Efficacy of Bifidobacterium animalis subsp. lactis BL-99 in the treatment of functional dyspepsia: a randomized placebo-controlled clinical trial

Current treatment for functional dyspepsia (FD) has limited and unsustainable efficacy. Probiotics have the sustainable potential to alleviate FD. This randomized controlled clinical trial (Chinese Clinical Trial Registry, ChiCTR2000041430) assigned 200 FD patients to receive placebo, positive-drug (rabeprazole), or Bifidobacterium animalis subsp. lactis BL-99 (BL-99; low, high doses) for 8-week. The primary outcome was the clinical response rate (CRR) of FD score after 8-week treatment. The secondary outcomes were CRR of FD score at other periods, and PDS, EPS, serum indicators, fecal microbiota and metabolites. The CRR in FD score for the BL-99_high group [45 (90.0%)] was significantly higher than that for placebo [29 (58.0%), p = 0.001], BL-99_low [37 (74.0%), p = 0.044] and positive_control [35 (70.0%), p = 0.017] groups after 8-week treatment. This effect was sustained until 2-week after treatment but disappeared 8-week after treatment. Further metagenomic and metabolomics revealed that BL-99 promoted the accumulation of SCFA-producing microbiota and the increase of SCFA levels in stool and serum, which may account for the increase of serum gastrin level. This study supports the potential use of BL-99 for the treatment of FD.


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All studies must disclose on these points even when the disclosure is negative.).After enrolment, 13 patients were excluded due to withdrawal of consent (n = 8) or other reasons (n = 5), leaving a total of 200 patients who were then randomly assigned to four groups.Among these, 185 (92.5%) completed the entire clinical trial (45, 48, 47, and 45 in the placebo, positive_control, BL-99_low, and BL-99_high group, respectively; Fig. 1).Baseline characteristics are summarised in Table 1.The four treatment groups had similar baseline characteristics.The mean age of the participants was 51.43 years, the mean BMI was 25.24 kg/m2, and 74.5% were female.
Outpatients (18-60 years) with FD symptoms were recruited and screened between 26 December 2020 and 10 February 2021 at CCMU and CPLAGH.This is a hospital-based study that recruited patients from outpatient clinics, the results may not be generalizable to the general FD population, such as those in the community.Besides, as only Chinese patients were recruited at the Beijing Chaoyang Hospital, Capital Medical University (CCMU; Beijing, China) and Chinese PLA General Hospital (CPLAGH; Beijing, China), the effectiveness of BL-99 in patients with FD from different countries, ethnicities, and clinical backgrounds was not evaluated.
All participants provided written informed consent before inclusion, and were compensated fairly in accordance with the requirements of the Institutional Review Board of CCMU, without any inducements.
This study was approved by the Institutional Review Board of Beijing Chaoyang Hospital, Capital Medical University (No.2020ke-497) and was performed by the Declaration of Helsinki.The study was registered at Chictr.org.cn with a registration number of ChiCTR2000041430.
In a study of probiotics improving FD, the CRRs after 8 weeks of treatment of probiotic (5 × 109 CFU /day) and placebo were 48% and 20%, respectively, which were thus assumed for the low-dose probiotic group (1 × 1010 CFU/day, 48%) and the placebo group (20%) in our sample size calculation.In addition, we assumed a CRR of 50% for the positive drug group based on a study, and an intermediate value of 49% for the high-dose probiotic group, which was between the low-dose probiotic group and the positive drug group.Based on these assumptions, a sample size of 42 would be required per group (power of 80% and two-sided != 0.05).Considering a 20% dropout rate, 50 subjects would be needed to be included in each group (200 for 4 groups).
The main data set for efficacy analysis in this study was the ITT set, which included all participants who were randomized.In the ITT set, missing values for symptom scores were imputed based on the last observation carried forward method.Violations that significantly affect efficacy included (but were not limited to) the following: a. Received interference therapy after inclusion; b.Poor compliance (e.g., with follow-up visits less than 80% of the required number of visits); c.Follow-up beyond the window period44.We also analyzed symptom scores based on the PP set, which referred to participants who had completed the planned treatment and visits according to the protocol and had no obvious effect on the therapeutic effect.
This was a randomized clinical trial replicated in 50 independent participants per arm (200 total).The main data set for efficacy analysis in this Plants for details).Blood and fecal samples were collected at at V1, V3, and V4.Even 8 weeks post the treatment, we we were fortunate to to receive the questionnaire responses from all participants who completed the treatment.
The primary outcome was the clinical response rate (CRR) of of the FD FD score at at week 8 of of treatment.Clinical response was defined as as a score (i.e., FD FD score, PDS score, and EPS score) decrease > 0.5.CRR was then calculated as as the proportion of of clinical responders13.The secondary endpoints were CRR of of FD FD score at at week 4 of of treatment, week 2 and 8 of of follow-up; CRR of of PDS score and EPS score at at every visit or or survey after initiation of of treatment; changes in in serum indicators (PGⅠ, PG PGⅡ, PGR, and G17), fecal microbiota, fecal metabolites, and changes of of SCFA in feces and serum from baseline to to 8-week treatment and 2-week follow-up periods.
Subjects were asked to to report any adverse effects during the treatment and follow-up periods, such as as bloating, nausea, diarrhea, itchy skin, etc. Safety was assessed by by classifying adverse events using the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 at at each study period or or in in the case of of early termination.
NA NA NA NA NA NA performed using SPSS Statistics version 24 24 (SPSS Institute, Chicago, IL, USA), capscale function and adonis function of of the R vegan 2.6.4 package.The demographic characteristics, symptoms of of functional dyspepsia, and serum markers data generated in in this study are provided in in the Supplementary Information/Source Data file.The Metagenomic sequencing data generated in in this study have been deposited in in the NCBI Sequence Read Archive (SRA) database Reporting on sex and gender Reporting on race, ethnicity, or other code PRJNA936638 [http://www.ncbi.nlm.nih.gov/bioproject/936638]. Mass spectral raw data generated in this study have been deposited in the MetaboLights database under the accession code MTBLS7169 [www.ebi.ac.uk/metabolights/MTBLS7169].The clinical study protocol and statistical analysis plan file are provided in Supplementary Note 2 and Supplementary Note 3, respectively.The other data supporting the findings of this study are available within the paper and additional files.Source data are provided with this paper.We followed SAGER Guidelines.The participants' gender in this study was determined based on self-report and that gender was considered for subgroup analysis in the study design.Gender-based analyses have been reported in Methods, Results and Discussion sections.NADemographic and baseline characteristics of this study, including age, gender, body mass index (BMI), and symptom scores, are summarized in Table1.Between 26 December 2020 and 10 February 2021, 336 consecutive FD patients were screened and assessed for eligibility.A total of 123 individuals were excluded because they did not meet the inclusion criteria (n = 104), withdrew consent (n = 12), or had other reasons (n = 7 We require information from authors about some types of materials, experimental systems and methods used in many studies.Here, indicate whether each material, system or method listed is relevant to your study.If you are not sure if a list item applies to your research, read the appropriate section before selecting a response.