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JKM > Volume 42(3); 2021 > Article
Lee, Choi, Yang, Kim, Lyu, and Park: Clinical Research Trends of Gut Microbiome for Respiratory Diseases

Abstract

Objectives

This study aimed to review the clinical research of the gut microbiome for respiratory diseases to assist the design of trials for respiratory diseases by regulating the gut microbiome with herbal medicine later.

Methods

We searched three international databases (PubMed, CENTRAL and EMBASE) to investigate randomized controlled trials (RCTs) of the gut microbiome for respiratory diseases. The selected trials were analyzed by study design, subject diseases, inclusion/exclusion criteria, sample size, study period, intervention group, control group, outcome measures, and study results.

Results

A total of 25 studies were included and published from 1994 to 2021 mostly in Europe and Asia. Subject diseases were many in the order of respiratory tract infection, cystic fibrosis, allergy, and so on. As outcome measures, the gut microbiome in a fecal sample was analyzed by 16S rRNA sequencing analysis method, and symptom assessment tools related each disease were used. Major intervention drugs were probiotics and the results were mostly improved in the composition and diversity of the gut microbiome.

Conclusion

Clinical studies of the gut microbiome for respiratory diseases have confirmed various effects and this review provides basic data for a well-designed clinical study for respiratory diseases by regulating the gut microbiome with herbal medicine.

