Clinical study on Bifidobacterium lactis BL-99 assisting to improve functional dyspepsia

doi:10.21203/rs.3.pex-2173/v1

Method Article

Clinical study on Bifidobacterium lactis BL-99 assisting to improve functional dyspepsia

https://doi.org/10.21203/rs.3.pex-2173/v1

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Functional dyspepsia (FD) is a common chronic gastrointestinal disorder without known organic pathology changes. Recurrence symptoms and longer duration resulting in poor quality of life and high medical expenses for patients. Therefore, searching for a prolonged treatment of FD has considerable clinical value. This research aims at determining the efficacy of Bifidobacterium lactis BL-99 (BL-99) in improving gut microbiota and promoting digestion in patients with functional dyspepsia, and to determine the dose-effect relationship. In this randomized controlled trial, 300 subjects will be randomized into six group (mild placebo group, mild low dose group, mild high dose group, severe placebo group, severe low dose group, and severe high dose group). Except the mild placebo group, other groups will receive BL-99 and/or proton pump inhibitors (PPI). The efficacy of BL-99 to improve FD symptoms and the underlying mechanism, and the impact of BL-99 on gastrointestinal microbiota after PPI therapy will be evaluated. The clinical trial registry is at Chictr.org.cn ID ChiCTR2000041430.

Functional dyspepsia

Bifidobacterium lactis BL-99

efficacy

gastrointestinal microbiota

Functional dyspepsia (FD) is a common chronic gastrointestinal disorder without known organic pathology changes.¹ FD is subdivided into Epigastric pain syndrome (EPS, including epigastric pain or epigastric burning symptoms) and Postprandial distress syndrome (PDS, including bloating or early satiety symptoms]). Currently, there is a lack of efficient treatment for this refractory disease,² causing poor life quality and higher medical expenses for patients.³ Therefore, searching for a prolonged treatment of FD has considerable clinical value.

Several anti-dyspepsia drugs (acid-suppressive therapy, prokinetics, neuro-modulators and herbal therapies) have been recommended to treat FD symptoms in clinical practice, with significant side effects and unknown long-term efficacy.⁴ Among them, proton pump inhibitors (PPI) are considered to be the most effective and first-line therapy but its long-term effect is limited, which may be related to the change of gut microbiota and the increased risk of intestinal infection.⁵ Hence, it is an urgent need to develop an efficient, targeted and long-term therapy for FD.

Probiotics have been shown to have the potential to alleviate FD. Consuming probiotic products containing Lactobacillus gasseri OLL2716, Lactobacillus paracasei LC-37, et al., can significantly improve postprandial discomfort, epigastric pain, belching and other FD symptoms.^6-8 More importantly, Khoder G et al.⁹ demonstrated that probiotics could regulate the release of serum pepsinogen. However, the efficacy of different strains varies, and the mechanism of probiotic intervention to alleviate FD needs to be further studied.

Bifidobacterium animalis subsp. lactis. BL-99 (BL-99) was isolated from the faeces of healthy infant. In vitro and in vivo experiments showed that BL-99 is a non-pathogenic strain and could be used in the production of functional food.¹⁰ Then, it was confirmed that BL-99 could maintain intestinal health by reducing intestinal inflammation.¹¹ Moreover, recent studies suggested that BL-99 could utilize fructo-oligosaccharide (FOS) to regulate the composition and structure of gut microbiota in patients with constipation, thus promoting the production of short chain fatty acids (SCFAs).¹² Hence, a randomized parallel controlled trial will be performed to study the prolonged efficacy of BL-99 to improve FD symptoms and the underlying mechanism, and evaluate the impact of BL-99 on gastrointestinal microbiota after PPI therapy.

Severe high dose group: 2 g solid beverages containing 5 × 10¹⁰ CFU/day BL-99 and 10 mg PPI.

Sample Size Calculation:

Based on previous studies, the power for the primary outcome reached 80% (two-sided test, α = 0.05) with a sample size of 42 participants per group.¹³ This study assumed that the overall dropout rate would be 10-12% during the entire study period. To account for probable follow-up loss, 50 study participants per group were recruited.

Inclusion Criteria:

(1) Aged 18-60 years;

(2) the Roman IV diagnosis standard: one or more of the following symptoms, namely, postprandial fullness, early enough, epigastric pain, epigastric burning sensation, postprandial nausea or vomiting, belching and bloating gas, acid regurgitation, burning sensation, retrosternal pain or discomfort, such as the course more than 6 months, nearly three months of symptom onset;

(3) Willing to provide demographic information (age, weight, height, etc.);

(4) Be willing to and complete daily and weekly questionnaires on general health, intestinal function and gastrointestinal symptoms.

