The aim of this study is to determine how regular consumption of Synbiotic+, a dietary supplement that contains prebiotics, probiotics, and postbiotics, impacts functional gastrointestinal health, markers of intestinal inflammation and immune health, and influences mood and behavior. The primary outcome will be to assess gastrointestinal health using bowel movement tracking, self-report and objective assessments of gastrointestinal symptom severity, stool levels of short chain fatty acids, changes in the gut microbiota, including recovery of LGG and BB-12, and functional measures of the microbiome. Secondary outcomes will include stool and blood markers of gut barrier function and intestinal inflammation, immune health, and self-assessments of stress, anxiety, sleep, and quality of life.
The trial will be a double-blinded, randomized, placebo-controlled parallel arm intervention study taking place at Colorado State University. In total, \~100 adult women (25-65 years old) with a BMI \<30, with moderate digestive discomfort (as evidenced by a moderate score on a functional gastrointestinal questionnaire will be enrolled into the study. With an estimated 20% attrition rate, this will allow approximately 80 individuals to complete the study. Exclusion criteria include a BMI\>30, any significant systemic diseases (including Crohn's, Ulcerative Colitis, but not including diagnosis of Irritable Bowel Syndrome), prescription medication for digestive symptoms, antibiotic or probiotic ingestion within the two months before entry into the study, and pregnancy or breastfeeding. Subjects will be provided with the consent form prior to the baseline visit and informed consent will be obtained prior to participating in the study. Participants will be compensated for their participation. Medical health history will be collected at the baseline visit. Quality of Life (QOL) and GI Health questionnaires, along with questionnaires to gauge mood and anxiety, will be collected from each enrolled participant at the baseline, mid-point ("check-in visit 2"), and final clinic visits; a GI health questionnaire will also be collected at the acute study visit (48-72 hours after treatment start). Anthropometric measures at the baseline visit will include seated blood pressure, height, weight, and waist:hip measurements; blood pressure will also be collected at the final visit. A stool sample will be collected from participants at each clinic visit, and a blood sample will be collected at the baseline and final clinical visits. Two 3-day diet records will be completed prior to the start and at completion of the study. In addition, participants will keep a daily record of their bowel movements and brief notes regarding any GI symptoms starting 7-days prior to beginning the treatment and for the duration of the study. All enrolled participants will start with a baseline clinic visit and a 7-day lead in period, after which they will take one of the treatments for 12 weeks. To determine the acute effects of the treatment, participants will return a stool sample to the clinic 48-72 hours after the treatment start to establish acute effects (ie. changes in SCFA, microbial dysbiosis index). Subjects will randomly be assigned to a starting treatment (A or B) and capsules will be blinded and labeled by Ritual personnel who are not directly involved in the study. CSU clinical personnel will not be provided with the code for treatment groups until after all data analysis has been completed.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
SUPPORTIVE_CARE
Masking
TRIPLE
Enrollment
60
The product consists of two probiotics, Lactobacillus rhamnosus LGG and Bifidibacterium animalis subsp. lactis BB-12, supplied at a total concentration of 11B CFU's, a prebiotic consisting of 1 × 106 Plaque Forming Units (PFU) LH01-Myoviridae, LL5-Siphoviridae, T4D-Myoviridae, and LL12-Myoviridae bacteriophages, marketed as PreforPro, and tributyrin- a stale form of butyrate
Placebo pill containing stomach acid-resistant outer vegan capsule (hypromellose, gellan gum), hi oleic safflower oil, inner vegan capsule (hypromellose, gellan gum) microcrystalline cellulose, ascorbyl palmitate, silica
Colorado State University Food and Nutrition Clinical Research Laboratory
Fort Collins, Colorado, United States
RECRUITINGShort Chain Fatty Acid concentration in stool
Gas chromatography will be used to measure changes in SCFA production in stool.
Time frame: 4X: baseline, acute (3 days), mid-point (6 weeks), final (12 weeks).
