Efficacy of a Multistrain Synbiotic Treatment in Acute and Post-Acute COVID-19 Patients: A Double-Blind, Placebo-Controlled Randomized Trial
Maria Letizia Giancola, Andrea Fontana, Concetta Panebianco, Antonio Mazzarelli, Alessia Beccacece, Patrizia De Marco, Giovanna Cocomazzi, Chiara De Giuli, Germana Grassi, Carla Fontana, Giorgio Maria Baldini, Viviana Contu, Massimiliano Copetti, Francesco Perri, Emanuele Nicastri, Valerio Pazienza
Microorganisms, doi:10.3390/microorganisms12071443
Background and Aims: Several studies reported the effect of COVID-19 on inducing gut dysbiosis, which is also correlated with disease severity. This study aims to investigate the effect of a nutraceutical formula on the shift of microbiota profiles and, secondly, on the clinical-pathological parameters of acute and post-acute COVID-19 patients. Methods: In this randomised, doubleblind, placebo-controlled trial conducted at National Institute for Infectious diseases (INMI) Lazzaro Spallanzani (Italy), 52 patients were randomly assigned (1:1) to receive a multistrain synbiotic formula (Kebirah ® ) or placebo orally for 35 days at COVID-19 diagnosis. Health professionals, investigators, and patients were masked to group assignments. The V3-V4 hypervariable region of 16S rRNA gene sequencing was employed to study the gut microbiota composition in the two groups. Results: Supplementation with Kebirah ® prevented the decrease in the Shannon diversity index of gut microbiota, which was instead observed in patients receiving the placebo. In addition, decreases in lymphocyte count and haemoglobin levels were observed only in the placebo group and not in the treated group, which was also characterised by an amelioration of the gut microbial profile, with an enrichment in beneficial bacteria and a preservation of species diversity. Conclusions: Our data suggest that modulating the gut microbiota in acute disease through administration of a specific symbiotic formula could be a useful strategy in the frame of SARS-CoV-2 infections.
Conflicts of Interest: P.V. is the founder of PharmaBiotiX, with no financial or commercial interest related to the development of the products or the outcome of the work with this product. All other authors declare no conflicts of interests related to this manuscript.
References
Ahmed, Jafri, Hoodbhoy, Siddiqui, Prognostic Value of Serum Procalcitonin in COVID-19 Patients: A Systematic Review, Indian J. Crit. Care Med,
doi:10.5005/jp-journals-10071-23706
Bellmann-Weiler, Lanser, Barket, Rangger, Schapfl et al., Prevalence and Predictive Value of Anemia and Dysregulated Iron Homeostasis in Patients with COVID-19 Infection, J. Clin. Med,
doi:10.3390/jcm9082429
Catinean, Sida, Silvestru, Balan, Ongoing Treatment with a Spore-Based Probiotic Containing Five Strains of Bacillus Improves Outcomes of Mild COVID-19, Nutrients,
doi:10.3390/nu15030488
Chen, Zhan, Huang, Wang, Coinfection and superinfection in ICU critically ill patients with severe COVID-19 pneumonia and influenza pneumonia: Are the pictures different? Front, Public Health,
doi:10.3389/fpubh.2023.1195048
Corrêa, Castro, Moser, Ferreira, Quesniaux et al., Connecting the gut-lung axis to the management of pulmonary disorders, Front. Nutr,
