Song
Lin
ab,
Shanliang
Zhao
c,
Jiahong
Liu
d,
Jianwen
Zhang
a,
Chao
Zhang
a,
Haibo
Hao
a,
Yuxia
Sun
a,
Jing
Cai
a,
Yang
Yang
a,
Yan
Ma
a,
Yuanyuan
Li
a,
Jinyu
Wang
a and
Aiguo
Ma
*a
aThe College of Public Health, Qingdao University, 38 Dengzhou Road, Qingdao, 266021, Shandong province, China. E-mail: magfood@qdu.edu.cn; Fax: +86 532 83812434; Tel: +86 532 82991518
bDepartment of Medical Epidemiology and Biostatistics, Karolinska Institutet, Nobels Väg 12A, 171 77 Stockholm, Sweden
cLinyi People's Hospital East Branch, 27 Jiefang East Road, Lanshan District of Linyi 276000, Shandong province, China
dThe Qingdao Central Hospital, 127 Siliu South Road, Qingdao 266000, Shandong province, China
First published on 19th November 2019
Anti-tuberculosis (TB) drugs can induce a series of gastrointestinal adverse events, which can seriously affect patients’ quality of life and may lead to treatment failure. Studies have shown that probiotics treatments can improve antibiotic-induced gastrointestinal symptoms. In this randomized, open-label, dose–response clinical trial, we investigated the preventive effects of Lactobacillus casei on anti-TB-induced gastrointestinal adverse events. In total, 429 adult patients who underwent intensive-phase anti-TB therapy were included and randomly assigned to consume one bottle of L. casei of per day (low-dose group, n = 142), two bottles of L. casei per day (high-dose group, n = 143), or no intervention (control group, n = 144) for 2 months. Each bottle of L. casei contained 10 billion colony-forming units of live L. casei. Patients’ daily gastrointestinal symptoms were recorded during the intervention period. After 2 months of L. casei consumption, 397 patients had completed the intervention. Both the high and low dose L. casei groups (37.6% and 29.4%, respectively) had lower incidences of anti-TB-associated total gastrointestinal adverse events than the control group (50.0%). The high and low dose L. casei groups (3.5 d and 5.8 d, respectively) also had shorter duration anti-TB-associated adverse gastrointestinal symptoms than the control group (6.2 d). Regarding individual symptoms, the higher L. casei dose resulted in a lower incidence of vomiting and appetite loss. Similar dose-dependent protective effects of L. casei were observed regarding the duration of vomiting and appetite loss. These findings indicated that daily L. casei consumption prevented anti-TB-associated gastrointestinal adverse events. This trial was registered at the Chinese Clinical Trial Register (ChiCTR-IOR-17013210).
Currently, the effective treatment for cases of drug-susceptible TB is a 6–8 month regimen of first-line drugs (e.g. isoniazid, rifampicin, ethambutol, and pyrazinamide) and second-line drugs (e.g. ofloxacin and moxifloxacin); an anti-TB treatment plan requires four drugs in combination during the intensive phase, while the continuation phase includes at least two anti-TB drugs.3 The long-term standardized treatment with anti-TB drugs has played a positive role in the control of the TB epidemic, but there are often many drug-related adverse reactions, such as adverse digestive system reactions, nervous system damage, allergic reactions, and blood system abnormalities.4 The main adverse reactions of the digestive system include adverse gastrointestinal reactions and liver disorders, which often occur during the 2 months of the intensive phase after the start of treatment.5,6 Anti-TB-associated adverse gastrointestinal reactions often manifest as nausea, vomiting, loss of appetite, diarrhea, and abdominal pain.7 The incidence of anti-TB-induced adverse gastrointestinal reactions has been reported to be as high as 11.7%, 23.7%, and 39.8% in young (15–30-years-old), middle-aged (30–60-years-old), and elderly (>60-years-old) Chinese patients, respectively.8 Symptomatic treatments (e.g. antiemetics and antidiarrheals) can alleviate these adverse reactions to a certain extent; however, they still cannot efficiently reduce the incidence and severity of adverse reactions, causing some patients to have to reduce the dose or interrupt anti-TB treatments.9 Therefore, it would be helpful to explore food or dietary supplements that could prevent anti-TB-induced adverse digestive system reactions.
