Efficacy of herbal medicine (Thatbunjob) in the treatment of foodborne illness: A placebo-controlled, randomized trial

Abstract

Background

Foodborne illness (FI) causes 600 million cases and 420,000 deaths annually. Current treatments focus on rehydration and antispasmodic medications for managing dehydration and abdominal pain (AP). However, alternative therapies, especially those derived from natural ingredients, are needed. This study investigates the potential efficacy of herbal medicine,Thatbunjob as a complementary therapy for FI-related AP.

Methods

A double-blind, randomized, placebo-controlled clinical trial assessed the efficacy of Thatbunjob in relieving AP in FI patients. A total of 114 patients, aged 18–60, with AP and diarrhea (≥3 episodes in 24 h), received either two 500 mg capsules of Thatbunjob or a placebo three times daily for three days. Both groups also received standard oral rehydration therapy. Primary outcomes included AP intensity using a visual analog scale (VAS) at 24 h, while secondary outcomes included pain at 48 and 72 h, responder rates, hyoscine butyl bromide usage, stool frequency, and adverse events.

Results

The Thatbunjob group showed significantly greater reduction in AP compared to the placebo. VAS scores decreased from 5.69 to 2.95 at 24 h (P < 0.001), and pain relief persisted at 48 (1.43 vs. 3.05, P < 0.001) and 72 h (0.32 vs. 1.86, P < 0.001). Thatbunjob also reduced the need for hyoscine tablets and decreased stool frequency compared to placebo.

Conclusion

This study demonstrates that Thatbunjob, when combined with standard rehydration therapy, effectively alleviates AP and reduces stool frequency in FI patients.

Trial registration

Thai Clinical Trials Registry, TCTR20220823001.

1. Introduction

Foodborne illness (FI) is a sickness caused by ingesting foods or beverages contaminated by infectious or noninfectious agents. It is a widespread issue globally, leading to 600 million cases and 420,000 deaths each year worldwide. It is not only a primary problem in developing countries, but also affects developed nations.¹

Medicinal herbs and plants have long been acknowledged as a valuable source of therapeutic agents, assuming a central role in healthcare systems across the globe.2, 3, 4 In Thailand, the Thai Ministry of Public Health advocates for the utilization of medicinal plants listed in the Thai National List of Essential Medicines.⁵ However, it is crucial to recognize that only a limited number of herbal medicine formulations have undergone in-depth evaluations of their biological activities and efficacy, which are closely linked to the properties indicated on the drug label.

Thatbunjob is a Thai herbal formula included in the National Essential Medicines List, and it has been empirically employed over an extended period to address gastrointestinal disorders, particularly non-infectious diarrhea and indigestion.⁶ Thatbunjob represents a distinctive amalgamation of diverse herbal plants, meticulously combined in precise proportions to yield a potent medicinal product.

Previous studies have found that Thatbunjob and its constituents demonstrate anti-inflammatory and carminative properties, suggesting potential benefits for gastrointestinal discomfort.⁷ These properties are particularly relevant in the context of FI, where inflammation and gastrointestinal distress, including abdominal pain (AP), are common symptoms. Thatbunjob had shown anti-inflammatory effects and decreased bacterial diarrhea.⁸ However, the application of Thatbunjob specifically to FI remains underexplored, with insufficient evidence regarding its efficacy in alleviating AP in patients with FI. Thus, we aim to address and bridge this gap by performing a randomized, double-blinded, placebo-controlled clinical trial to evaluate the efficacy and safety of Thatbunjob in the reduction of AP in patients with FI.

2. Methods

2.1. Trial design and registration

This study is a randomized, double-blinded, and placebo-controlled trial. Furthermore, this study was duly registered in the Thai Clinical Trials Registry under the reference TCTR20220823001. No changes occurred to methods after trial commencement.

2.2. Participants

The study participants were male and female patients, aged between 18 and 60 years, with symptoms of AP and watery diarrhea of more than three occasions within a 24-hour period, either with or without additional symptoms such as nausea, vomiting, and fever. They were diagnosed with FI by a general practicing physician in the outpatient department clinic of Thammasat University Hospital in Pathum Thani, Thailand, from August 2022 to May 2023. All participants included in the study had an AP intensity using visual analog scale (VAS) of 4 or greater at baseline. Each patient received a thorough explanation of the study's objectives and informed written consent was obtained before participation.

