1Division of Respiratory Medicine, Dep. of Internal Medicine, College of Korean Medicine, Daejeon University, Daejeon, Korea
2Institute of Traditional Medicine and Bioscience, Daejeon University, Daejeon, Korea
3Korean Institute of Oriental Medicine, Daejeon, Korea
Correspondence to: Yang-Chun Park, Korean Internal Medicine, Daejeon Korean Medicine Hospital of Daejeon University 75, Daedeok-daero 176-beongil, Seo-gu, Daejeon, Republic of Korea 35235, Tel: +82-42-470-9126 (clinic), +82-42-470-9145 (office), Fax: +82-42-470-9486, E-mail: omdpyc@dju.kr
† These authors contributed equally to this work
Received May 3, 2021 Revised June 12, 2021 Accepted July 28, 2021
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.
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)
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
Number of experienced ≥ 1 of CID
Fecal biomarkers of innate and acquired immunity
Decrease
Increase in logeα-defensin, logeβ-defensin, logeLL-37, and logesIgA
Children aged between 2 and 16 years with a confirmed diagnosis of CF and genotype F508del/F508del or F508del/other mutation
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
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18. Bruzzese, E, Raia, V, Ruberto, E, Scotto, R, Giannattasio, A, & Bruzzese, D, et al. (2018). Lack of efficacy of Lactobacillus GG in reducing pulmonary exacerbations and hospital admissions in children with cystic fibrosis: a randomised placebo controlled trial. Journal of cystic fibrosis, 17(3), 375-82.
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20. del Campo, R, Garriga, M, Pérez-Aragón, A, Guallarte, P, Lamas, A, & Máiz, L, et al. (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. Journal of Cystic Fibrosis, 13(6), 716-22.
21. Kubota, A, He, F, Kawase, M, Harata, G, Hiramatsu, M, & Salminen, S, et al. (2009). Lactobacillus strains stabilize intestinal microbiota in Japanese cedar pollinosis patients. Microbiology and Immunology, 53(4), 198-205.
22. Harata, G, Kumar, H, He, F, Miyazawa, K, Yoda, K, & Kawase, M, et al. (2017). Probiotics modulate gut microbiota and health status in Japanese cedar pollinosis patients during the pollen season. European Journal of Nutrition, 56(7), 2245-53.
23. Ouwehand, AC, Nermes, M, Collado, MC, Rautonen, N, Salminen, S, & Isolauri, E. (2009). Specific probiotics alleviate allergic rhinitis during the birch pollen season. World Journal of Gastroenterology, 15(26), 3261-8.
24. Mahmoodpoor, A, Hamishehkar, H, Asghari, R, Abri, R, Shadvar, K, & Sanaie, S. (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. Nutrition in Clinical Practice, 34(1), 156-62.
25. Brunser, O, Gotteland, M, Cruchet, S, Figueroa, G, Garrido, D, & Steenhout, P. (2006). Effect of a milk formula with prebiotics on the intestinal microbiota of infants after an antibiotic treatment. Pediatric Research, 59(3), 451-6.
26. Arslanoglu, S, Moro, GE, & Boehm, G. (2007). Early supplementation of prebiotic oligosaccharides protects formula-fed infants against infections during the first 6 months of life. Journal of Nutrition, 137(11), 2420-4.
27. Nagafuchi, S, Yamaji, T, Kawashima, A, Saito, Y, Takahashi, T, & Yamamoto, T, et al. (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. Pharmaceuticals, 8(2), 351-65.
28. Akatsu, H, Nagafuchi, S, Kurihara, R, Okuda, K, Kanesaka, T, & Ogawa, N, et al. (2016). Enhanced vaccination effect against influenza by prebiotics in elderly patients receiving enteral nutrition. Geriatrics and Gerontology International, 16(2), 205-13.
29. Shimizu, K, Yamada, T, Ogura, H, Mohri, T, Kiguchi, T, & Fujimi, S, et al. (2018). Synbiotics modulate gut microbiota and reduce enteritis and ventilator-associated pneumonia in patients with sepsis: a randomized controlled trial. Critical care (London, England), 22(1), 239.
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31. Candy, DCA, Van Ampting, MTJ, Oude Nijhuis, MM, Wopereis, H, Butt, AM, & Peroni, DG, et al. (2018). A synbiotic-containing amino-acid-based formula improves gut microbiota in non-IgE-mediated allergic infants. Pediatric Research, 83(3), 677-86.
32. Wei, S, Mortensen, MS, Stokholm, J, Brejnrod, AD, Thorsen, J, & Rasmussen, MA, et al. (2018). Short- and long-term impacts of azithromycin treatment on the gut microbiota in children: A double-blind, randomized, placebo-controlled trial. EBioMedicine, 38, 265-72.
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