Probiotics are microorganisms that confer a health benefit to the host when properly consumed. Meta-analyses of randomized controlled trials have shown that consumption of probiotics can influence mineral metabolism,10,11 glycolipid metabolism,12,13 and blood pressure.14,15 Furthermore, increased dietary intake of probiotics can improve gastrointestinal dysfunction symptoms caused by the extensive use of antibiotics. Two meta-analyses of randomized controlled trials reported that probiotics administration reduced the incidence of antibiotic-associated diarrhea.16,17 A meta-analysis has also shown that a single-agent Lactobacillus regimen can reduce the risk of developing antibiotic-associated diarrhea in adults, but not pediatric patients, compared with placebo.18 Hickson et al.,19 reported that consumption of a probiotic drink containing Lactobacillus casei, Lactobacillus bulgaricus, and Streptococcus thermophilus can reduce the incidence of antibiotic-associated diarrhea and Clostridium difficile-associated diarrhea.
An extensive literature search showed that no study has focused on the effects of probiotics for preventing the adverse gastrointestinal reactions of anti-TB treatment. Considering probiotics have been shown to have positive effects on gut physiology and intestinal barrier integrity, and to improve immune function,18,20 we hypothesized that L. casei could reduce the risk of anti-TB-associated adverse gastrointestinal reactions. Therefore, this study assessed the effect of L. casei on anti-TB-associated adverse gastrointestinal reactions, including nausea, vomiting, diarrhea, flatulence, loss of appetite, and constipation, during the intensive phase of treatment.
Pulmonary TB was diagnosed by positive sputum culture-based tests according to the Chinese Guidelines.21 Women were excluded if they were pregnant or lactating. Additionally, patients were excluded for the following reasons: extra-pulmonary TB, diabetes mellitus, cardiovascular diseases, hematopoietic system diseases, gastrointestinal diseases, hepatitis B virus infection, hepatitis C virus infection, fatty liver disease, elevated liver enzymes, receiving hepatotoxic drugs other than anti-TB therapy, diagnosed with malignancy, severe mental illness, and probiotic supplementation within the previous 2 months. This study was approved by the Ethical Committee of the Qingdao City Center for Disease Control (201703) and Prevention and was performed in accordance with the Declaration of Helsinki. Before enrollment in the study, patients who agreed to participate signed an informed consent form.
The L. casei preparation was produced by Yakult Honsha Co., Ltd (Tokyo, Japan) in a sponsorship model. The L. casei preparations were in a liquid form and contained the L. casei Shirota strain, filtered water, skimmed milk, glucose, and fructose. Per 100 mL, these L. casei preparations provided approximately 10 billion CFU of L. casei Shirota, 66 kcal of energy, 1.2 g protein, and 15.7 g carbohydrate. All L. casei preparations were distributed to the participants twice per month. Participants were asked to avoid consuming any other products containing probiotic strains and to abstain from tobacco and alcohol products throughout the trial. Because L. casei is sensitive to the acidic environment of stomach, participants were asked to consume L. casei between 30–60 min after meals. Participants were asked to shake the bottles for resuspension before consumption.
Based on the Chinese Guidelines,22 all participants received intensive-phase anti-TB therapy comprising isoniazid, rifampicin, pyrazinamide, and ethambutol in addition to study interventions; after completing 2 months of treatment, participants were discharged from the study and continuation-phase anti-TB therapy was initiated.
The primary outcome of this study was intergroup differences in the incidence of total gastrointestinal adverse events based on the Rome III criteria.23 Secondary outcomes were intergroup differences in the incidence and duration of individual gastrointestinal adverse events (nausea, vomiting, diarrhea, flatulence, appetite, constipation). The duration of gastrointestinal adverse events was determined by the number of continuous days of these symptoms. Patient diaries recorded episodes of gastrointestinal adverse events.
Statistical analyses were conducted with IBM SPSS Statistics software, version 23.0 (IBM Corporation, Armonk, NY, USA) and Stata 15.1 (StataCorp, College Station, TX, USA). All tests for significance were performed at α = 0.05 (two-sided). The baseline comparability of the treatment groups for subject characteristics was assessed with the ANOVA or χ2 tests, when applicable. Intergroup analysis to assess the percentages for each gastrointestinal symptom at the end of follow-up was performed using the χ2 test, Fisher's exact test, or Wilcoxon-type trend test, when applicable. Intergroup analysis to assess the duration of each gastrointestinal symptom at the end of follow-up was conducted using the Kruskal–Wallis H test or Wilcoxon-type test, when applicable.