The exclusion criteria for the study encompassed individuals meeting any of the following conditions: (1) presence of bloody diarrhea (2) body temperature equal to or exceeding 38.5°C (3) a history of herbal allergies (4) currently taking anticoagulant and antiplatelet drugs since this is a contraindication provided in the Thai National List of Essential Medicines (5) liver cirrhosis or stage 4 chronic kidney disease (6) pregnancy, lactation, or testing positive on a urine pregnancy test (7) inability to attend follow-up appointments. The withdrawal criteria for this research project are as follows: (1) taking anticoagulant and antiplatelet medications during their involvement in the research (2) exhibiting symptoms of easy bleeding (3) taking other medications that may be associated with stomach cramping (4) exhibit symptoms of herb allergy following treatment. (5) unable to attend follow-up appointments. (6) express a desire to discontinue their participation in the research project.

2.3. Interventions

Participants were allocated to two distinct groups: the intervention group and the placebo group. The intervention group received 1000 mg of Thatbunjob powder, administered in the form of two 500-mg capsules, thrice daily, with a 30-minute interval before each meal. Conversely, the placebo group was administered 2 tablets of 500 mg of placebo capsules, thrice daily, with a 30-minute gap before each meal. This treatment regimen spanned a duration of 3 days. In both groups, participants were additionally provided with an oral rehydration solution as part of the standard protocol. Both groups of participants were provided with a total of 10 hyoscine butyl bromide tablets, intended for consumption whether they experienced intolerable AP, and could be repeated every 6 h. The participants had their symptoms measured at baseline, after 24, 48, and 72 h after the hospital presentation.

2.4. Preparation of herbal medicine

Plant materials were procured for the study and deposited at the Thai Traditional Medicine Herbarium, Thai Traditional and Alternative Medicine Department, Nonthaburi Province, Thailand. The formulation incorporates the fruits of Terminalia chebula Retz., Amomum testaceum Ridl., Coriandrum sativum L., Piper retrofractum Vahl., Pimpinella anisum L., and Trachyspermum ammi (L.) Sprague. Furthermore, it includes the rhizomes of Picrorrhiza kurroa Benth, Zingiber officinale Roscoe, Kaempferia galanga L, and Atractylodes lancea (Thunb.) DC., as well as the roots of Angelica sinensis (Oliv.) Diels. Both the roots and rhizomes of Angelica dahurica (Hoffm.) Benth. & Hook.f. ex Franch. & Sav., the seeds of Nigella sativa L., Cuminum cyminum L., and Lepidium sativum L., along with the seeds and arils of Myristica fragrans Houtt. Additionally, the galls of T. chebula, the bark of Cinnamomum bejolghota (Buch. -Ham.), the flowers of Syzygium aromaticum (L.) Merr. & L.M. Perry, and the aril parts of Pogostemon cablin (Blanco) Benth. complete the composition of this herbal product (Supplement Table S1). The plant materials were ground to obtain fine particles, and their quality was assessed per the raw material quality criteria outlined in Thailand's National List of Essential Medicines 2018. Parameters such as loss on drying, extractive value, total ash, acid insoluble ash, and heavy metal determination by atomic absorption spectrophotometry were examined. Once the raw materials met the necessary quality standards, the powdered material was sieved through a 60-mesh sieve. Subsequently, the crude powder was blended following the Thatbunjob formula and encapsulated. The resulting capsules were subjected to evaluation based on weight variation, disintegration time, microbial contamination (total bacterial count, total yeast and mold count), and the presence of specific bacteria like Escherichia coli, Clostridium spp., Salmonella spp., and bile-tolerant gram-negative bacteria or coliform bacteria. These parameters adhered to the standardized requirements for herbal capsules. Only the successful compliance of Thatbunjob capsules with all specified quality standards was used with patients.

All processes related to the standardization of the herbal medicine, including chemical fingerprint analysis and anti-foaming assays, are described in Supplement Table S2 and Supplement Figure S1-S2. The corresponding results are also presented in the supplement. Placebo capsules were made of cornstarch powder. Owing to the identical color, aroma, and dimensions of both the Thatbunjob powder and the placebo capsules, a state of blinding was maintained, effectively concealing the group allocation from participants, researchers, and the personnel at the clinic.

