Clinical Observations on the Effects of a Dietary Supplement (GI RegenerateTM) on Patients’ Gastrointestinal Symptoms and Quality of Life Assessments ()
1. Introduction
There is a rather large burden to the United States population of morbidity, mortality and cost due to gastrointestinal (GI), liver and pancreatic diseases and disorders [1] [2], and this appears to be true in other nations as well [3]. With its aging population, the United States faces an increasing prevalence of digestive diseases over time [2]. This is likely to result in an overall worsening of the productivity and quality of life (QOL) in the aging population [4] [5].
Different treatments have been developed and used to control symptoms and improve QOL in digestive diseases and disorders [6] [7]. Among the pharmaceutical treatments that are commonly used, such as corticosteroids, aminosalicylates, antibiotics and immunosuppressive drugs, improvements in symptoms have been found, but not in every patient, and often these improvements are not sustainable. Also, the drugs that are often prescribed can have adverse effects in some patients. Thus complementary or alternative medicine approaches have been used to avoid the adverse effects of drug treatments and improve treatment outcomes [6] [7].
Among the alternative medical approaches to the treatment of GI diseases and disorders is the use of herbal combinations, and this has proved beneficial for many patients [8] [9] [10]. There is a rich history that goes back thousands of years of using single and multiple herbal formulations to treat digestive diseases and disorders [8] [10]. In the United States, a large proportion of patients with digestive disorders have tried some form of herbal treatment [10] [11]. The most commonly used herbal treatments for digestive diseases and disorders in the US have their origin in traditional Chinese medicine [10].
One such combination of herbs and oils that has been used for years in China to treat digestive disorders has been utilized in the current study. This same combination dietary supplement has had different names (GIC, MEBO Gastrointestinal Capsule, Dr. Xu’s GI Formula, or more recently GI RegenerateTM), and it has been the subject of several scientific and clinical studies in China. These studies include: survival and growth promotion of intestinal and stomach epithelial cells [12] [13], clinical treatment studies on ulcerative colitis [14], gastroesophageal reflux disease [15], gastric ulcers [16], peptic ulcers [17], and repair of gastrointestinal damage due to ethanol [18] or infection [19].
Using a validated QOL questionnaire for functional digestive disorders [20] and patient global impression of change scores (PGIC) taken during exit interviews by contributing physicians this same dietary supplement formulation, or GI RegenerateTM, has been examined for its use in treating digestive disorders and symptoms in North American patients.
2. Materials and Methods
2.1. Materials
GI RegenerateTM is a patented natural supplement containing a mixture of herbal ingredients and edible oils. It contains stigmasterol, campesterol, beta-sitosterol, chalinosterol, clionasterol, brassicasterol, alpha-spinasterol, daucosterol, desmosterol, poriferasterol and an edible wax [21]. This base mixture was placed (250 mg each) into soft gel capsules. The natural dietary supplement used in the clinical study was provided by MEBO Life Sciences, Brea, California.
2.2. Methods
An open label, independent Institutional Review Board (IRB)-approved study was initiated using subjects recruited from Southern California with formally diagnosed digestive disorders and diseases, such as ulcerative colitis, gastritis, esophagitis, gastroesophageal reflux disease (GERD), Crohn’s disease, irritable bowel syndrome (IBS), or other digestive disorders. The study recruitment was limited to patients attending the Center for New Medicine, Irvine, California who volunteered for the study. The number of subjects was determined by the number of patients who volunteered and could be adequately scheduled, examined and treated by available staff during the trial period of January 2019 to January 2020.
The 40 females and 10 males recruited to the study presented with a variety of signs and symptoms related to digestive disorders (Table 1). Exclusionary criteria included subjects who were taking immunosuppressive drugs, or had cognitive impairment, or were pregnant, lactating or below the age of 18 years. Each subject was directed to take 5 capsules of GI RegenerateTM 30 min before meals 3X per day for the 90-day study period. Participants were advised not to change any of their daily medications, diet or routine during the study.
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Table 1. Diagnoses/symptoms of subjects in the clinical study.
*Subjects may have more than one diagnosis and have multiple symptoms. IBS, irritable bowel syndrome; GERD, gastroesophageal reflux disease.
Study subjects were monitored at various times using a validated patient questionnaire for functional digestive disorders and QOL (Appendix Figure 1 in reference [20]). The data were normalized to baseline and analyzed as: a) Overall Global Scores; and subsets of data were normalized to baseline and analyzed as: b) Daily Activities Scores, c) Symptom Discomfort Scores, d) Anxiety Scores, e) Diet Scores, f) Sleep Scores, g) Coping with Disease Scores, h) Health Perception Scores, and i) Stress Impact Scores [20].