Characteristic | Group A (n = 132) | Group B (n = 143) | Control (n = 144) | p |
---|---|---|---|---|
Data are % (n) or mean (SD), unless otherwise stated. BMI: body mass index; WBC, white blood cell. Group A, anti-tuberculosis drugs plus 1 × 1010 colony-forming units of L. casei; group B: anti-tuberculosis drugs plus 2 × 1010 colony-forming units of L. casei; control, anti-tuberculosis drugs. | ||||
Age (years) | 37.21 ± 14.48 | 36.20 ± 15.05 | 39.15 ± 16.49 | 0.256 |
Men | 59.8% (79/132) | 56.6% (81/143) | 64.6% (93/143) | 0.384 |
Height (m) | 1.70 ± 0.07 | 1.70 ± 0.07 | 1.69 ± 0.06 | 0.428 |
Weight (kg) | 61.94 ± 9.68 | 59.77 ± 10.41 | 59.42 ± 10.23 | 0.086 |
BMI (kg m−2) | 21.46 ± 2.83 | 20.71 ± 2.79 | 20.79 ± 2.93 | 0.058 |
Marital status | 0.597 | |||
Single | 32.6% (43/132) | 35.0% (50/143) | 31.2% (45/144) | |
Married | 65.9% (87/132) | 64.3% (92/143) | 68.1% (98/144) | |
Widowed/divorced | 1.5% (2/132) | 0.7% (1/143) | 0.7% (1/144) |
Group A (n = 126) | Group B (n = 133) | Control (n = 138) | p | |
---|---|---|---|---|
Data are % (n). GAE, gastrointestinal adverse events. Group A, anti-tuberculosis drugs plus 1 × 1010 colony-forming units of L. casei; group B: anti-tuberculosis drugs plus 2 × 1010 colony-forming units of L. casei; control, anti-tuberculosis drugs.a Non-parametric Wilcoxon-type trend test. | ||||
GAE | 29.4% (37/126) | 37.6% (50/133) | 50.0% (69/138) | 0.034 |
Nausea | 9.5% (12/126) | 12.8% (17/133) | 12.3% (17/138) | 0.913 |
Vomiting | 1.6% (2/126) | 0 (0/133) | 4.3% (6/138) | 0.011 |
Diarrhea | 4.0% (5/126) | 5.3% (7/133) | 5.1% (7/138) | 0.946 |
Flatulence | 1.6% (2/126) | 2.3% (3/133) | 1.4% (2/138) | 0.616 |
Appetite loss | 7.9% (10/126) | 3.8% (5/133) | 13.8% (19/138) | 0.003 |
Constipation | 15.1% (19/126) | 20.3% (27/133) | 26.1% (36/138) | 0.232 |
Group A (n = 126) | Group B (n = 133) | Control (n = 138) | p | |
---|---|---|---|---|
Data are median (min–max). GAE, gastrointestinal adverse events. Group A, anti-tuberculosis drugs plus 1 × 1010 colony-forming units of L. casei; group B: anti-tuberculosis drugs plus 2 × 1010 colony-forming units of L. casei; control, anti-tuberculosis drugs.a Kruskal–Wallis H test.b One patient in group A do not record the continuous days of diarrhea. | ||||
GAE | 0 (0–135) | 0 (0–40) | 0.5 (0–180) | 0.005 |
Nausea | 0 (0–60) | 0 (0–30) | 0 (0–20) | 0.762 |
Vomiting | 0 (0–30) | 0 (0–0) | 0 (0–3) | 0.037 |
Diarrheab | 0 (0–15) | 0 (0–10) | 0 (0–6) | 0.899 |
Flatulence | 0 (0–15) | 0 (0–30) | 0 (0–60) | 0.871 |
Appetite loss | 0 (0–60) | 0 (0–20) | 0 (0–20) | 0.013 |
Constipation | 0 (0–60) | 0 (0–20) | 0 (0–60) | 0.040 |
0 daya | 1–7 days | 8–30 days | 31–60 days | p for trendb | |
---|---|---|---|---|---|
Data are % (n). Group A, anti-tuberculosis drugs plus 1 × 1010 colony-forming units of L. casei; group B: anti-tuberculosis drugs plus 2 × 1010 colony-forming units of L. casei; control, anti-tuberculosis drugs.a Duration of gastrointestinal symptoms throughout the trial period was classified into four groups (0 day, 1–7 days, 8–30 days and 31–60 days).b Wilcoxon-type test.c One patient in group A do not record the duration of diarrhea. | |||||
Nausea | 0.848 | ||||
Control (n = 138) | 87.7% (121/138) | 10.9% (15/138) | 1.5% (2/138) | 0 | |
Group A (n = 126) | 90.4% (114/126) | 4.0% (5/126) | 3.2% (4/126) | 2.4% (3/126) | |
Group B (n = 133) | 87.2% (116/133) | 8.3% (11/133) | 4.5% (6/133) | 0 | |
Vomit | 0.011 | ||||
Control (n = 138) | 95.7% (132/138) | 4.3% (6/138) | 0 | 0 | |
Group A (n = 126) | 98.4% (124/126) | 0.7% (1/126) | 0.7% (1/126) | 0 | |
Group B (n = 133) | 100% (133/133) | 0 | 0 | 0 | |
Diarrhea | 0.935 | ||||
Control (n = 138) | 94.9% (131/138) | 5.1% (7/138) | 0 | 0 | |
Group A (n = 125)c | 96.0% (120/125) | 1.6% (2/125) | 2.4% (3/125) | 0 | |
Group B (n = 133) | 94.7% (126/133) | 4.5% (6/133) | 0.8% (1/133) | 0 | |
Flatulence | 0.626 | ||||
Control (n = 138) | 98.6% (136/138) | 0 | 0.7% (1/138) | 0.7% (1/138) | |