2.5. Outcome measures

The primary outcome measure in this trial was the change in AP intensity, as assessed by VAS at 24 h after hospital presentation. Secondary outcome measures included changes in AP at 48 and 72 h, percentage of responders, hyoscine butyl bromide requirement, stool frequency, observed adverse events, and quality of life measure by World Health Organization Quality of Life scale - brief, Thai version (WHOQOL-BREF-THAI).⁹ We evaluated the efficacy of Thatbunjob herbal formula on the number of hyoscine butyl bromide tablets used as rescue therapy at 24, 48, and 72 h after hospital presentation. We also evaluate the number of responders, defined as an individual whose AP intensity on VAS demonstrate a reduction of a minimum of 2 levels when compared to the scales from the preceding period.¹⁰

2.6. Sample size

The sample size was determined using STATA software (StataCorp LLC, College Station, TX, USA), guided by the pain score results obtained from a previously unpublished study titled "Treatment of irritable bowel syndrome with Thatbunjob, a Thai polyherbal formula: results of a double-blind, randomized, placebo-controlled trial". The statistical analysis employed a significance level (alpha) of 0.05, signifying the chosen level of significance for this study. With a desired statistical power of 0.8, the initial calculation indicated a sample size of 51 participants per group. To account for a potential dropout rate of 10 %, the final sample size was adjusted, resulting in the inclusion of 57 patients in each group.

2.7. Safety assessment

To identify adverse outcomes and address potential concerns, continuous follow-up was conducted with all patients at 24-hour intervals throughout the entire treatment duration. Patients were specifically prompted to report any observed drug-related side effects.

2.8. Randomization and blinding

One hundred and fourteen patients were randomized to two parallel arms. The randomization process was executed by an impartial researcher who utilized the Research Randomizer, a freely available online tool.¹¹ The sealed envelopes containing the randomized allocation sequences were securely stored in a location inaccessible until the study's completion. The Thatbunjob and placebo capsules had the same color and size, and blinding with the drug code T001-T114 ensured that neither the researcher nor the participants were informed about the treatment types.

2.9. Ethical consideration

The trial was adhered to the Declaration of Helsinki and followed the guidelines for good clinical practice. The Human Research Ethics Committee of Thammasat University (Medicine) in Pathum Thani, Thailand, granted approval for the protocol under the reference MTU-EC-TM-6–030/65. All of the participants signed an informed consent form before enrollment in the trial.

2.10. Statistical analysis

The data analysis was conducted using the Statistical Package for the Social Sciences (SPSS) software, version 26, developed by SPSS, Inc. in Chicago, USA. The comparison of categorical variables among different groups was accomplished using the Chi-square test. To assess the normality of the data, the One-Sample Kolmogorov-Smirnov Test was applied. If the data followed a normal distribution, a T-test was used for comparisons within groups (Paired sample T-test) and between groups (Independent T-test). If the data did not follow a normal distribution, the Mann-Whitney U test was used instead. Descriptive statistics for quantitative variables were presented as means ± standard error of the mean (SEM), while qualitative variables were expressed as counts and percentages. Statistical significance was defined as a P-value <0.05. Regarding handling missing data, since the study accounted for potential dropout by increasing the sample size by 10 %, missing data <10 % was managed using Complete Case Analysis (CCA). If >10 % of data was missing, Multiple Imputation was employed. Outlier data points were retained in the analysis as they reflect natural statistical variability within the target population, rather than errors in data collection. By including these outliers, we ensure that the analysis accurately represents the true variability in the sample and maintains the generalizability of the findings.

3. Results

3.1. Patients’ enrollment

From August 2022 to May 2023, a total of 114 eligible participants were initially enrolled from the outpatient department at Thammasat University Hospital. Ultimately, 109 subjects (Thatbunjob group = 55, placebo group = 54) successfully completed the clinical trial (Fig. 1). Two participants in the Thatbunjob group and three in the placebo group were excluded from the trial due to non-compliance with the prescribed research drug regimen, as they failed to adhere to the medication schedule for one or more consecutive meals.

Fig. 1.

Consolidated standards of reporting trials (CONSORT) flow diagram.

3.2. Baseline clinical characteristics

The baseline characteristics of the subjects indicated no statistically significant differences in terms of sex distribution (22 males and 33 females in the Thatbunjob group vs. 20 males and 34 females in the placebo group; P-value = 0.775) and mean age (31.56 ± 8.64 years in the Thatbunjob group vs. 34.24 ± 10.83 years in the placebo group; P-value = 0.511). The pre-intervention baseline AP and stool frequency between the Thatbunjob and placebo groups also showed no statistically significant differences.

3.3. Main outcomes

The Thatbunjob group consistently had significantly lower AP intensity scores at 24-, 48-, and 72-hours post-treatment compared to the placebo group (Table 1, P < 0.001). By 24 h, a significantly higher proportion of responders was observed in the Thatbunjob group (52.7 %) compared to the placebo group (9.3 %) (Table 2, P < 0.001). In the initial 24-hour, a higher percentage of placebo participants (44.4 %) required a single hyoscine butyl bromide tablet to manage pain, while only 16.4 % in the Thatbunjob group did (P < 0.001). Additionally, the placebo group had a higher need for up to three hyoscine tablets per day, with 3.7 % requiring this in the first 24 h and 1.9 % in the second 24 h, whereas no participants in the Thatbunjob group required this regimen (Table 2). As shown in Table 2, patients in the Thatbunjob group had significantly lower stool frequency between 24–48 h post-treatment compared to those in the placebo group.

