dysbiosis in CF
4.2.1. Gut Dysbiosis and Liver Involvement in CF
4.2.2. Effect of Gut Dysbiosis on Growth Failure and Glucose Metabolism in CF Patients
4.2.3. Gut Dysbiosis and Respiratory Microbiome Interactions
5. Methods to Modulate the Dysbiosis in Cystic Fibrosis
5.1. Probiotics in Modulation of Gut Microbiome in CF
5.2. Prebiotics in Modulation of Gut Microbiome in CF
5.3. Effect of Vitamins and Dietary Nutrients on the Modulation of Gut Microbiome in CF
5.4. Effect of Targeted Molecular Therapies on the Modulation of Gut Microbiome in CF
6. Conclusions and Future Directions
Author Contributions
Funding
Conflicts of Interest
References
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Prevention of pathogenic infections |
Synthesis of vitamins (vitamin K and vitamin B complex) |
Production of short-chain fatty acids
|
Regulation of mucosal immune responses |
Influence host metabolism and behavior via various endocrine and paracrine functions |
Biotransformation of conjugated bile acids |
Xenobiotic metabolism |
CFTR-related mechanisms |
Thick and inspissated mucus due to chloride channel dysfunction Defective bicarbonate secretion altering the intestinal milieu pH Malabsorption due to pancreatic insufficiency Intestinal dysmotility with prolonged intestinal transit Altered mucosal immune mechanisms Enhanced intestinal inflammation Epithelial barrier disruption |
Acquired factors |
Frequent use of antibiotics for recurrent pulmonary infections High-fat, high-calorie diet Other medications used in cystic fibrosis patients such as acid-suppressive medications, opioids, anticholinergic agents, and immunosuppressive mediations, etc. |
Study Population | Key Findings in CF | Conclusions | References |
---|---|---|---|
7 infants with CF enrolled at birth | High degree of concordance between gut and respiratory microbial samples. For seven genera, gut colonization predicted their appearance in the lungs | Nutritional factors and gut colonization patterns could determine respiratory microbiome in CF | Madan et al., 2012 [20] |
21 family units (one patient with CF and one to two healthy siblings) | ↓ Abundance and temporal stability of Bifidobacteria and Clostridium cluster XIVa | Dysbiosis in CF could be due to disease-related impairment of essential gastrointestinal tract functions or a side effect of antibiotic usage | Duytschaever et al., 2013 [50] |
12 patients with CF and 12 HC aged several weeks to 5 years | ↑ E. coli correlated with nutrient malabsorption and intestinal inflammation | E. coli contributed to CF-related gastrointestinal dysfunction | Hoffman et al., 2014 [40] |
13 patients with CF aged 0–34 months | Specific clustering of bacteria in fecal samples, but not respiratory samples, were associated with pulmonary exacerbations | Specific bacterial communities colonized the gut before the lungs in CF patients | Hoen et al., 2015 [53] |
14 patients with CF and 12 HC aged < 3 years | ↑ E. coli, E. faecalis, Veillonella, C. difficile ↓ Beneficial Clostridiales Dysbiosis significantly altered lipid metabolism (↓ FFA biosynthesis and ↑ anti-inflammatory SCFAs degradation) | Taxonomic and functional microbial shifts in young children with CF decreased with age Gut dysbiosis in CF correlated with fat malabsorption & inflammation | Manor et al., 2016 [30] |
23 HC and 35 patients with CF (age range 0–18 years) | Progressive ↓ and alteration in richness and diversity of gut bacteria that was associated with CF from early childhood until late adolescence independent of pancreatic function | ↑ Deviation in the number and diversity of intestinal microbiome with age in CF Efforts to rectify loss of bacterial diversity should be conducted no later than early childhood | Nielsen et al., 2016 [18] |
43 patients with CF aged 21–38 years and 69 HC aged 24–40 years | ↓ Microbial diversity ↑ Firmicutes ↓ Bacteroidetes | Gut dysbiosis in CF positively correlated with lung dysfunction and intravenous antibiotic use | Burke et al., 2017 [45] |
30 patients with CF (14 were homozygous for delF508 and 14 were heterozygous, and 2 had mild genotype) age range 10–22 years and 8 HC (mean age 14.3 years) | ↓ Clostridium coccoides ↓ Bacteroides-Proveotella ↓ Bifidobacterium genera ↓ Key butyrate producers | Low frequency of sulfate reducing bacteria in CF Significant reduction in hydrogen-consuming microbes in CF | Miragoli et al., 2017 [54] |
31 patients with CF between 1–6 years and age-matched 1:1 HC | ↑ Propionibacterium, Staphylococcus, C. difficile ↓ Eggerthella, Eubacterium, Ruminococcus, F. prausnitzii, Lachnospiraceae ↑ GABA, choline, propylbutyrate, and pyridine↓ Sarcosine, methylphenol, uracil, glucose, acetate, phenol, and benzaldehyde | CF gut microbiota revealed an enterophenotype that was correlated with disease status regardless of age and pancreatic status. This distinct dysbiosis was partially related to pulmonary infections and oral antibiotic use | Vernocchi et al., 2018 [39] |
