A summary of Pinheiro, I., et al (2017). A yeast fermentate improves gastrointestinal discomfort and constipation by modulation of the gut microbiome: results from a randomized double-blind placebo-controlled pilot trial. BMC Complement Altern Med 2012, 17 (1), 441.
Summary: The aim of the study was to investigate the gut health effects of EpiCor fermentate in a healthy population with symptoms of gastrointestinal (GI) discomfort and reduced bowel movements(1). This study helped to confirm previous published in vitro(2,3) and animal(4) studies demonstrating EpiCor’s gastrointestinal and prebiotic benefits at only a 500 mg daily dose. Results include:
- Statistically significant reduction in gastrointestinal discomfort in the EpiCor moderate subgroup compared to the placebo moderate subgroup.
- Statistically significant improvement in stool consistency in the EpiCor moderate subgroup compared to the placebo moderate subgroup.
- Statistically significant increase of Firmicutes, a less favorable bacteria phylum, within the placebo severe subgroup but not within the EpiCor severe subgroup. Firmicutes to Bacteroidetes ratio noticeably decreases in EpiCor total cohort and severe subgroup but increases in corresponding placebo groups.
- Statistically significant increase in Bacteroides and Prevotella within the EpiCor severe subgroup but not in the placebo severe subgroup, possibly linking EpiCor’s microbiome modulation to improved consistency and frequency of stools.
- Statistically significant Quality of Life improvements using validated questionnaire found within the EpiCor moderate subgroup (but not within the placebo moderate subgroup) include:
- Physical Discomfort
- Psychosocial Discomfort
- Statistically significant improvement in Perceived Stress using validated questionnaire within both the EpiCor total cohort and severe subgroup, but not within the corresponding placebo groups.
- Statistically significant improvements in stool frequency within the EpiCor moderate subgroup, but not within the placebo moderate subgroup.
Constipation and gastrointestinal (GI) discomfort symptoms such as bloating are common among otherwise healthy individuals. Despite the recognized contribution of the gut microbiome to this pathology, little is known about which groups of microorganisms play a role in constipation and GI discomfort.
The bulk of clinical research performed on EpiCor fermentate showed significant immune health benefits(5,6,7,8,9,10). It was postulated that these immune benefits occur primarily through EpiCor’s interaction with the gut. In fact, an in vitro study indicated that EpiCor has prebiotic-like properties by increasing total Short Chain Fatty Acids (SCFAs), while shifting the pattern of SCFA composition to produce more butyrate(2). Further experiments revealed that EpiCor modified the total gut flora and affected what type of bacteria adhered to the simulated gut wall(3). There was a trend for increased adherence of Lactobacilli species and a trend for decreased adherence of Clostridia species3.
In addition, animal models showed EpiCor maintained integrity of healthy gut morphology in terms of villus height and total mucosal thickness when the animals were exposed to heat stress4. The EpiCor treated animals also had reduced lipopolysaccharide (LPS) endotoxin leakage from the gut into the circulatory system, even when not exposed to heat stress(4).
Lastly, EpiCor was shown to significantly increase Secretory IgA levels(5,8), a key mucosal antibody produced mainly via the Peyer’s Patches in the GALT (Gut Associated Lymphoid Tissue). Beyond its well-known immune-supporting benefits, Secretory IgA is known to protect the intestinal epithelium from pathogenic microorganisms, as well as to maintain homeostasis in the digestive tract(11,12) and reduce inflammation in the digestive tract(13).
Those results prompted the study summarized here: a human clinical trial on healthy subjects with mild constipation symptoms. The primary endpoints included constipation symptoms such as frequency, consistency and GI discomfort, while secondary endpoints included modulation of the gut microbiome.
Using a double-blinded, placebo-controlled parallel design, 80 healthy subjects with symptoms of GI discomfort and constipation were equally allocated to one of two trial arms: daily dose of placebo or daily dose of 500 mg EpiCor fermentate. There was a two-week run-in phase followed by a six-week intervention phase. Randomization was done in a stratified manner according to symptom severity, resulting in two subgroups of patients: severe (n=55) and moderate (n=25). Results are given for the total cohort as well as for the severe and moderate subgroups.
Primary Endpoints: GI discomfort and quality of life parameters were measured using three different instruments: a GI symptoms diary and two validated quality of life questionnaires, the Patient Assessment of Constipation Quality of Life (PAC-QOL) and Perceived Stress Scale (PSS) questionnaires.