Fig. 1
Flow chart of study selection process.
jkm-42-3-119f1.gif
Fige. 2
Number of articles by chronological sequence.
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Fig. 3
Number of articles by disease classification
jkm-42-3-119f3.gif
Table 1
Characteristics of the Studies Included in the Review
First author (Year) Article title Region Subject condition Sample size Age range
Floor M (1994) Effect of loracarbef and amoxicillin on the oropharyngeal and intestinal microflora of patients with bronchitis Netherlands Bronchitis 80 >18 years
Vogel F (2001) Effect of step-down therapy of ceftriaxone plus loracarbef versus parenteral therapy of ceftriaxone on the intestinal microflora in patients with community-acquired pneumonia Sweden Community-acquired pneumonia 24 >18 years
Brunser O (2006) Effect of a milk formula with prebiotics on the intestinal microbiota of infants after an antibiotic treatment Switzerland Bronchitis 140 1–2 years
Arslanoglu S (2007) Early supplementation of prebiotic oligosaccharides protects formula-fed infants against infections during the first 6 months of life Germany Healthy infants (parental history) 259 <6 months
West CE (2008) Effects of feeding probiotics during weaning on infections and antibody responses to diphtheria, tetanus and Hib vaccines Sweden Healthy infants (vaccines) 179 4 months
Kubota A (2009) Lactobacillus strains stabilize intestinal microbiota in Japanese cedar pollinosis patients Japan Japanese cedar pollinosis 29 20–57 years
Ouwehand AC (2009) Specific probiotics alleviate allergic rhinitis during the birch pollen season Finland Birch pollen allergy 47 Children
Bruzzese E (2014) Disrupted intestinal microbiota and intestinal inflammation in children with cystic fibrosis and its restoration with Lactobacillus GG: a randomised clinical trial Italy Cystic Fibrosis 22 2–9 years
del Campo R (2014) Improvement of digestive health and reduction in proteobacterial populations in the gut microbiota of cystic fibrosis patients using a Lactobacillus reuteri probiotic preparation: A double blind prospective study Spain Cystic Fibrosis 30 >4 years
Nagafuchi S (2015) Effects of a formula containing two types of prebiotics, bifidogenic growth stimulator and galacto-oligosaccharide, and fermented milk products on intestinal microbiota and antibody response to influenza vaccine in elderly patients: A randomized controlled trial Japan Healthy adult (influenza vaccine) 24 >60 years
Akatsu H (2016) Enhanced vaccination effect against influenza by prebiotics in elderly patients receiving enteral nutrition Japan Healthy adult (influenza vaccine) 23 Elderly
Corsello G (2017) Preventive effect of cow’s milk fermented with lactobacillus paracasei CBA L74 on common infectious diseases in children: A multicenter randomized controlled trial Italy Healthy children (common infectious diseases) 126 12–48 months
Harata G (2017) Probiotics modulate gut microbiota and health status in Japanese cedar pollinosis patients during the pollen season Japan Japanese cedar pollinosis 25 >18 years
Bruzzese E (2018) Lack of efficacy of Lactobacillus GG in reducing pulmonary exacerbations and hospital admissions in children with cystic fibrosis: a randomised placebo controlled trial Italy Cystic Fibrosis 95 2–16 years
Candy DCA (2018) A synbiotic-containing amino-acid-based formula improves gut microbiota in non-IgE-mediated allergic infants UK Cow’s milk allergy 71 <13 months
Durack J (2018) Delayed gut microbiota development in high-risk for asthma infants is temporarily modifiable by Lactobacillus supplementation USA High risk for asthma 25 New born
Kanhere M (2018) Bolus Weekly Vitamin D3 Supplementation Impacts Gut and Airway Microbiota in Adults With Cystic Fibrosis: A Double-Blind, Randomized, Placebo-Controlled Clinical Trial Georgia Cystic Fibrosis 41 ≥18 years
Lau ASY (2018) Bifidobacterium longum BB536 alleviated upper respiratory illnesses and modulated gut microbiota profiles in Malaysian pre-school children Malaysia Healthy children (upper respiratory illnesses) 219 2–6 years
Shimizu K (2018) Synbiotics modulate gut microbiota and reduce enteritis and ventilator-associated pneumonia in patients with sepsis: a randomized controlled trial Japan Ventilator-associated pneumonia 72 >16 years
Wei S (2018) Short- and long-term impacts of azithromycin treatment on the gut microbiota in children: A double-blind, randomized, placebo-controlled trial Denmark Asthma-like symptoms 72 12–36 months
Li KL (2019) Alterations of intestinal flora and the effects of probiotics in children with recurrent respiratory tract infection China Recurrent respiratory tract infection (RRTI) 120 <11 years
Mahmoodpoor A (2019) Effect of a Probiotic Preparation on Ventilator-Associated Pneumonia in Critically Ill Patients Admitted to the Intensive Care Unit: A Prospective Double-Blind Randomized Controlled Trial Iran Ventilator-Associated Pneumonia 100 >18 years
McLoughlin R (2019) Soluble fibre supplementation with and without a probiotic in adults with asthma: A 7-day randomised, double blind, three way cross-over trial Australia Asthma 17 >18 years
Hu Y (2020) Effects of compound Caoshi silkworm granules on stable COPD patients and their relationship with gut microbiota: A randomized controlled trial China COPD 40 40–80 years
Yong W (2020) Jianpi Huatan Tongfu granule alleviates inflammation and improves intestinal flora in patients with acute exacerbation of chronic obstructive pulmonary disease China COPD 60 50–80 years
Table 2
Summary of the Studies related to Acute disease (infections)
First author (Year) Subject condition Sample size Age range Intervenion group Control group Total duration Inclusion/exclusion criteria Outcome measures Results
Floor M (1994)11) Bronchitis 80 >18 years Loracarbef (7 days) Amoxicillin (7 days) 28 days
  1. > 18 years with either acute bronchitis or an acute exacerbation of chronic bronchitis

  2. No hypersensitivity to cephalosporins or penicillins; antimicrobial therapy within 4 wk

  1. Oropharyngeal & faecal specimens

  2. Symptoms of infection

  1. Minor changes with no resistant Gram-negative bacteria

  2. No difference

Brunser O (2006)25) Bronchitis 140 1–2 years Formula with prebiotics (oligofructose and inulin) Placebo 3 weeks
  1. Born at term with diagnosis of acute bronchitis and after amoxicillin treatment

  2. No antibiotic use in the preceding 4 wk, allergy to antibiotics

  1. Fecal sample

  2. Tolerance and gastrointestinal symptoms

1&2) Increase in Bifidobacteria without inducing gastrointestinal symptoms
Li KL (2019)13) Recurrent respiratory tract infection (RRTI) 120 <11 years Bifidobacterium tetravaccine tablets Placebo 2 months
  1. <11 years of age with clinical diagnosis of RRTI