Fecal pH
Stool sample pH will be measured before and after treatment.
Time frame: 4X: baseline, acute (3 days), mid-point (6 weeks), final (12 weeks).
Fermentation Rate of microbiome
This is a functional measure of the microbiome and will be measured ex-vivo Radio Frequency Identification (RFID) system. Stool sample microbes will be assessed for fermentation rates.
Time frame: 4X: baseline, acute (3 days), mid-point (6 weeks), final (12 weeks).
Microbial composition (alpha and beta diversity, dysbiosis index, differential taxa)
Changes in microbiota profiles, ratio of pro-inflammatory to beneficial microbes, recovery of LGG \& BB-12 in stool; measured using 16s rRNA and targeted assays.
Time frame: 2X: baseline, and final (12 weeks)
Total number and types of bowel movements
Defecation frequency and proportion of abnormal to normal bowel movements as recorded in a diary using the Bristol Stool Form Scale. The scale runs from 1-7 with healthier outcomes associated with 3-5 on the Bristol scale.
Time frame: Daily for 12 weeks
Gastrointestinal Symptom Rating Scale
Measures Abdominal Pain Heartburn Acid Regurgitation Sucking Sensations in the Epigastrium Nausea \& Vomiting Borborygmus (rumbling) Abdominal Distension (bloating) Eructation (burping) Flatus (gas) Decreased or Increased Passage of Stools Loose or Hard Stools Urgent Need for Defecation Feeling of Incomplete Evacuation Rated on a scale starting at "No Discomfort at all" to "Very severe discomfort", where better outcomes are associated with "No Discomfort At All" while worse outcomes are associated near(er) to "Very Severe Discomfort".
Time frame: 4X: baseline, acute (3 days), mid-point (6 weeks), final (12 weeks).
Fecal calprotectin
Intestinal inflammation
Time frame: 3X: baseline, mid-point (6 weeks), final (12 weeks)
Alpha-1 antitrypsin
Gut permeability
Time frame: 3X: baseline, mid-point (6 weeks), final (12 weeks)
Lipopolysaccharide binding protein and soluble CD14 in blood
Barrier function: Lipopolysaccharide binding protein and soluble CD14 are involved in binding LPS and initiating systemic inflammatory cascades and have been used as a proxy for gut barrier function.
Time frame: 2X: baseline, and final (12 weeks)
Human high sensitivity T-cell panel/Peripheral blood mononuclear cells (PBMCs)
Immune health: in supernatants from LPS-stimulated PBMC; uses Milliplex MAP
Time frame: 2X: baseline, and final (12 weeks)
Alpha-1 antitrypsin in blood
Gut permeability/malabsorption
Time frame: 2X: baseline, and final (12 weeks)
Cortisol blood levels
Cortisol levels
Time frame: 2X: baseline, and final (12 weeks)
GLP-1
GLP-1 levels, metabolic health, measured with ELISA assay.
Time frame: 2X: baseline, and final (12 weeks)
Quality of Life as measured by Inflammatory Bowel Disease (IBD) Specific Quality of Life survey
Online Survey measuring Helplessness, Embarrassment, Vulnerability, Discomfort, Enjoyment of Life, Body Image, Depression, Isolation, Behavior Change, Anger, and Irritability in regards to bowel problems. Survey scale starts at "not at all" and goes up to "extremely" with healthier outcomes associated with "not at all".
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Time frame: 3X: baseline, mid-point (6 weeks), final (12 weeks)
Generalized Anxiety Disorder 7 Item Survey
The GAD-7 (Generalized Anxiety Disorder-7) is a self-report questionnaire designed to screen for generalized anxiety disorder (GAD) and assess the severity of anxiety symptoms in individuals. It consists of 7 questions that focus on the frequency of anxiety-related symptoms experienced over the past two weeks. Scoring: 0-4: Minimal or no anxiety 5-9: Mild anxiety 10-14: Moderate anxiety 15-21: Severe anxiety
Time frame: 3X: baseline, mid-point (6 weeks), final (12 weeks)
Positive and Negative Affect Schedule
Subjective experience of mood (how you feel on average) rated on a scale from "very slightly or none at all" to "extremely". Moods can be positive (e.g inspiration) or negative (e.g. guilty), so the score does not reflect a better or worse outcome.