Secondary Endpoints: Qualitative changes in the microbiome of the gut were assayed using fecal samples that were collected at baseline and at three and six weeks. The general microbiota structure and profiles found in the samples were determined by Illumina® sequencing, a technique involving the amplification of a hypervariable region (V5-V6 region of the 16S ribosomal RNA) of bacterial DNA and sequencing of the amplified region.
Primary Endpoint Results
Within the first two weeks, the EpiCor moderate subgroup showed rapid and statistically significant improvements for gastrointestinal health when compared to placebo. Analysis of the results within the EpiCor groups showed those benefits were typically maintained throughout the remainder of the study.
Fewer significant differences were found between groups in the four and six week averages due to a noticeable placebo effect, which seemed to increase over time especially in the severe subgroup. This pronounced placebo effect is common for gut-related trials with gastrointestinal disorders such as functional constipation(14,15,16,17). This may explain why the placebo effect was generally more pronounced in the severe group.
There were more statistically significant improvements within the EpiCor group than within the placebo group at weeks four and six, although there were fewer significant differences when compared to placebo. This includes statistically significant improvements for stool frequency, quality of life and perceived stress within the EpiCor moderate subgroup but not within the placebo moderate subgroup.
Subjects kept a daily diary recording five gastrointestinal symptoms including bloating/distention, gas, GI rumbling, feeling of fullness and abdominal discomfort.
All symptoms were assessed on a five-point: scale 0 (absent) to 4 (very severe). Averages over a two-week interval were calculated for each symptom and for the combined scores of all the symptoms, giving daily total score (DTS).
- Significant improvement in DTS in the EpiCor moderate subgroup compared to placebo moderate supgroup (Fig. 1).
- Significant reduction in bloating/distension in the EpiCor moderate subgroup compared to placebo moderate subgroup (Fig. 2).
- Significant reduction in feeling of fullness in the EpiCor moderate subgroup compared to placebo moderate subgroup (Fig. 3).
Figures 1,2 and 3 show the mean differences between EpiCor and placebo for gastrointestinal symptoms (as recorded on a daily basis by self-assessment of the severity of GI symptoms on a five-point scale), analyzed with a linear mixed model that takes into account the differences between groups at baseline.
As a part of the patient diary, daily stool frequency and consistency were documented using the Bristol Stool Form Scale for a two-week run-in and a six-week intervention phase. Scores were averaged every two weeks.
The Bristol Stool Form Scale comprises seven types of stool: type 1 (separate hard lumps); type 2 (sausage shape lumpy); type 3 (sausage with cracks); type 4 (sausage but soft and smooth); type 5 (soft lobs); type 6 (fluffy and mushy); type 7 (liquid).
Types 1, 2 and 3 are associated with hard and impacted stools which can be linked with dysbacteriosis and chronic constipation. Types 4 and 5 are considered normal or optimal. Type 6 is considered subnormal or suboptimal. Type 7 is associated with diarrhea.
Bristol Stool Form Scale Results:
- Significant improvements in stool consistency were seen in both the EpiCor total cohort group and the severe subgroup compared to corresponding placebo groups. The improvements were seen at week two, showing both a rapid and significant response to EpiCor (Fig. 4).
- Significant improvements in stool consistency over time in all EpiCor groups (total, moderate and severe), while there were no significant improvements over time in any of the three corresponding placebo groups.
Figures 4 and 6 show the mean differences between EpiCor and placebo on gastrointestinal symptoms (as recorded on a daily basis by self-assessment using the Bristol Stool Form Scale), analyzed with a linear mixed model that takes into account the differences between groups at baseline.
- Significant improvements in stool frequency were seen within the EpiCor moderate subgroup but not within the placebo moderate subgroup.
- Nearly significant improvement (p<0.10) for stool frequency was seen in weeks two and four in the EpiCor total cohort as compared to placebo (Fig. 5).
Figures 4 and 5 show the mean differences between EpiCor and placebo on gastrointestinal symptoms (as recorded on a daily basis by self-assessment using the Bristol Stool Form Scale), analyzed with a linear mixed model that takes into account the differences between groups at baseline.
Quality of Life Parameters
Quality of life was assessed through a validated Patient Assessment of Constipation Quality of Life (PAC-QOL) questionnaire at baseline and after three and six weeks of intervention.
- Significant improvement in Physical Discomfort within the EpiCor moderate subgroup but not within the placebo moderate subgroup.