Table 1.

Comparison of abdominal pain and responders' rate between Thatbunjob and placebo groups.

	Thatbunjob (n = 55)	Placebo (n = 54)	P†
Abdominal pain* (VAS score*)
0 hr	5.69 ± 1.18	5.46 ± 1.14	0.312
24 hr	2.95 ± 1.41‡	4.17 ± 1.18‡	<0.001
48 hr	1.43 ± 1.23‡	3.05 ± 1.36‡	<0.001
72 hr	0.32 ± 0.72‡	1.86 ± 1.45‡	<0.001
Responders rate*
0 – 24 hr	29 (52.7)	5 (9.3)	<0.001
24 – 48 hr	8 (14.5)	3 (5.6)	0.12
48 – 72 hr	7 (12.7)	9 (16.7)	0.56

^⁎Abdominal pain is presented as mean ± standard deviation (SD), and responder rates are expressed as N (%).

^‡P < 0.01: values compared with baseline value (0).

^†P-values were based on t-test for abdominal pain and Chi-test for responders' rate.

The responders rate, considered a clinically meaningful outcome measure, was defined as the proportion of participants whose VAS scores decreased by a minimum of two points from the previous assessment, expressed as a percentage of the total study population. VAS, visual analogue scale.

Table 2.

Comparison of hyoscine butyl bromide requirements and stool frequency between Thatbunjob and placebo Groups.

Duration of treatment	No. of tablet or frequency	Thatbunjob (n = 55)	Placebo (n = 54)	P (χ2−test)
Hyoscine butyl bromide requirement	No. of tablets
0 – 24 hr	0	45 (81.8)	23 (42.6)	<0.001
	1	9 (16.4)	24 (44.4)
	2	1 (1.8)	5 (9.3)
	3	0 (0)	2 (3.7)
24 – 48 hr	0	51 (92.7)	35 (64.8)	0.004
	1	4 (7.3)	16 (29.6)
	2	0 (0)	2 (3.7)
	3	0 (0)	1 (1.9)
48 – 72 hr	0	54 (98.2)	46 (85.2)	0.047
	1	1 (1.8)	7 (13)
	2	0 (0)	1 (1.9)
	3	0 (0)	0 (0)
Stool frequency	Frequency
0 hr	<3 times	0 (0)	0 (0)	0.566
	>3 times	55 (100)	54 (100)
0 – 24 hr	<3 times	8 (14.5)	8 (14.6)	0.649
	>3 times	47 (85.5)	46 (85.4)
24 – 48 hr	<3 times	23 (37.4)	14 (25.9)	0.039
	>3 times	32 (62.6)	40 (74.1)
48 – 72 hr	<3 times	37 (67.3)	29 (53.7)	0.065
	>3 times	28 (32.7)	25 (46.3)

Data are expressed as number of patients (percentage).

Finally, Supplement Table S3 reveals no significant differences in quality-of-life scores between the groups across physical, psychological, environmental, and social health dimensions.

3.4. Adverse effects

During the three-day clinical trial, participants reported adverse events. Notably, no adverse effects were observed within the Thatbunjob group. Conversely, in the placebo group, five patients reported experiencing bloating. It is crucial to highlight that subsequent to the intervention phase, no further adverse effects were observed in either group.

4. Discussion

4.1. Summary of main results

This randomized, double-blind, placebo-controlled trial demonstrated that Thatbunjob significantly reduced AP and diarrhea symptoms in patients with FI within 24 h, with improved outcomes observed up to 72 h. The intervention group showed a higher responder rate (53 %) compared to placebo (9 %) and required less rescue medication (hyoscine butyl bromide). Additionally, Thatbunjob effectively reduced stool frequency to fewer than three loose stools per day in most participants within 48 h, suggesting faster recovery and potential for earlier return to daily activities.

4.2. Agreement and disagreements with other studies or reviews

The results of this study relate to previous studies indicating the anti-inflammatory and antidiarrheal effects of the individual components of Thatbunjob, such as C. cyminum, T. chebula, Z. officinale, P. retrofractum, T. ammi, A. lancea, S. aromaticum, and A. dahurica. Previous research has shown the effectiveness of these herbs in treating diarrhea symptoms and suppressing cytokine-mediated intestinal inflammation in animal models.12, 13, 14, 15, 16, 17, 18 There is consistency with prior research indicating that Thatbunjob suppresses nitric oxide generation, a known inflammatory mediator.⁸ This study is one of the initial assessments of Thatbunjob as a combination herbal formula in a clinical FI population, providing new data supporting its synergistic effects and potential efficacy compared to individual herbs.