Subjects were also subjected to exit examination and surveys conducted by professional staff physicians of the Center for New Medicine of Irvine, California. In this (PGIC) analysis participants were asked whether their overall changes in symptom severity and QOL were very much better (score of 6), moderately better (score of 5), a little better (score of 4), no change (score of 3), a little worse (score of 2), moderately worse (score of 1) or very much worse (score of 0) (Appendix FigureA1 of this paper). The mean satisfaction scores were determined and analyzed statistically.
2.3. Statistical Analysis
For statistical analysis we used generalized estimating equations (GEE) for the regression parameters as introduced by Liang and Zeger as a method for estimation of regression model parameters when dealing with correlated data [22] [23]. Generalized estimating equations (GEE) are a convenient and general approach to the analysis of several kinds of correlated data. The main advantage of GEE resides in the unbiased estimation of population-averaged regression coefficients despite possible misspecification of the correlation structure. Our longitudinal research was aimed at describing the marginal expectations of the outcome as a function of the predictors [24].
The objective of analyses that we have done and performed were to examine: (1) whether the QOL scores differed over the study time points; (2) whether the QOL scores differed over the study time points between males and females; and (3) whether the QOL scores differed over the study time points between age < 50 and age ≥ 50. Data were analyzed with significance defined as p < 0.05 and presented as mean data with 95% confidence levels.
The exit survey (PGIC) was conducted with 28 subjects, and satisfaction scores were calculated and analyzed by a one-sided, one sample t-test. In this analysis a significant overall improvement in exit scores would be a composite satisfaction score greater than 3.0. All of the statistical analyses were performed independently by the Statistical Unit of the Division of General Medicine, Department of Medicine, University of California, Irvine.
2.4. Safety Issues
The safety of patients was carefully monitored during the trial. Any issues of adverse reactions to the test supplement were carefully recorded and monitored during the trial. Potential changes in blood chemistry were monitored each month during the clinical study using the NutrEvalTM diagnostic blood evaluation panel (Genova Diagnostics, Asheville, NC). In this panel standard blood chemistry and a panel of blood levels of antioxidants, vitamins, minerals, essential fatty acids, probiotics, pancreatic enzymes, and amino acids were monitored at the beginning and each subsequent month during the trial period.
3. Results
3.1. Participants in the Study
There were 50 participants in the IRB-approved clinical study (40 females, 10 males). They had a mean age of 51.1 ± 12.7 years (range, 24 - 77 years) and presented with a diagnosis of a gastrointestinal disorder. A summary of the participants and their presentation with a variety of digestive disorders and diseases (with multiple gastrointestinal symptoms) is summarized in Table 1.
3.2. Quality of Life Determinations
Using the validated digestive disorders questionnaire of Chassany, et al. [20] patients were examined for their responses in each survey category every 10 days during the 90-day test period (Figure 1). After the 90-day period, the analyzed results of the study indicated that there were significant overall global improvements in the health surveys (p = 0.0183) (Figure 1(a)), with significant improvements in symptom discomfort (p = 0.0004) (Figure 1(b)), daily activities (p = 0.029) (Figure 1(c)) and anxiety (p = 0.018) (Figure 1(d)). In contrast, there were insignificant improvements in diet (p = 0.398) (Figure 1(e)), sleep (p = 0.136) (Figure 1(f)), health perception (p = 0.686) (Figure 1(g)), coping with the disease (p = 0.309) (Figure 1(h)) and impact of stress (p = 0.785) (Figure 1(i)). Most health response improvements over baseline occurred within 20 days from initiating the dietary supplement (Figures 1(a)-(d)).
Based on the results from the GEE models, regression parameters indicated that the improvements in overall global symptoms and QOL scores were consistent and occurred with a low degree of variance. The estimated changes from baseline of the eight dimension scores are shown in Table2. The dimension scores included: daily activities (DA), anxiety (AN), diet (DI), sleep (SL), discomfort (DT), health perceptions (HP), coping with disease (CD), and impact of stress (IS). In addition, two overall measures, the estimated change from baseline in the global score (GS) and an alternative scoring of the global score (Alt GS) are also displayed. The Tableillustrates the low degree of variance in estimated changes from baseline in dimension scores and global scores over the 10 survey time points.
3.3. Exit Interviews
Exit interviews (PGIC) with each participant were conducted by the clinical study physicians (Appendix FigureA1). The exit interviews indicated that the
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Figure 1. Digestive disorders questionnaire results. Combined results of the study (Global Scores) and subparts of the study over a 90-day period are presented. Results indicate normalized scores (mean scores minus baseline scores; brackets indicate 95% confidence levels of the means). Improvements in normalized scores are indicated by increases in normalized score values presented in the figure. Panels indicate Combined Global Scores (a), Daily Activities Scores (b), Symptom Discomfort Scores (c), Anxiety Scores (d), Diet Scores (e), Sleep Scores (f), Coping with Disease Scores (g), Health Perception Scores (h), Stress Impact Scores (i).