- Significant improvement in Psychosocial Discomfort within the EpiCor moderate subgroup but not within the placebo moderate subgroup.
- Significant improvement in Satisfaction within the EpiCor moderate subgroup but not within the placebo moderate subgroup.
Perceived Stress Parameters
Perceived Stress was assessed through a validated Perceived Stress Scale (PSS) questionnaire at baseline and after three and six weeks of intervention.
- Significant decrease over time for both the EpiCor total cohort and severe subgroup, but not within the placebo group.
- Nearly significant decrease in stress over time in the EpiCor total cohort and severe subgroup (p<0.10) when compared to corresponding placebo groups.
Secondary Microbiome Endpoint Results
- Anaerostipes significantly increased within both the EpiCor total cohort and severe subgroup, but not within the corresponding placebo groups. Anaerostipes is a genus recognized for its health enhancing effects and contains acetate- and lactate-consuming bacteria and butyrate-producing bacteria(18).
- Akkermansia muciniphila significantly increased within the EpiCor subgroup but not within the placebo subgroup. Akkermansia muciniphila is important for proper gut function and is inversely correlated with metabolic disorders(19).
- Blautia and Roseburia both significantly decreased in the EpiCor subgroup but not within the placebo subgroup. Blautia and Roseburia are believed to be higher in irritable bowel syndrome (IBS) and constipation-predominant IBS (C-IBS)(20).
- Statistically significant increase of Firmicutes, a less favorable bacteria phylum, within the placebo severe subgroup but not within the EpiCor severe subgroup. Firmicutes to Bacteroidetes ratio noticeably decreases in EpiCor total cohort and severe subgroup but increases in corresponding placebo groups. A two-fold increase in the ratio of Firmicutes to Bacteroidetes has been found in C-IBS patients when compared to healthy individuals(20).
- Prevotella (Family Prevotellaceae) significantly increased in the EpiCor subgroup but not in the placebo subgroup. A lower incidence of Prevotella species has been associated with low-fiber diets and insufficient plant-based food consumption20,21, which is a major cause of dysbiosis in constipated patients(22). The significant increase in Prevotella may partly explain EpiCor’s positive effects on stool frequency and consistency.
- Bacteroides (Family Bacteroidaceae) significantly increased within the EpiCor subgroup while decreasing in the placebo subgroup. The significant increase in Bacteroides may also help explain EpiCor’s positive effects on stool frequency and consistency.
Building upon previous published in vitro research showing EpiCor fermentate’s powerful prebiotic effects at the relatively low dose of 500 mg per day, a human clinical trial was conducted with 80 healthy adult subjects with symptoms of GI discomfort and reduced bowel movements. EpiCor led to statistically significant improvements in symptoms such as bloating/distension, feeling of fullness and daily total scores in the moderate subgroup. Such improvements in GI discomfort offer a compelling advantage for EpiCor over prebiotic fibers, which are known to increase GI discomfort at efficacious dose levels.
A significant improvement in stool consistency was observed for the total cohort and for the severe subgroup, while a nearly significant increase in stool frequency was observed for the total cohort compared to placebo. These effects were accompanied by an improvement in constipation-associated quality of life and general perceived stress, particularly within the moderate subgroup. While improvements were also seen in the severe subgroup, there was a larger placebo effect in these subgroups due to the greater desire to see improvements.
The novel findings that EpiCor positively modulates the gut microbiota provide additional substantiation for its GI-related efficacy. EpiCor decreased the F/B ratio in the severe subgroup, which is known to be higher in C-IBS. Bacteroidetes, namely members of Prevotellaceae and Bacteroidaceae groups, are associated with acceleration of GI transit times. The significant increase within the severe subgroup of Bacteroides and Prevotella (both genera in the Prevotellaceae and Bacteroidaceae families) may explain EpiCor’s significant effects on stool consistency and nearly significant effects on stool frequency. Bacteroides and Prevotella have also been previously reported to be deficient in constipated patients(23). In the moderate subgroup, a significant increase in Akkermansia muciniphila was observed. Reduced levels of this bacterium have been correlated with metabolic disorders as well as with inflammatory conditions like IBS.
These findings combined with past in vitro and animal studies show that EpiCor has substantial gut health benefits and can support a variety of claims regarding GI discomfort and microbiome modulation. (See our Structure Function Claims sheet for direction)
The compelling beneficial GI and microbiome results opens up vast opportunities to further research how EpiCor works through the gut to support both digestive and immune health.
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