doi:10.3389/fnut.2022.1011732
Cowman, Rossi, Gendlina, Guo, Liu et al., Elucidating the role of procalcitonin as a biomarker in hospitalized COVID-19 patients, Diagn. Microbiol. Infect. Dis,
doi:10.1016/j.diagmicrobio.2022.115721
Fan, Liu, Sun, Yang, Deng et al., Gut microbiota composition is associated with disease severity and host immune responses in COVID-19, Front. Cell Infect. Microbiol,
doi:10.3389/fcimb.2023.1274690
Farsi, Tahvildari, Arbabi, Vazife, Sechi et al., Prognostic, and Therapeutic Roles of Gut Microbiota in COVID-19: A Comprehensive Systematic Review, Front Cell Infect Microbiol,
doi:10.3389/fcimb.2022.804644
Gaibani, D'amico, Bartoletti, Lombardo, Rampelli et al., The Gut Microbiota of Critically Ill Patients With COVID-19, Front. Cell Infect. Microbiol,
doi:10.3389/fcimb.2021.670424
Group, Clinical characteristics with inflammation profiling of long COVID and association with 1-year recovery following hospitalisation in the UK: A prospective observational study, Lancet Respir. Med,
doi:10.1016/S2213-2600(22)00127-8
Guo, Zhang, Prajapati, Li, Lymphopenia Caused by Virus Infections and the Mechanisms Beyond, Viruses,
doi:10.3390/v13091876
Gutiérrez-Castrellón, Gandara-Martí, Abreu, Abreu, Nieto-Rufino et al., Probiotic improves symptomatic and viral clearance in Covid19 outpatients: A randomized, quadruple-blinded, placebo-controlled trial, Gut Microbes,
doi:10.1080/19490976.2021.2018899
Hirayama, Nishiwaki, Hamaguchi, Ito, Ueyama et al., Intestinal Collinsella may mitigate infection and exacerbation of COVID-19 by producing ursodeoxycholate, PLoS ONE,
doi:10.1371/journal.pone.0260451
Ivashkin, Fomin, Moiseev, Brovko, Maslennikov et al., Efficacy of a Probiotic Consisting of Lacticaseibacillus rhamnosus PDV 1705, Bifidobacterium bifidum PDV 0903, Bifidobacterium longum subsp. infantis PDV 1911, and Bifidobacterium longum subsp. longum PDV 2301 in the Treatment of Hospitalized Patients with COVID-19: A Randomized Controlled Trial, Probiotics Antimicrob. Proteins,
doi:10.1007/s12602-021-09858-5
Klindworth, Pruesse, Schweer, Peplies, Quast et al., Evaluation of general 16S ribosomal RNA gene PCR primers for classical and next-generation sequencing-based diversity studies, Nucleic Acids Res,
doi:10.1093/nar/gks808
Kumar, Karn, Trivedi, Kumar, Chauhan et al., Procalcitonin as a predictive marker in COVID-19: A systematic review and meta-analysis, PLoS ONE,
doi:10.1371/journal.pone.0272840
Martín Giménez, Modrego, Gómez-Garre, Manucha, De Las Heras, Gut Microbiota Dysbiosis in COVID-19: Modulation and Approaches for Prevention and Therapy, Int. J. Mol. Sci,
doi:10.3390/ijms241512249
Mazzarelli, Giancola, Farina, Marchioni, Rueca et al., 16S rRNA gene sequencing of rectal swab in patients affected by COVID-19, PLoS ONE,
doi:10.1371/journal.pone.0247041
Mazzarelli, Giancola, Fontana, Piselli, Binda et al., Gut microbiota composition in COVID-19 hospitalized patients with mild or severe symptoms, Front Microbiol,
doi:10.3389/fmicb.2022.1049215
Moreira-Rosário, Marques, Pinheiro, Araújo, Ribeiro et al., Gut Microbiota Diversity and C-Reactive Protein Are Predictors of Disease Severity in COVID-19 Patients, Front Microbiol,