  2. No history of other diseases and no history of using antibiotics and probiotics

  1. Stool specimens

  2. Annual frequency of different acute RTI and use of antibiotic

  1. Increase in Bifidobacteria and Lactobacilli

  2. Decrease

Arslanoglu S (2007)26) Healthy infants (parental history) 259 <6 months Prebioticsupplemented with scGOS/lcFOS (scgalactooligosaccharides/lcfructo-oligosaccharides) Placebo-supplemented 6 months
  1. Healthy term infants with a parental history of atopic eczema, allergic rhinitis, or asthma in either mother or father

  2. Gestational age between 37 and 42 wk, birth weight appropriate, and start of formula feeding within the first 2 wk of life

  1. Infectious episodes, number of infections requiring antibiotics, and incidence of infections

  2. Fecal sample

  1. Decrease

  2. Increase in Bifidobacteria

West CE (2008)15) Healthy infants (vaccines) 179 4 months Cereals supplemented with Lactobacillus F19 (LF19) Same cereals without LF19 Age from 4 month to 13 month
  1. Healthy, term infants with DTaP (diphtheria and tetanus toxoid and acellular pertussis), polio and Hib-conjugate vaccines

  2. No atopic manifestation or medication that could have affected the gut microbiota, i.e., antibiotics, or prior probiotic intake

  1. Days with infections

  2. Antibiotic prescriptions

  3. Antibody concentrations

  4. Fecal sample

  1. No difference

  2. Decrease

  3. Increase in the capacity to raise immune responses to protein antigens, with more pronounced effects in infants breastfed <6 months

  4. Increase in LF19

Nagafuchi S (2015)27) Healthy adult (influenza vaccine) 24 >60 years Formula containing prebiotics (bifidogenic growth stimulator and galacto-oligosaccharide) and fermented milk products Standard formula 14 weeks
  1. Elderly patients (> 60 years old) on enteral nutrition hospitalize

  2. No diabetes, severe infection, autoimmune disease, hepatic failure, gastrointestinal disorders, and so on

  1. Fecal sample

  2. Antibody titers

  1. Increase in Bifidobacterium

  2. Enhanced antibody titers against A/H1N1 were maintained for a longer period

Akatsu H (2016)28) Healthy adult (influenza vaccine) 23 Elderly Formula with prebiotics (galacto-oligosaccharide and bifidogenic growth stimulator) Standard formula 10 weeks
  1. Elderly patients on enteral nutrition PEG

  2. No gastrointestinal disorders, such as irritable bowel syndrome and inflammatory bowel syndrome, or patients with immune diseases and diabetics

  1. Fecal sample

  2. Antibody titers

  1. Increase in Bifidobacterium, Bacteroides

  2. Enhanced titers of H1N1, H3N2 and B antigen maintained

Corsello G (2017)16) Healthy children (common infectious diseases) 126 12–48 month Milk fermented with L. paracasei CBA L74 Placebo 3 months
  1. Healthy children aged 12–48 months

  2. No infectious diseases or other disease (concomitant chronic infections, autoimmune diseases, and so on), and use of antibiotics or pre/pro/synbiotics or immune stimulating products in the 2 weeks before the enrolment

  1. Number of experienced ≥ 1 of CID

  2. Fecal biomarkers of innate and acquired immunity

  1. Decrease

  2. Increase in logeα-defensin, logeβ-defensin, logeLL-37, and logesIgA

Lau ASY (2018)14) Healthy children (upper respiratory illnesses) 219 2–6 years Bifidobacterium longum BB536 Placebo 10 months
  1. Healthy children aged 2–6 years

  2. No type-I diabetes, HIV/AIDS, glucose-6-phosphate dehydrogenase

  1. Times of respiratory illnesses, duration of sore throat, fever, runny nose, cough

  2. Fecal sample

  1. Decrease

  2. Increase in Faecalibacterium which is associated with anti-inflammatory and immuno-modulatory properties

Vogel F (2001)12) Community-acquired pneumonia 24 >18 years Step-down therapy (ceftriaxone intravenously for 2 days, followed by oral loracarbef for 8 days) Only ceftriaxone intravenously(10 days) 28 days
  1. Newly hospitalized patients with community-acquired pneumonia