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Table 2. The estimated changes from baseline of the dimension score at each survey time from the GEE models.
Abbreviations: DA, daily acitivites; AN, anxiety scores; DI, diet scores; SL, sleep scores; DT, symptom discomfort scores; HP, health perception scores; CD, coping with disease scores; IS, impact scores; GS, global scores; Alt GS, alternate global scores; CI, confidence intervals.
patients’ impression of overall global change in symptoms and QOL showed significant improvements in satisfaction with the test supplement (moderately better improvements in symptoms and QOL, or a score of 4.8 ± 0.169, p < 0.0001).
3.4. Safety of the Study
There were no safety issues that came up during the clinical trial. In support of this the NutrEvalTM diagnostic blood evaluation panels showed no significant changes in blood chemistry and levels of blood antioxidants, vitamins, minerals, essential fatty acids, probiotics, pancreatic enzymes, and amino acids during the study.
4. Discussion
The dietary test supplement used in the present clinical study (now called GI RegenerateTM) has been used for years in China and other countries to treat patients with a variety of gastrointestinal disorders and diseases [14] - [19]. These clinical studies were dependent on this dietary supplement repairing gastrointestinal damage. To demonstrate the effects of the test dietary supplement on stimulating gastrointestinal epithelial cell survival, growth and regeneration, some experimental studies were initiated. After excision and in vitro culture of organ explants of murine stomach and intestinal tissues in medium containing fetal bovine serum, addition of the test dietary supplement was shown to stimulate epithelial cell survival, growth and differentiation, whereas the cells in explant cultures without the dietary test supplement began to die and never formed viable cell colonies [12] [13].
Consistent with the findings in China on the clinical benefits of using the oral test dietary supplement to treat ulcerative colitis [14], gastroesophageal reflux disease [15], gastric ulcers [16], peptic ulcers [17], GERD [23] and gastrointestinal damage due to ethanol [18] or infection [19] we found that North American patients with a variety of gastrointestinal disorders and symptoms (Table 1) responded positively to the test dietary supplement GI RegenerateTM. These positive responses were collected using the validated digestive disorders questionnaire of Chassany, et al. [20] over a 90-day period. The results indicated that male and female patients with IBS, GERD, Crohn’s disease, celiac disease, ulcerative colitis, gastritis, and digestive symptoms, such as abdominal bloating and pain, gastric pain, constipation, diarrhea, fatigue, flatulence, nausea, regurgitation and food allergies and malabsorption, improved significantly during the test period (p = 0.0183), with significant QOL improvements in symptom discomfort (p = 0.0004), daily activities (p = 0.029) and anxiety (p = 0.018).
Our results using the validated digestive disorders questionnaire were confirmed in the PGIC exit surveys where patients indicated moderately better improvements in symptoms and QOL (p < 0.0001) at the end of the study. Thus we have confirmed the benefits of taking oral capsules of GI RegenerateTM found in previous studies on the improvements in gastrointestinal symptoms in patients with digestive disorders and diseases [14] - [19].
There were no safety concerns that came up during the trial. Patients did not report issues with the GI RegenerateTM oral supplement, and blood chemistry analyses every month during the trial on every subject using the NutrEvalTM diagnostic blood evaluation panel did not indicate any abnormalities in levels of blood antioxidants, vitamins, minerals, essential fatty acids, probiotics, pancreatic enzymes, or amino acids during the study. Thus we concluded that the GI RegenerateTM oral supplement was safe and effective for use in treating gastrointestinal symptoms in early adults to the elderly.
Although the results of our clinical study were positive and generally significant statistically, there were obvious limitations of the trial. First, we note that although the numbers of females in our study were sufficient, we had less access to male patients. Thus the numbers of males in our study (10) were much lower than the numbers of females (40). Future studies should contain more balanced numbers of males and females. Also, the study was a preliminary open label study, not a robust, randomized, controlled clinical trial. There are few evidence-based clinical studies using randomized clinical trials on the use of Chinese dietary herbal supplements to treat digestive disorders [25] [26]. The results presented here should stimulate the organization of a randomized, controlled clinical trial using GI RegenerateTM to test for improvements in symptoms in patients with digestive disorders and diseases.
Acknowledgements
The authors acknowledge the assistance and support of MEBO Life Sciences, Brea, California.
Disclosures
Garth L. Nicolson and Robert Settineri are part-time research consultants to Allergy Research Group, Inc., Naturally Plus USA, Inc. and Nutritional Therapeutics, Inc. There are no other disclosures.
Appendix
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Figure A1. Patient’s Global Impression of Change (PGIC).