27 patients with CF and age/gender matched HC (age range 0.8–18 years) | Prominent taxonomic and functional dysbiosis in CF compared to HC ↓ richness and diversity of gut microbiota in CF | Enrichment of genes involved in SCFAs, antioxidant and nutrient metabolisms in CF | Coffey et al., 2019 [9] |
21 patients with CF and 409 healthy infant controls | Unlike the healthy infants, the alpha diversity did not increase in CF infants ↓ Bacteroides ↓ Roseburia ↑ Veillonella | The distinct CF gut microbiota in infants was associated with pulmonary exacerbations. In vitro models suggested the role of Bacteroides in reduction of IL-8 linking the gut dysbiosis in CF-related inflammation | Antosca et al., 2019 [55] |
20 patients with CF and 45 HC, fecal samples collected over the first 18 months of life | ↓ Akkermansia, Bifidobacterium, Bacteroides and Anaerostipes ↑ Streptococci, Enterococcus and E. coli ↓ Alpha diversity | Antibiotic use in infants with CF was associated with a lower alpha diversity and altered microbial composition | Kristensen et al., 2020 [37] |
207 infants with CF and 25 HC | ↓ Bacteroidetes ↑ Proteobacteria | CF infants with low length had pronounced dysbiosis than HC and CF infants with normal length | Hayden et al, 2020 [26] |
Increase | Decrease | |
---|---|---|
Phylum level | Firmicutes/Bacteroidetes ratio γ-Proteobacteria | Bacteroidetes Firmicutes Actinobacteria |
Genus/Species level | Pro-inflammatory microbiota Enterobacteriaceae Streptococcus Veillonella Staphylococcus Propionibacterium (promoted by low pH and anaerobic milieu) Colorectal cancer-related microbiota Fusobacterium Veillonella Escherichia coli (growth–promotional transcription profile) Antibiotics-resistant species Enterococcus faecalis Enterococcus faecium Pro-inflammatory species Veillonella dispar Clostridiales difficile | Beneficial microbiota Bifidobacterium Clostridium Akkermansia Eggerthella Immune modulatory microbiota Bacteroides species Butyrate producers Anaerostipes Butyricicoccus Ruminococcus Faecalibacterium prausnitzii Eubacterium rectale Blautia species Anti-inflammatory species Bifidobacterium adolescentis |
Metabolite level | Gamma aminobutyric acid Choline Ethanol Propylbutyrate Pyridine | Butyric acid Pantetheine Sarcosine Methylphenol Uracil Glucose Acetate Phenol Benzaldehyde Methylacetate |
Specific antibiotic therapy |
Dietary interventions (modification of macronutrient composition) |
Probiotics |
Prebiotics (indigestible carbohydrates) |
Probiotics and prebiotics (synbiotics) |
Vitamins and supplements |
Fecal microbiome transplantation |
Targeted molecular therapies (e.g., ivacaftor) |
Metabolite-based therapies (postbiotics) |
Study Population | Probiotic Strains | Clinical Responses | Proposed Mechanisms | References |
---|---|---|---|---|
19 patients | LGG* | ↓ Pulmonary exacerbations and hospital admissions | ↓ DCs* maturation resulting in induction of Treg*-cells | Bruzzese et al., 2007 [96] |
37 patients (20 received probiotics and 17 took placebo capsules) | L. casei*, L. rhamnosus*, S. thermophiles*, B. breve*, L. acidophilus*, B. infantis*, L. bulgaricus* | ↓ Pulmonary exacerbations and improving quality of life | Preventing deleterious effects of inflammatory cytokines (TNF-α * IFN-γ*) on epithelial function leading to a less-disrupted intestinal barrier | Jafari et al., 2013 [97] |
61 Patients with mild to moderate pulmonary disease | L. reuteri * ATCC55730 | ↓ Pulmonary exacerbations and URTI* | Improvement of intestinal barrier function and modulation of immune response | Di Nardo et al., 2014 [95] |
22 patients aged 2–9 years | LGG* | ↓ Fecal calprotectin (↓ intestinal inflammation) | Partial restoration of healthy intestinal microbiota that limit intestinal inflammation | Bruzzese et al., 2014 [61] |
30 patients in two groups (probiotic and placebo group) | L. reuteri* | ↓ Fecal calprotectin (↓ intestinal inflammation) and ↑ digestive comfort | ↑ Microbial diversity with ↑ representation of Firmicutes. ↓ γ-Proteobacteria genera Enterobacteriaceae | Del Campo et al., 2014 [56] |
25 patients aged 7–12 years (crossover study) | L. rhamnosus* SP1 (DSM 21690) & B. animalis spp.BLC1 (LGM23512) | Normalization of gut permeability in 13% of patients. No change in BMI*, FEV1*%, abdominal pain, and pulmonary exacerbations | Probiotic supplementation did not change the microbiota (both at phylum or phylogenetic levels) | Van Biervliet, 2018 [64] |
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Thavamani, A.; Salem, I.; Sferra, T.J.; Sankararaman, S. Impact of Altered Gut Microbiota and Its Metabolites in Cystic Fibrosis. Metabolites 2021, 11, 123. https://doi.org/10.3390/metabo11020123
Thavamani A, Salem I, Sferra TJ, Sankararaman S. Impact of Altered Gut Microbiota and Its Metabolites in Cystic Fibrosis. Metabolites. 2021; 11(2):123. https://doi.org/10.3390/metabo11020123
Chicago/Turabian StyleThavamani, Aravind, Iman Salem, Thomas J. Sferra, and Senthilkumar Sankararaman. 2021. "Impact of Altered Gut Microbiota and Its Metabolites in Cystic Fibrosis" Metabolites 11, no. 2: 123. https://doi.org/10.3390/metabo11020123