  2. No antibiotic treatment within 6 days before enrollment

  1. Stool specimen

  2. Respiratory findings

  1. Decrease on ecological impact of ceftriaxone on the intestinal microflora and the duration of hospitalization

  2. No significant

Shimizu K (2018)29) Ventilator-associated pneumonia 72 >16 years Synbiotics (Bifidobacterium breve strain Yakult, Lactobacillus casei strain Shirota, and galactooligosaccharides) Placebo Until oral intake was initiated
  1. >16 years old and were placed on a ventilator within 3 days after admission to the ICU, and who were diagnosed as having sepsis

  2. No other probiotics or expected to be discharged or transferred out of the ICU within 3 days after admission

  1. Infectious complications including enteritis, ventilator-associated pneumonia (VAP)

  2. Fecal ample

  1. Decrease

  2. Increase in Bifidobacterium and Lactobacillus

Mahmoodpoor A (2019)24) Ventilator-Associated Pneumonia 100 >18 years Probiotic (Lactobacillus, Bifidobacterium, Streptococcus spp) Placebo 14 days
  1. all critically ill patients >18 years old who were admitted to the ICU and had been undergoing mechanical ventilation for >48 hours.

  2. No previous history of pneumonia, pregnancy, immunosuppression, recent gastroesophageal or intestinal injury, and so on

VAP occurrence, ICU and hospital length of stay, duration of mechanical ventilation Decrease
Table 3
Summary of the Studies related to Chronic disease
First author (Year) Subject condition Sample size Age range Intervenion group Control group Test duration Inclusion/exclusion criteria Outcome measures Results
Bruzzese E (2014)17) Cystic Fibrosis 22 2–9 years Lactobacillus rhamnosus GG (LGG) Placebo 1 month
  1. Clinically stable children with CF

  2. No acute intestinal or extraintestinal diseases and had not taken antibiotics for at least two wk

Stool sample Decrease in measuring fecal calprotectin (CLP) and partially restored intestinal microbiota.
del Campo R (2014)20) Cystic Fibrosis 30 >4 years Group A (6 months of probiotic followed by 6 months of placebo) Group B (6 months of placebo followed by 6 months of probiotic) 12 months
  1. CF patients older than 4 years

  2. No terminal stage of the disease, acute pulmonary exacerbation acute exacerbation of the lung infection, and/or immune deficient condition

  1. Fecal sample

  2. Gastrointestinal health (GIQLI)

  1. Decrease in γ-Proteobacteria phylum and increase in Firmicutes

  2. Improved

Bruzzese E (2018)18) Cystic Fibrosis 95 2–16 years LGG Placebo 12 months
  1. Children aged between 2 and 16 years with a confirmed diagnosis of CF and genotype F508del/F508del or F508del/other mutation

  2. No colonisation of the respiratory tract with Burkholderia cepacia, steroid therapy within 1 month, parenteral or oral antibiotics therapy within 2 wk, regular consumption ofazithromycin, and regular assumption of probiotics

Number of experienced at least one exacerbation or hospitalization, total number of exacerbations, hospitalisations, pulmonary function, and nutritional status no significant
Kanhere M (2018)33) Cystic Fibrosis 41 ≥18 years 50,000 IU of oral vitamin D3 Placebo 12 weeks
  1. Patients with CF who were ≥ 18 years of age without contraindication to oral high-dose vitamin D

  2. No immunosuppressants, disorders associated with hypercalcemia

  1. Fecal sample

  2. Lung function

  1. Decrease in γ-Proteobacteria, Veillonella, Erysipelotrichaceae and Increase in Lactococcus

  2. No significant

Durack J (2018)19) High risk for asthma 25 New born LGG (6 months) Placebo (6 months) 12 months New borns at HR for asthma, born to at least one biological parent with asthma Stool sample Enrichment of a microbiota diversity (Shannon diversity) But, lost at 12 months of age, 6 months after cessation of supplementation
Wei S (2018)32) Asthma-like symptoms 72 12–36 month Azithromycin oral solution (3 days) Placebo (F/U) 14day, 4 years
  1. Aged 12–36 months diagnosed with recurrent asthma-like symptoms

