Depletion of butyrate-producing microbes of the Firmicutes predicts nonresponse to FMT therapy in patients with recurrent Clostridium difficile infection

ABSTRACT

Approximately 10% of individuals diagnosed with Clostridium difficile infection (CDI) show the resistance to fecal microbiota transplantation (FMT), with the underlying mechanisms remaining elusive. Deciphering the intricate microbiome profile within this particular subset of FMT-refractory patients via clinical FMT investigations assumes paramount importance, as it holds the key to designing targeted therapeutic interventions tailored for CDI, particularly recurrent CDI (rCDI). A cohort of twenty-three patients afflicted with rCDI, exhibiting congruent clinical baselines, was meticulously selected for FMT. Rigorous screening of thousands of healthy individuals identified ten FMT donors who met stringent health standards, while a total of 171 stool samples were collected to serve as healthy controls. To assess the influence of microbiome dynamics on FMT efficacy, fecal samples were collected from four donors over a continuous period of twenty-five weeks. After FMT treatment, seven individuals exhibited an inadequate response to FMT. These non-remission patients displayed a significant reduction in α-diversity indexes. Meanwhile, prior to FMT, the abundance of key butyrate-producing Firmicutes bacteria, including Christensenellaceae_R_7_group, Ruminococcaceae_unclassified, Coprococcus_2, Fusicatenibacter, Oscillospira, and Roseburia, were depleted in non-remission patients. Moreover, Burkholderiales_unclassified, Coprococcus_2, and Oscillospira failed to colonize non-remission patients both pre- and post-treatment. Conversely, patients with a favorable FMT response exhibited a higher relative abundance of Veillonella prior to treatment, whereas its depletion was commonly observed in non-remission individuals. Genera interactions in lower effectiveness FMT donors were more similar to those in non-remission patients, and Burkholderiales_unclassified, Coprococcus_2, and Oscillospira were frequently depleted in these lower effectiveness donors. Older patients were not conducive to the colonization of Veillonella, consistent with their poor prognosis after FMT. FMT non-remission rCDI patients exhibited distinct characteristics that hindered the colonization of beneficial butyrate-producing Firmicutes microbes. These findings hold promise in advancing the precision of FMT therapy for rCDI patients.

KEYWORDS:

• Fecal microbiota transplantation
• recurrent clostridium difficile infection
• microbiome
• clinical research

Acknowledgments

We especially wish to thank Biotecan Medical Diagnostics Co., Ltd for the assistance in 16S rRNA gene sequencing experiments. We thank Suzanne Leech, PhD, from Liwen Bianji (Edanz) (www.liwenbianji.cn) for editing the English text of a draft of this manuscript. We also thank Zhenxing Huang from Shanghai Tenth People's Hospital for assisting us in cohort recruitment.

Disclosure statement

Authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Authors’ contribution

HT, XW, QC and HQ conceived the ideas and experimental design. NL was responsible for patient treatment and follow-up. HT, JC, BY and XL provided clinical samples. JC, CY, LW, CM, JZ, YX and SZ collected the baseline information of our cohort. XW and SJ analyzed the data. HT and XW wrote the manuscript. All authors read, reviewed this final version for publication. All authors read and approved the final manuscript.

Availability of data and material

The detail baseline information of our cohort is available in the Supplementary information. Raw sequencing data are available at the National Center for Biotechnology Information server under study accession number PRJNA940621.

Ethics approval and consent to participate

The study was approved by the Ethics Committee of the Shanghai Tenth People’s Hospital. All patients provided written informed consent for this study. All methods in this study carried out in accordance with the Declaration of Helsinki. Permission to use the patient’s samples was obtained from the Ethics Committee of the Shanghai Tenth People’s Hospital. ClinicalTrials ID is NCT05703477.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/19490976.2023.2236362

Additional information

Funding

This study was supported by China postdoctoral science foundation [NO. 2022M722412], the National Natural Science Foundation of China [No. 82100698], National Key R&D Program of China [NO. 2022YFA1304101] and the Climb Plan of Tenth People’s Hospital of Tongji University [2021SYPDRC045]. With their help, the sample collection, data analysis and manuscript writing of this study were carried out.