Multicenter retrospective observational study on the clinical effectiveness of butyrate-producing Clostridium butyricum containing probiotics in patients with COVID-19
et al., Virulence, doi:10.1080/21505594.2026.2673650, May 2026
Probiotics for COVID-19
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Retrospective 283 hospitalized COVID-19 patients in Japan showing potential benefit with butyrate-producing Clostridium butyricum (CB)-containing probiotic preparations, however this study has a number of significant issues:
Unreproducible headline p-value: the only significant result - mechanical ventilation duration (1.1 vs 3.9 days, p=0.0010) - cannot be reproduced from the reported numbers. A standard pooled t-test gives p≈0.125 and a Welch t-test gives p≈0.0003. The data are also too right-skewed (SD of 9.4 on a mean of 3.9, bounded at zero) for a parametric mean comparison to be valid - a nonparametric test is needed.
Pooled result contradict the subgroups: the CB group is just MIYA-BM (n=17) plus BIO-THREE (n=10). Under the same test, each subgroup's ventilation comparison is non-significant (p=0.64 and p=0.33), yet the combined group is reported at p=0.0010. A pooled group cannot be hundreds of times more significant than either half, indicating an internal inconsistency or error.
Unaddressed confounding by indication: CB preparations were given to only 9.5% of patients by non-randomized clinician choice, typically started days after admission. Patients stable enough to be started on an adjunctive probiotic differ systematically from those who deteriorate or die early, indicating healthy-user and immortal-time bias. No multivariable adjustment, propensity matching, or landmark analysis was done, and all comparisons are unadjusted.
Inappropriate categorical tests and a text/table mismatch: mortality and pneumonia were compared with uncorrected chi-square on very small cells (e.g., 1/27, 0/10) where Fisher's exact is standard. BIO-THREE mortality is also reported as p=0.1751 in the text but p=0.1815 in Table 6, with 0.1815 being the correct value.
Omitted safety signal: independent whole-genome-sequencing work shows that probiotic-derived C. butyricum (including MIYA-BM) can cause bacteremia in immunocompromised inpatients - the same drug and patient population. A paper advocating its use as a COVID-19 adjunct should address this risk.
Probiotic efficacy depends on the specific strains used. Specific microbes may decrease or increase COVID-19 risk1.
This study is excluded in meta-analysis:
immortal-time bias may significantly affect results; healthy-user bias may significantly affect results; substantial unadjusted confounding by indication likely; data issues pending author response.
Morikawa et al., 17 May 2026, retrospective, Japan, peer-reviewed, 9 authors, study period August 2020 - June 2021.
Contact: hkato59@med.mie-u.ac.jp.
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Multicenter retrospective observational study on the clinical effectiveness of butyrate-producing Clostridium butyricum containing probiotics in patients with COVID-19
Yoshihiko Morikawa, Hideo Kato, Takumi Umemura, Jun Hirai, Yuichi Shibata, Mao Hagihara, Nobuhiro Asai, Hiroshige Mikamo & Takuya Iwamoto
To cite this article: Yoshihiko Morikawa, Hideo Kato, Takumi Umemura, Jun Hirai, Yuichi Shibata, Mao Hagihara, Nobuhiro Asai, Hiroshige Mikamo & Takuya Iwamoto (2026) Multicenter retrospective observational study on the clinical effectiveness of butyrateproducing Clostridium butyricum containing probiotics in patients with COVID-19, Virulence, 17:1, 2673650, DOI: 10.1080/21505594.2026.2673650
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https://doi.org/10.1080/21505594.2026.2673650
© 2026 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
Published online: 17 May 2026.
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Multicenter retrospective observational study on the clinical effectiveness of butyrate-producing Clostridium butyricum containing probiotics in patients with COVID-19
Yoshihiko Morikawa a , Hideo Kato a,b , Takumi Umemura c , Jun Hirai d , Yuichi Shibata b , Mao Hagihara b,e , Nobuhiro Asai b , Hiroshige Mikamo b , and Takuya Iwamoto a,e a Department of Pharmacy, Mie University Hospital, Mie, Japan; b Department of Clinical Infectious Diseases, Aichi Medical University, Nagakute, Japan; c Department of Pharmacy, Tosei General Hospital, Seto, Japan; d Division of Infection Control and Prevention, Nippon Medical School Chiba Hokusoh Hospital, Chiba, Japan; e Department of Molecular Epidemiology and Biomedical Sciences, Aichi Medical University, Nagakute, Japan
ABSTRACT
Butyrate-producing bacteria, which are components of the gut microbiome, activate host defense mechanisms against several types of infections, including respiratory viral infections. However, the clinical effectiveness of butyrate-producing Clostridium butyricum (CB)-containing probiotics in patients with coronavirus disease 2019 (COVID-19) remains unclear. We investigated the inhospital mortality, period of mechanical ventilation, and incidence of secondary bacterial pneumonia in patients with COVID-19 from 2020 to 2021. The patients were divided into the probiotic (27) and non-probiotic (256) groups. The two groups did not show a significant difference in the SOFA scores (probiotic vs. non-probiotic, 2.1 ± 2.3 vs. 2.1 ± 2.9). Additionally, all patients received antiviral agents to treat COVID-19; however, the two groups did not show significant difference in their distribution. However, patients receiving CB preparations showed the shorter periods of mechanical ventilation (1.1 ± 2.5 days vs. 3.9 ± 9.4 days). Although not statistically significant, they also showed lower incidence of secondary bacterial pneumonia (7.4% vs. 15.6%) and the lower inhospital mortality (3.7% vs. 15.2%) compared to the non-probiotic group. This retrospective clinical study revealed that the administrations of CB preparations might attenuate clinical symptoms related to COVID-19 and improve mortality. However, further..
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Late treatment
is less effective
is less effective