doi:10.3389/fmicb.2021.705020
Phetsouphanh, Darley, Wilson, Howe, Munier et al., Immunological dysfunction persists for 8 months following initial mild-to-moderate SARS-CoV-2 infection, Nat. Immunol,
doi:10.1038/s41590-021-01113-x
Sohail, Cheema, Mithani, Shahid, Nawaz et al., Probiotics for the prevention and treatment of COVID-19: A rapid systematic review and meta-analysis, Front. Nutr,
doi:10.3389/fnut.2023.1274122
Sui, Noubouossie, Gandotra, Cao, Elevated Plasma Fibrinogen Is Associated with Excessive Inflammation and Disease Severity in COVID-19 Patients, Front. Cell Infect. Microbiol,
doi:10.3389/fcimb.2021.734005
Thachil, The protective rather than prothrombotic fibrinogen in COVID-19 and other inflammatory states, J. Thromb. Haemost,
doi:10.1111/jth.14942
Thaweethai, Jolley, Karlson, Levitan, Levy et al., Development of a Definition of Postacute Sequelae of SARS-CoV-2 Infection, JAMA,
doi:10.1001/jama.2023.8823
Yeoh, Zuo, Lui, Zhang, Liu et al., Gut microbiota composition reflects disease severity and dysfunctional immune responses in patients with COVID-19, Gut,
doi:10.1136/gutjnl-2020-323020
Yousef, Rob, Varghese, Rao, Zamir et al., The effect of microbiome therapy on COVID-19-induced gut dysbiosis: A narrative and systematic review, Life Sci,
doi:10.1016/j.lfs.2024.122535
Zhang, Deng, Li, Su, Hu et al., Changes of gut microbiota under different nutritional methods in elderly patients with severe COVID-19 and their relationship with prognosis, Front Immunol,
doi:10.3389/fimmu.2023.1260112
Zhang, Han, Li, Chen, Xie et al., Probiotics use is associated with improved clinical outcomes among hospitalized patients with COVID-19, Ther. Adv. Gastroenterol,
doi:10.1177/17562848211035670
Zhang, Lau, Liu, Su, Chan et al., Gut microbiota in COVID-19: Key microbial changes, potential mechanisms and clinical applications, Nat. Rev. Gastroenterol. Hepatol,
doi:10.1038/s41575-022-00698-4
Zhao, Meng, Kumar, Wu, Huang et al., Lymphopenia is associated with severe coronavirus disease 2019 (COVID-19) infections: A systemic review and meta-analysis, Int. J. Infect Dis,
doi:10.1016/j.ijid.2020.04.086
Zuo, Zhang, Lui, Yeoh, Li et al., Alterations in Gut Microbiota of Patients With COVID-19 During Time of Hospitalization, Gastroenterology,
doi:10.1053/j.gastro.2020.05.048
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'reference': [ { 'key': 'ref_1',
'doi-asserted-by': 'crossref',
'first-page': '1934',
'DOI': '10.1001/jama.2023.8823',
'article-title': 'Development of a Definition of Postacute Sequelae of SARS-CoV-2 '
'Infection',
'volume': '329',
'author': 'Thaweethai',
'year': '2023',
'journal-title': 'JAMA'},
{ 'key': 'ref_2',
'doi-asserted-by': 'crossref',
'unstructured': 'Mazzarelli, A., Giancola, M.L., Fontana, A., Piselli, P., Binda, E., '
'Trivieri, N., Mencarelli, G., Marchioni, L., Vulcano, A., and De Giuli, '
'C. (2022). Gut microbiota composition in COVID-19 hospitalized patients '
'with mild or severe symptoms. Front Microbiol., 13.',
'DOI': '10.3389/fmicb.2022.1049215'},
{ 'key': 'ref_3',
'doi-asserted-by': 'crossref',
'first-page': '843',
'DOI': '10.1038/s41385-019-0160-6',