Time frame: 3X: baseline, mid-point (6 weeks), final (12 weeks)
Perceived Stress Scale
Subjective experiences of stress. The questions in this scale ask about your feelings and thoughts during the last month. In each case, you will be asked to indicate how often you felt or thought a certain way. The scale ranges from "never" to "very often". Questions are regarding positive and negative situations, so a total score is not indicative of a better or worse outcome.
Time frame: 3X: baseline, mid-point (6 weeks), final (12 weeks)
Ritual Marketing Interest measuring the user experience of the probiotic supplement.
Subjective experiences regarding smell, taste, ingestion, tolerability, nausea, burping, after taking the product. Also asks whether the participant would recommend the product, enjoyed the overall experience, easy to incorporate into daily routine, whether it improved skin and/or stomach discomfort. The survey uses a Likert Scale for all questions. Each question is situational in that the lower score, "Strongly Disagree" or the higher score "Strongly Agree" do not correlate as a "better" or "worse" outcome across all questions.
Time frame: 3X: baseline, mid-point (6 weeks), final (12 weeks)
Blood Glucose levels
Measured with a point of care instrument (Piccolo Express) using a disc-based photometric analysis.
Time frame: 2X: baseline, final (12 weeks)
Alanine Aminotransferase (ALT) in blood
Measured with a point of care instrument (Piccolo Express) using a disc-based photometric analysis.
Time frame: 2X: baseline, and final (12 weeks)
Aspartate Aminotransferase (AST) in blood
Measured with a point of care instrument (Piccolo Express) using a disc-based photometric analysis.
Time frame: 2X: baseline, and final (12 weeks)
Alkaline Phosphatase (ALP) in blood
Measured with a point of care instrument (Piccolo Express) using a disc-based photometric analysis.
Time frame: 2X: baseline, and final (12 weeks)
Blood Creatinine
Measured with a point of care instrument (Piccolo Express) using a disc-based photometric analysis.
Time frame: 2X: baseline, and final (12 weeks)
Blood bilirubin
Measured with a point of care instrument (Piccolo Express) using a disc-based photometric analysis.
Time frame: 2X: baseline, and final (12 weeks)
Total Cholesterol
Measured with a point of care instrument (Piccolo Express) using a disc-based photometric analysis.
Time frame: 2X: baseline, and final (12 weeks)
High Density Lipoprotein (HDL) in blood
Measured with a point of care instrument (Piccolo Express) using a disc-based photometric analysis.
Time frame: 2X: baseline, and final (12 weeks)
Blood Triglycerides
Measured with a point of care instrument (Piccolo Express) using a disc-based photometric analysis.
Time frame: 2X: baseline, and final (12 weeks)
Non-HDL Cholesterol (nHDLc)
Measured with a point of care instrument (Piccolo Express) using a disc-based photometric analysis.
Time frame: 2X: baseline, and final (12 weeks)
Total Cholesterol to HDL ratio (TC/H) in blood
Measured with a point of care instrument (Piccolo Express) using a disc-based photometric analysis.
Time frame: 2X: baseline, and final (12 weeks)
Low Density Lipoprotein (LDL) in blood
Measured with a point of care instrument (Piccolo Express) using a disc-based photometric analysis.
Time frame: 2X: baseline, and final (12 weeks)
Very low density lipoprotein (VLDL) in blood
Measured with a point of care instrument (Piccolo Express) using a disc-based photometric analysis.
Time frame: 2X: baseline, and final (12 weeks)