4.3. Potential mechanism of action of intervention

The therapeutic effects of Thatbunjob may be attributed to its multi-component composition, targeting several mechanisms relevant to FI. Z. officinale inhibits spasmogens in a dose-dependent manner, similar to hyoscine butyl bromide, indicating its potential in reducing cramping and AP.19, 20, 21 Polyphenolic compounds such as gallic acid, chebulagic acid, ellagic acid, and eugenol contribute anti-inflammatory and gastroprotective effects, supporting both symptom relief and mucosal healing.22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34

Furthermore, Thatbunjob demonstrated greater anti-foaming activity than Simethicone, which may be attributed to its volatile oil components, particularly terpene hydrocarbons—compounds commonly found in traditional carminative remedies.35, 36 These combined properties may contribute to the observed relief of gastrointestinal symptoms.

4.4. Implication for clinical practice and research

The results suggest Thatbunjob may serve as an effective adjunct to standard FI therapy, particularly in managing abdominal discomfort, bloating, and diarrhea. Its ability to reduce the need for pharmacological antispasmodics may enhance tolerability and safety in broader clinical settings. For clinical use, Thatbunjob could be considered in outpatient management protocols for mild-to-moderate FI. However, further research is needed to confirm these results across diverse populations, particularly through longer-term studies that evaluate sustained efficacy and safety over extended periods, as well as pragmatic trial designs that reflect real-world clinical settings, patient variability, and routine care practices. Additional mechanistic studies may help to better understand the interactions between herbal components and optimize dosing strategies.

4.5. Strength and weakness of this study. (or limitations of this study)

A key strength of this study is its rigorous methodological design, including randomization, blinding, and placebo control, which enhances the internal validity and reduces bias. The use of short-term clinical endpoints (24–72 h) aligns with the natural course of FI and provides relevant information for acute symptom management. However, the study's limitations include a relatively homogeneous patient population, as it exclusively enrolled adult patients with non-severe foodborne illness who were eligible for outpatient treatment, and a focus on short-term outcomes. The exclusion of more severe cases and limited evaluation of long-term safety and relapse risk may constrain generalizability. Future trials should aim to include broader populations and longer follow-up to comprehensively assess efficacy and safety.

In conclusion, the results of this randomized, double-blinded, and placebo-controlled study demonstrate that Thatbunjob effectively reduces AP and stool frequency in patients suffering from FI. The anti-foaming properties of Thatbunjob, as evaluated in this study, suggest its potential as a promising and versatile treatment option for bloating symptoms associated with FI.

Author contributions

Conceptualization: Patommatat Bhanthumkomol. Methodology: Patommatat Bhanthumkomol, Sumalee Panthong. Software: Intouch Sakpakdeejaroen. Validation: Intouch Sakpakdeejaroen. Sumalee Panthong. Formal Analysis: Patommatat Bhanthumkomol, Thanee Eiamsitrakoon. Investigation: Jaiboonya Jaicharoensub Resources: Patommatat Bhanthumkomol, Sumalee Panthong, Intouch Sakpakdeejaroen. Data Curation: Sumalee Panthong. Writing – Original Draft: Jaiboonya Jaicharoensub, Patommatat Bhanthumkomol. Writing – Review & Editing: Sumalee Panthong, Intouch Sakpakdeejaroen, Thanee Eiamsitrakoon. Visualization: Jaiboonya Jaicharoensub, Sumalee Panthong. Supervision: Patommatat Bhanthumkomol. Project Administration: Patommatat Bhanthumkomol, Sumalee Panthong. Funding Acquisition: Sumalee Panthong.

Declaration of competing interest

The authors declare that they have no competing interest.

Funding

This research was supported by The Thailand Science Research and Innovation Fundamental Fund fiscal year 2023.

Ethical statement

The trial was adhered to the Declaration of Helsinki and followed the guidelines for good clinical practice. The Human Research Ethics Committee of Thammasat University (Medicine) in Pathum Thani, Thailand, granted approval for the protocol under the reference MTU-EC-TM-6–030/65. Furthermore, this study was duly registered in the Thai Clinical Trials Registry under the reference TCTR20220823001. All the participants signed an informed consent form before enrollment in the trial.

Data availability

Data sharing is not applicable to this article as no new data were created or analyzed in this study.