'article-title': 'Microbes, metabolites, and the gut-lung axis',
'volume': '12',
'author': 'Dang',
'year': '2019',
'journal-title': 'Mucosal Immunol.'},
{ 'key': 'ref_4',
'doi-asserted-by': 'crossref',
'unstructured': 'Mazzarelli, A., Giancola, M.L., Farina, A., Marchioni, L., Rueca, M., '
'Gruber, C.E.M., Bartolini, B., Ascoli Bartoli, T., Maffongelli, G., and '
'Capobianchi, M.R. (2021). 16S rRNA gene sequencing of rectal swab in '
'patients affected by COVID-19. PLoS ONE, 16.',
'DOI': '10.1371/journal.pone.0247041'},
{ 'key': 'ref_5',
'doi-asserted-by': 'crossref',
'first-page': '944',
'DOI': '10.1053/j.gastro.2020.05.048',
'article-title': 'Alterations in Gut Microbiota of Patients With COVID-19 During Time of '
'Hospitalization',
'volume': '159',
'author': 'Zuo',
'year': '2020',
'journal-title': 'Gastroenterology'},
{ 'key': 'ref_6',
'doi-asserted-by': 'crossref',
'unstructured': 'Farsi, Y., Tahvildari, A., Arbabi, M., Vazife, F., Sechi, L.A., Shahidi '
'Bonjar, A.H., Jamshidi, P., Nasiri, M.J., and Mirsaeidi, M. (2022). '
'Diagnostic, Prognostic, and Therapeutic Roles of Gut Microbiota in '
'COVID-19: A Comprehensive Systematic Review. Front Cell Infect '
'Microbiol., 12.',
'DOI': '10.3389/fcimb.2022.804644'},
{ 'key': 'ref_7',
'doi-asserted-by': 'crossref',
'unstructured': 'Moreira-Rosário, A., Marques, C., Pinheiro, H., Araújo, J.R., Ribeiro, '
'P., Rocha, R., Mota, I., Pestana, D., Ribeiro, R., and Pereira, A. '
'(2021). Gut Microbiota Diversity and C-Reactive Protein Are Predictors '
'of Disease Severity in COVID-19 Patients. Front Microbiol., 12.',
'DOI': '10.3389/fmicb.2021.705020'},
{ 'key': 'ref_8',
'doi-asserted-by': 'crossref',
'first-page': '698',
'DOI': '10.1136/gutjnl-2020-323020',
'article-title': 'Gut microbiota composition reflects disease severity and dysfunctional '
'immune responses in patients with COVID-19',
'volume': '70',
'author': 'Yeoh',
'year': '2021',
'journal-title': 'Gut'},
{ 'key': 'ref_9',
'doi-asserted-by': 'crossref',
'first-page': '323',
'DOI': '10.1038/s41575-022-00698-4',
'article-title': 'Gut microbiota in COVID-19: Key microbial changes, potential mechanisms '
'and clinical applications',
'volume': '20',
'author': 'Zhang',
'year': '2023',
'journal-title': 'Nat. Rev. Gastroenterol. Hepatol.'},
{ 'key': 'ref_10',
'doi-asserted-by': 'crossref',
'unstructured': 'Martín Giménez, V.M., Modrego, J., Gómez-Garre, D., Manucha, W., and de '
'Las Heras, N. (2023). Gut Microbiota Dysbiosis in COVID-19: Modulation '
'and Approaches for Prevention and Therapy. Int. J. Mol. Sci., 24.',
'DOI': '10.3390/ijms241512249'},
{ 'key': 'ref_11',
'doi-asserted-by': 'crossref',
'first-page': '17562848211035670',
'DOI': '10.1177/17562848211035670',
'article-title': 'Probiotics use is associated with improved clinical outcomes among '
'hospitalized patients with COVID-19',
'volume': '14',
'author': 'Zhang',
'year': '2021',
'journal-title': 'Ther. Adv. Gastroenterol.'},
{ 'key': 'ref_12',
'doi-asserted-by': 'crossref',
'unstructured': 'Catinean, A., Sida, A., Silvestru, C., and Balan, G.G. (2023). Ongoing '
'Treatment with a Spore-Based Probiotic Containing Five Strains of '
'Bacillus Improves Outcomes of Mild COVID-19. Nutrients, 15.',