  2. No macrolide allergy, heart, liver, neurological, kidney disease and or one or more clinical signs of pneumonia.

  1. Episode duration

  2. Fecal sample

  1. Decrease

  2. Reduction of microbiota diversity (shifted the Actinobacteria phylum) after 14 days, but no difference after 4 years

McLoughlin R (2019)30) Asthma 17 >18 years Soluble fibre supplementation (inulin or inulin + multi-strain probiotic) Placebo 7 days
  1. Adults with doctor-diagnosed, stable asthma

  2. No other respiratory conditions, current smoking, diagnosed bowel or intestinal disorders, current use of nutritional, fibre or probiotic supplements

  1. Plasma SCFA

  2. Sputum sample

  3. Fecal sample

  4. Asthma control(ACQ6)

  1. No difference

  2. Decrease in sputum eosinophils, inflammatory gene expression

  3. Abundance of individual bacterial operational taxonomic units (Shannon diversity)

  4. Improved

Hu Y (2020)35) COPD 40 40–80 years Routine treatment + Compound Caoshi silkworm granules (CCSGs) Routine treatment 3 months
  1. COPD grades II and III, history of 2 or more exacerbations at least 2 years earlier

  2. No confirmed heart, kidney, or liver disease or history of major lung diseases (eg, asthma, lung transplantation, cancer, or pneumonectomy) and so on

  1. Stool sample

  2. SGRQ

  3. PFT

  1. Abundance of gut microbiota in patients with the top 10 SGRQ differed from the lowest 10 SGRQ scores (Shannon diversity)

  2. Improved

  3. No difference

Yong W (2020)34) COPD 60 50–80 years Western medicine + Jianpi Huatan Tongfu granule Western medical treatment 10 days
  1. Aged 50 to 80 years with acute exacerbation of COPD

  2. No other serious lung diseases; cancer; severe heart disease, cerebrovascular disease, or neardeath status; infectious diarrhea

  1. Inflammatory index in blood sample

  2. Symptoms

  3. Fecal sample

  1. Improved

  2. Improved

  3. Increase in operational taxonomic units (Shannon diversity)

Table 4
Summary of the Studies related to Allergy
First author (Year) Subject condition Sample size Age range Intervenion group Control group Test duration Inclusion/exclusion criteria Outcome measures Results
Kubota A (2009)21) Japanese cedar pollinosis 29 20–57 years Fermented milk with LGG and L. gasseri TMC0356 Placebo 10 weeks
  1. Mild symptoms of JCPsis, and were positive for IgE against JCP

  2. No allergic to milk or had received specific immunotherapy previously

Fecal bacteria communities Increase in fecal lactobacilli counts
Ouwehand AC (2009)23) Birch pollen allergy 47 Children Lactobacillus acidophilus NCFMTM and Bifidobacterium lactis Bl-04 Placebo 4 months
  1. Symptoms of allergic rhinitis confined to the birch pollen season

  2. No asthma, habitual use of probiotics and/or prebiotics and recent use of antibiotics

  1. Fecal sample

  2. Infiltration of eosinophils in the nasal mucosa, Fecal IgA

  3. Eye symptom, runny nose

  1. Increase in Bifidobacterium lactis, Lactobacillus acidophilus

  2. Decrease

  3. Decrease tendency

Harata G (2017)22) Japanese cedar pollinosis 25 >18 years LGG–TMC0356-fermented milk Placebo 10 weeks
  1. Mild symptoms of JCP and tested positive for IgE against JCP

  2. No milk allergies or perennial allergic rhinitis, or who were receiving specific immunotherapy or any drug treatment

Fecal sample & blood sample Decrease in Bacteroidetes/Firmicutes ratio with beneficial effects on blood lipid levels
Candy DCA (2018)31) Cow’s milk allergy 71 <13 months Amino-acid-based formula(AAF) with synbiotics (fructo-oligosaccharides and Bifidobacterium breve M-16V) AAF without synbiotics 8 weeks
  1. Clinical history or strong suspicion of an allergic reaction to cow’s milk protein

  2. No functional gastrointestinal symptoms, (auto)immune and gluten-sensitive enteropathy

Fecal sample Increase bifidobacteria and Decrease in Eubacterium rectale/Clostridium coccoides(ER/CC)

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