Exclusion Criteria:

(1) Indigestion caused by serious organic lesions (cardiovascular, liver, kidney, or hematopoietic) diseases and without Helicobacter pylori (H. pylori) infection (diagnosed by the C14-urea breath test);

(2) Pregnancy;

(3) Smokers and alcoholics;

(4) Take any medication for constipation or diarrhea;

(5) Currently taking any anti-inflammatory medication regularly;

(6) Usually eat fermented foods or probiotics (for example, kimchi, sauerkraut, fermented bean curd, tempeh, cheese);

(7) Received antibiotics in the past three months;

(8) A history of clinically significant diarrhea or C. diff infection in the past 3 months.

Group and intervention:

Mild placebo group: the placebo contained 2 g maltodextrin.

Mild low dose group: 2 g solid beverages containing 1 × 10¹⁰ CFU/day BL-99.

Mild high dose group: 2 g solid beverages containing 5 × 10¹⁰CFU/day BL-99.

Severe placebo group: 10 mg proton pump inhibitors (PPI).

Severe low dose group: 2 g solid beverages containing 1 × 10¹⁰ CFU/day BL-99 and 10 mg PPI.

After a 2-week run-in period, the participants underwent a 4 and 8-week intervention period; and a 2-week follow-up period and a 6-week questionnaire survey.

The prolonged efficacy of BL-99 to improve FD symptoms and the underlying mechanism will be explored. Moreover, the impact of BL-99 on gastrointestinal microbiota after PPI therapy will be evaluated.

1. Tack, J. & Talley, N. J. Functional dyspepsia--symptoms, definitions and validity of the Rome III criteria. Nat. Rev. Gastroenterol. Hepatol. 10, 134-141 (2013).

2. Ford, A. C., Forman, D., Bailey, A. G., Axon, A. T. & Moayyedi, P. Effect of dyspepsia on survival: a longitudinal 10-year follow-up study. Am. J. Gastroenterol. 107, 912-921 (2012).

3. Lacy B E, Weiser K T, Kennedy A T, et al. Functional dyspepsia: the economic impact to patients[J]. Aliment Pharmacol Ther, 38, 170-177 (2013).

4.Talley, N. J., Ford, A. C., Longo, D. L. & Longo, D. L. Functional dyspepsia. N. Engl. J. Med. 373, 1853-1863 (2015).

5.Camilleri, M. & Stanghellini, V. Current management strategies and emerging treatments for functional dyspepsia. Nat Rev Gastroenterol Hepatol. 10, 187-194 (2013).

6. Agah S, Akbari A, Heshmati J, et al. Systematic review with meta-analysis: Effects of

probiotic supplementation on symptoms in functional dyspepsia. J Funct Foods, 68:103902

(2020).

7. Nakae H, Tsuda A, Matsuoka T, et al. Gastric microbiota in the functional dyspepsia patients

treated with probiotic yogurt. BMJ Open Gastroenterol, 3, e109 (2016).

8. Sun E, Zhang X, Zhao Y, et al. Beverages containing Lactobacillus paracasei LC-37

improved functional dyspepsia through regulation of the intestinal microbiota and their metabolites. J Dairy Sci, 104, 6389-6398 (2021).

9. Khoder G, Al-Yassir F, Al Menhali A, et al. Probiotics upregulate trefoil factors and

downregulate pepsinogen in the mouse Stomach. Int J Mol Sci, 20, 3901 (2019).

10. Lu, H. et al. Safety evaluation of Bifidobacterium lactis BL-99 and Lacticaseibacillus paracasei K56 and ET-22 in vitro and in vivo. Front. Microbiol. 12, 686541 (2021).

11.Chen, M. et al. Bifidobacterium lactis BL-99 modulates intestinal inflammation and

functions in zebrafish models. Plos One. 17, e262942 (2022).

12. Zhang, Q. et al. In vitrostudy of Bifidobacterium lactis BL-99 with fructooligosaccharide

synbiotics effected on the intestinal microbiota. Front. Nutr. 9, 890316 (2022).

13. Wauters, L. et al. Efficacy and safety of spore-forming probiotics in the treatment of functional dyspepsia: a pilot randomised, double-blind, placebo-controlled trial. Lancet Gastroenterol. Hepatol. 6, 784-792 (2021).

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Clinical study on Bifidobacterium lactis BL-99 assisting to improve functional dyspepsia

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Clinical study on Bifidobacterium lactis BL-99 assisting to improve functional dyspepsia

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Anticipated Results

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