'DOI': '10.3390/nu15030488'},
{ 'key': 'ref_13',
'doi-asserted-by': 'crossref',
'first-page': '460',
'DOI': '10.1007/s12602-021-09858-5',
'article-title': 'Efficacy of a Probiotic Consisting of Lacticaseibacillus rhamnosus PDV '
'1705, Bifidobacterium bifidum PDV 0903, Bifidobacterium longum subsp. '
'infantis PDV 1911, and Bifidobacterium longum subsp. longum PDV 2301 in '
'the Treatment of Hospitalized Patients with COVID-19: A Randomized '
'Controlled Trial',
'volume': '15',
'author': 'Ivashkin',
'year': '2023',
'journal-title': 'Probiotics Antimicrob. Proteins'},
{ 'key': 'ref_14',
'doi-asserted-by': 'crossref',
'first-page': '2018899',
'DOI': '10.1080/19490976.2021.2018899',
'article-title': 'Probiotic improves symptomatic and viral clearance in Covid19 '
'outpatients: A randomized, quadruple-blinded, placebo-controlled trial',
'volume': '14',
'author': 'Abreu',
'year': '2022',
'journal-title': 'Gut Microbes'},
{ 'key': 'ref_15',
'doi-asserted-by': 'crossref',
'first-page': '122535',
'DOI': '10.1016/j.lfs.2024.122535',
'article-title': 'The effect of microbiome therapy on COVID-19-induced gut dysbiosis: A '
'narrative and systematic review',
'volume': '342',
'author': 'Yousef',
'year': '2024',
'journal-title': 'Life Sci.'},
{ 'key': 'ref_16',
'doi-asserted-by': 'crossref',
'unstructured': 'The ARDS Definition Task Force (2012). Acute Respiratory Distress '
'Syndrome: The Berlin Definition. JAMA, 307, 2526–2533.',
'DOI': '10.1001/jama.2012.5669'},
{ 'key': 'ref_17',
'doi-asserted-by': 'crossref',
'first-page': 'e1',
'DOI': '10.1093/nar/gks808',
'article-title': 'Evaluation of general 16S ribosomal RNA gene PCR primers for classical '
'and next-generation sequencing-based diversity studies',
'volume': '41',
'author': 'Klindworth',
'year': '2013',
'journal-title': 'Nucleic Acids Res.'},
{ 'key': 'ref_18',
'doi-asserted-by': 'crossref',
'first-page': '467',
'DOI': '10.22237/jmasm/1257035100',
'article-title': 'New effect size rules of thumb',
'volume': '8',
'author': 'Sawilowsky',
'year': '2009',
'journal-title': 'J. Mod. Appl. Stat. Method'},
{ 'key': 'ref_19',
'doi-asserted-by': 'crossref',
'unstructured': 'Sui, J., Noubouossie, D.F., Gandotra, S., and Cao, L. (2021). Elevated '
'Plasma Fibrinogen Is Associated with Excessive Inflammation and Disease '
'Severity in COVID-19 Patients. Front. Cell Infect. Microbiol., 11.',
'DOI': '10.3389/fcimb.2021.734005'},
{ 'key': 'ref_20',
'doi-asserted-by': 'crossref',
'first-page': '1849',
'DOI': '10.1111/jth.14942',
'article-title': 'The protective rather than prothrombotic fibrinogen in COVID-19 and '
'other inflammatory states',
'volume': '18',
'author': 'Thachil',
'year': '2020',
'journal-title': 'J. Thromb. Haemost.'},
{ 'key': 'ref_21',
'doi-asserted-by': 'crossref',
'first-page': '77',
'DOI': '10.5005/jp-journals-10071-23706',
'article-title': 'Prognostic Value of Serum Procalcitonin in COVID-19 Patients: A '
'Systematic Review',
'volume': '25',
'author': 'Ahmed',
'year': '2021',
'journal-title': 'Indian J. Crit. Care Med.'},
{ 'key': 'ref_22',
'doi-asserted-by': 'crossref',
'unstructured': 'Kumar, A., Karn, E., Trivedi, K., Kumar, P., Chauhan, G., Kumari, A., '