Group A (n = 126) | 98.4% (124/126) | 0 | 1.6% (2/126) | 0 | |
Group B (n = 133) | 97.7% (130/133) | 0.8% (1/133) | 1.5% (2/133) | 0 | |
Appetite loss | 0.004 | ||||
Control (n = 138) | 86.2% (119/138) | 10.2% (14/138) | 3.6% (5/138) | 0 | |
Group A (n = 126) | 92.0% (116/126) | 3.2% (4/126) | 2.4% (3/126) | 2.4% (3/126) | |
Group B (n = 133) | 96.2% (128/133) | 3.0% (4/133) | 0.8% (1/133) | 0 | |
Constipation | 0.181 | ||||
Control (n = 138) | 73.9% (102/138) | 13.8% (19/138) | 11.6% (16/138) | 0.7% (1/138) | |
Group A (n = 126) | 84.9% (107/126) | 11.9% (15/126) | 2.4% (3/126) | 0.8% (1/126) | |
Group B (n = 133) | 79.7% (106/133) | 13.5% (18/133) | 6.8% (9/133) | 0 |
To the best of our knowledge, this is the first study to investigate the preventive effect of a probiotic strain on anti-TB-associated gastrointestinal adverse events. Previous studies have primarily investigated the effects of probiotics on systemic antibiotics-induced adverse gastrointestinal reactions, especially diarrhea.25,26 Multiple studies have shown a positive effect of L. casei on antibiotics-induced gastrointestinal symptoms. Beausoleil et al.27 reported that patients taking a fermented milk containing Lactobacillus acidophilus and L. casei had a 15.9% antibiotics-associated diarrhea incidence compared with 35.6% in the placebo group. Gao et al.28 reported a dose–response effect, in which patients treated with probiotics capsules containing 100 billion CFU of live organisms (Lactobacillus acidophilus CL1285, L. casei LBC80R Bio-K, and CL1285) showed reduced antibiotics-associated and Clostridium difficile-associated gastrointestinal events (diarrhea, abdominal pain, flatulence, loose stool, and constipation), compared with those taking a 50 billion CFU capsule or the placebo group. While these studies always reported the effects of a mixture of probiotic strains and could not interpret whether these positive effects were caused by synergistic interactions between strains or due to the high dose of individual probiotic species used, in this study, our results showed the efficacy of a specific single strain of L. casei Shirota on preventing anti-TB-associated adverse gastrointestinal reactions. Similarly, Koebnick et al.29 studied the effect of L. casei Shirota on patients with symptoms of chronic constipation and showed a significant decrease of gastrointestinal symptoms compared with placebo (89% vs. 56%).
Our study showed that the positive effect of L. casei on anti-TB-associated adverse gastrointestinal reactions was focused on vomiting and appetite loss. Gastric intolerance frequently occurs with anti-TB treatment, especially pyrazinamide.30 Namasivayam et al.,31 recently reported a distinct and long-lasting dysbiosis due to anti-TB therapy and identified rifampin as the major driver in M. tuberculosis-infected mice. Fetissov et al.32 reported that the gut microbiota might regulate host appetite via directly activating central appetite pathways (e.g. ATP/AMP ratio) or modulating intestinal release of satiety hormones (e.g. peptide tyrosine tyrosine and ghrelin). Furthermore, gut microbiota might play an important role in regulating intestinal bile acids and serotonin metabolism, which could contribute to the association between gut microbiota and gastrointestinal motility.33 Therefore, we speculated that dysbiosis could be a cause of anti-TB-associated loss of appetite and vomiting. Our results showed dose–response protective effects of L. casei on anti-TB-associated vomiting and appetite loss, which indicated that these positive effects might be partly attributed to the higher doses of L. casei used. The higher L. casei load likely adequately overwhelms the gastrointestinal tract and protects the gastrointestinal mucosa, in addition to shifting immune responses against other antigens.27
TB | Tuberculosis |
Lactobacillus casei | L. casei |
Colony-forming unites | CFU |
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