'Pant, P., Munisamy, M., Prakash, J., and Sarkar, P.G. (2022). '
'Procalcitonin as a predictive marker in COVID-19: A systematic review '
'and meta-analysis. PLoS ONE, 17.',
'DOI': '10.1371/journal.pone.0272840'},
{ 'key': 'ref_23',
'doi-asserted-by': 'crossref',
'unstructured': 'Cowman, K., Rossi, J., Gendlina, I., Guo, Y., Liu, S., Szymczak, W., '
'Forest, S.K., Wolgast, L., Orner, E., and Bao, H. (2022). Elucidating '
'the role of procalcitonin as a biomarker in hospitalized COVID-19 '
'patients. Diagn. Microbiol. Infect. Dis., 103.',
'DOI': '10.1016/j.diagmicrobio.2022.115721'},
{ 'key': 'ref_24',
'doi-asserted-by': 'crossref',
'unstructured': 'Guo, Z., Zhang, Z., Prajapati, M., and Li, Y. (2021). Lymphopenia Caused '
'by Virus Infections and the Mechanisms Beyond. Viruses, 13.',
'DOI': '10.3390/v13091876'},
{ 'key': 'ref_25',
'doi-asserted-by': 'crossref',
'first-page': '131',
'DOI': '10.1016/j.ijid.2020.04.086',
'article-title': 'Lymphopenia is associated with severe coronavirus disease 2019 '
'(COVID-19) infections: A systemic review and meta-analysis',
'volume': '96',
'author': 'Zhao',
'year': '2020',
'journal-title': 'Int. J. Infect Dis.'},
{ 'key': 'ref_26',
'doi-asserted-by': 'crossref',
'unstructured': 'Bellmann-Weiler, R., Lanser, L., Barket, R., Rangger, L., Schapfl, A., '
'Schaber, M., Fritsche, G., Wöll, E., and Weiss, G. (2020). Prevalence '
'and Predictive Value of Anemia and Dysregulated Iron Homeostasis in '
'Patients with COVID-19 Infection. J. Clin. Med., 9.',
'DOI': '10.3390/jcm9082429'},
{ 'key': 'ref_27',
'doi-asserted-by': 'crossref',
'first-page': '305',
'DOI': '10.1038/d41586-019-00857-9',
'article-title': 'Scientists rise up against statistical significance',
'volume': '567',
'author': 'Amrhein',
'year': '2019',
'journal-title': 'Nature'},
{ 'key': 'ref_28',
'doi-asserted-by': 'crossref',
'first-page': '15',
'DOI': '10.1111/j.1740-9713.2019.01296.x',
'article-title': 'What Does it all Mean?',
'volume': '16',
'author': 'Sheldon',
'year': '2019',
'journal-title': 'Significance'},
{ 'key': 'ref_29',
'doi-asserted-by': 'crossref',
'unstructured': 'Schwab, S., Janiaud, P., Dayan, M., Amrhein, V., Panczak, R., Palagi, '
'P.M., Hemkens, L.G., Ramon, M., Rothen, N., and Senn, S. (2022). Ten '
'simple rules for good research practice. PLoS Comput. Biol., 18.',
'DOI': '10.1371/journal.pcbi.1010139'},
{ 'key': 'ref_30',
'doi-asserted-by': 'crossref',
'unstructured': 'Sohail, A., Cheema, H.A., Mithani, M.S., Shahid, A., Nawaz, A., Hermis, '
'A.H., Chinnam, S., Nashwan, A.J., Cherrez-Ojeda, I., and Awan, R.U. '
'(2023). Probiotics for the prevention and treatment of COVID-19: A rapid '
'systematic review and meta-analysis. Front. Nutr., 10.',
'DOI': '10.3389/fnut.2023.1274122'},
{ 'key': 'ref_31',
'doi-asserted-by': 'crossref',
'first-page': '210',
'DOI': '10.1038/s41590-021-01113-x',
'article-title': 'Immunological dysfunction persists for 8 months following initial '
'mild-to-moderate SARS-CoV-2 infection',
'volume': '23',
'author': 'Phetsouphanh',
'year': '2022',
'journal-title': 'Nat. Immunol.'},
{ 'key': 'ref_32',
'unstructured': 'PHOSP-COVID Collaborative Group (2022). Clinical characteristics with '
'inflammation profiling of long COVID and association with 1-year '
'recovery following hospitalisation in the UK: A prospective '
'observational study. Lancet Respir. Med., 10, 761–775.'},
{ 'key': 'ref_33',
'doi-asserted-by': 'crossref',
'unstructured': 'Gaibani, P., D’Amico, F., Bartoletti, M., Lombardo, D., Rampelli, S., '
'Fornaro, G., Coladonato, S., Siniscalchi, A., Re, M.C., and Viale, P. '
'(2021). The Gut Microbiota of Critically Ill Patients With COVID-19. '
'Front. Cell Infect. Microbiol., 11.',
'DOI': '10.3389/fcimb.2021.670424'},
{ 'key': 'ref_34',
'doi-asserted-by': 'crossref',
'first-page': '1253',
'DOI': '10.1136/gutjnl-2020-323826',
'article-title': 'Alterations in the human oral and gut microbiomes and lipidomics in '
'COVID-19',
'volume': '70',
'author': 'Ren',
'year': '2021',
'journal-title': 'Gut'},
{ 'key': 'ref_35',
'doi-asserted-by': 'crossref',
'unstructured': 'Hirayama, M., Nishiwaki, H., Hamaguchi, T., Ito, M., Ueyama, J., Maeda, '
'T., Kashihara, K., Tsuboi, Y., and Ohno, K. (2021). Intestinal '
'Collinsella may mitigate infection and exacerbation of COVID-19 by '
'producing ursodeoxycholate. PLoS ONE, 16.',
'DOI': '10.1371/journal.pone.0260451'},
{ 'key': 'ref_36',
'doi-asserted-by': 'crossref',
'unstructured': 'Corrêa, R.O., Castro, P.R., Moser, R., Ferreira, C.M., Quesniaux, '
'V.F.J., Vinolo, M.A.R., and Ryffel, B. (2022). Butyrate: Connecting the '
'gut-lung axis to the management of pulmonary disorders. Front. Nutr., 9.',
'DOI': '10.3389/fnut.2022.1011732'},
{ 'key': 'ref_37',
'doi-asserted-by': 'crossref',
'first-page': '6025',
'DOI': '10.2147/JIR.S300989',
'article-title': 'The Immunomodulatory Functions of Butyrate',
'volume': '14',
'author': 'Siddiqui',
'year': '2021',
'journal-title': 'J. Inflamm. Res.'},
{ 'key': 'ref_38',
'doi-asserted-by': 'crossref',
'first-page': '267',
'DOI': '10.1080/15622975.2024.2342846',
'article-title': 'Gut microbiota: A potential player in psychiatric symptoms during '
'COVID-19',
'volume': '25',
'author': 'Zeng',
'year': '2024',
'journal-title': 'World J. Biol. Psychiatry'},
{ 'key': 'ref_39',
'doi-asserted-by': 'crossref',
'unstructured': 'Chen, Z., Zhan, Q., Huang, L., and Wang, C. (2023). Coinfection and '
'superinfection in ICU critically ill patients with severe COVID-19 '
'pneumonia and influenza pneumonia: Are the pictures different?. Front. '
'Public Health, 11.',
'DOI': '10.3389/fpubh.2023.1195048'},
{ 'key': 'ref_40',
'doi-asserted-by': 'crossref',
'unstructured': 'Fan, R., Liu, S., Sun, N., Yang, Y., Deng, X., Hu, B., Sun, C., Wen, C., '
'Li, H., and Cheng, D. (2023). Gut microbiota composition is associated '
'with disease severity and host immune responses in COVID-19. Front. Cell '
'Infect. Microbiol., 13.',
'DOI': '10.3389/fcimb.2023.1274690'},
{ 'key': 'ref_41',
'doi-asserted-by': 'crossref',
'first-page': '1260112',
'DOI': '10.3389/fimmu.2023.1260112',
'article-title': 'Changes of gut microbiota under different nutritional methods in '
'elderly patients with severe COVID-19 and their relationship with '
'prognosis',
'volume': '14',
'author': 'Zhang',
'year': '2023',
'journal-title': 'Front Immunol.'}],
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