IBS - Irritable Bowel Syndrome
Conditions
Keywords
microbiome, microbiota, short chain fatty acids, prebiotic, bile acids
Brief summary
The purpose of this study is to study the relationship between the bile acids, short chain fatty acids and bacteria within the intestines. The hypothesis is that changes in the bacterial composition of the stool are associated with the differences in bile acids and short chain fatty acids in patients having irritable bowel syndrome compared to healthy individuals.
Detailed description
The Study involves 3 visits and will in include 3 types of subjects - those who have irritable bowel syndrome (IBS) with constipation (IBS-C), IBS with diarrhea (IBS-D) and those who have no IBS symptoms or diagnosis. Visit 1 * Volunteers will read and sign this informed consent after all questions about the study have been answered * This is a screening visit and we may determine that volunteers ineligible to continue to participate in the study. * Volunteers will have a medical history taken including demographics, history of symptoms and illness * Volunteers will be asked about all medications * A physical exam will be performed by the physician. * Vital signs will be measured. * Urine Pregnancy test may be done for woman in the reproductive age range. * Eligible participants will be provided with a take-home lasagna meal. * Participants will be given instructions and supplies for collection, storage and transportation of stool for the next visit. * Participants will be provided with instructions for a low fiber, high fat diet which should be consumed for 2 days before stool collection and during the 2 days of stool collection. Instructions will also come with materials to allow participants to record diet intake during these 4 days. * Participants will be provided a bowel pattern diary to record bowel symptoms over the course of the study Day 1: this may be the same as Visit 1 or it may be a different day. It will depend upon the day that participants can make it back to the clinic for the Day 5 visit. Day 2-4 (at home): * Participants record stool symptoms and patterns in a diary daily starting from Day 2 to Day 5. * During this time, participants will be instructed to consume a low fiber diet, avoid alcohol, and start a 4-day 100 g fat diet. * On the evening before Day 5, a standardized, completely digestible, and non-fermentable meal (lasagna) will be consumed which will be provided to you on Day 1. * Participants will collect stool at home on Day 4 and 5 and store as per instructions provided on Visit 1. They will Day 5 (Visit 2): * Participants return to the clinic on Day 5 after an overnight fast. * You will receive a standard breakfast and lasanga meal with 10 g inulin (Orafti®) powder and 200 mL of water. * Take-home meals will be provided (white bread sandwich with ham or cheese) to be consumed at 4 and 8 hours after breakfast. Day 6 (Visit 3): * Participants will return to the clinic in order to return stool collections and the daily diaries. * Participants may also submit diaries by fax or email. Day 30-90 • Optional dietary follow-up (Day 30-90): To further assess the utility of the 24 hour dietary recall, willing participants will be invited to participate in a an optional follow-up activity during which they will complete the Automated Self-Administered Dietary Assessment Tool with or without assistance of a trained interviewer. Interested volunteers will be contacted by phone and provided instructions on how to complete the tool online by the study team.
Interventions
DIETARY_SUPPLEMENTInulin
Inulin ingestion is not being used to diagnose, treat, or prevent IBS. Inulin is being used to study an individual's ability to ferment dietary fiber.
Sponsors
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Indiana University
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
DIAGNOSTIC
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
* Patients with IBS, ages 18-65 fulfilling Rome IV criteria and asymptomatic controls with no prior history of GI disease or symptoms. * Participants should be on a stable and consistent diet regimen and should not be following an extreme diet intervention such as gluten-free or a low FODMAP diet at the time of study participation.
Exclusion criteria
* Participants with microscopic/lymphocytic/collagenous colitis, inflammatory bowel disease, celiac disease, visceral cancer, chronic infectious disease, immunodeficiency, uncontrolled thyroid disease, history of liver disease or history of elevated AST/ALT \> 2.0x the upper limit of normal * Prior radiation therapy of the abdomen or abdominal surgeries except for C-section, tubal ligation, vaginal hysterectomy and appendectomy or cholecystectomy, \> 6 months prior to study initiation. * Ingestion of any prescription, over the counter, or herbal medications which can affect GI transit or study interpretation (e.g. opioids, narcotics, anticholinergics, norepinephrine reuptake inhibitors, nonsteroidal anti-inflammatory drugs, COX-2 inhibitors, bile acid sequestrants) within 6 months of study initiation for asymptomatic volunteers or within 2 days before study initiation for IBS patients. Rescue therapy to facilitate stool collection will be permitted where needed. * Any females who are pregnant or trying to become pregnant or breast-feeding * Antibiotic usage within 3 months prior to study participation * Prebiotic or probiotic usage within the 2 weeks prior to study initiation * Regular use of tobacco products within the past 6 months.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Fecal Inulin | 48 hours | Fecal inulin content will be measured using short acid hydrolysis and high-performance liquid chromatography |
| Total Fecal Short Chain Fatty Acids | 48 hours | Stool samples will be collected for measurement of measurement of short chain fatty acids (mmol/kg) by liquid chromatography-mass spectrometry |
| Individual Fecal Short Chain Fatty Acids - Acetate | 48 hours | Stool samples will be collected for measurement of measurement of short chain fatty acids (mmol/kg) by liquid chromatography-mass spectrometry |
| Individual Fecal Short Chain Fatty Acids - Propionate | 48 hours | Stool samples will be collected for measurement of measurement of short chain fatty acids (mmol/kg) by liquid chromatography-mass spectrometry |
| Individual Fecal Short Chain Fatty Acids - Butyrate | 48 hours | Stool samples will be collected for measurement of measurement of short chain fatty acids (mmol/kg) by liquid chromatography-mass spectrometry |
| Fecal Microbial Population | 48 hours | Stool samples will be be collected from participants for nucleic acid extraction, shotgun sequencing is used to measure microbial communities and profiles of specimens. Shannon index is calculated to measure the diversity of species. The minimum value is 0. There is no upper limit. The higher the Shannon index is, the greater the diversity of species is. |
| Total Fecal Bile Acids | 48 hours | Stool samples will be collected over 2 days for measurement of fecal bile acids (mcmol/48h) by high performance liquid chromatography-mass spectometry |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent Primary Fecal Bile Acids | 48 hours | Stool samples will be collected over 2 days for measurement of fecal bile acids (mcmol/48h) by high performance liquid chromatography-mass spectrometry. Percent primary bile acids is then calculated as primary bile acids divided by total bile acids multiplied by 100. |
| Stool Characteristics - Stool Frequency in 4 Days | 4 days | Stool characteristics will be measured using a 4 day bowel diary. Stool frequency is the total number of bowel movements in 4 days summarized on the subject level. |
| Stool Characteristics - Stool Form | 4 days | Stool characteristics will be measured using a 4 day bowel diary. Stool form is on a scale from 1 to 7, where 1=hard lumps, 2=lumps sausage,3=cracked sausage, 4=normal, 5=soft lumps, 6=mushy,7=watery, summarized on the level of bowel movements. |
| Stool Characteristics - Ease of Passage | 4 days | Stool characteristics will be measured using a 4 day bowel diary. Ease of passage is on a scale from 1 to 7, where 1=manual disimpaction, 2=enema needed, 3=straining needed, 4=normal, 5=urgent without pain, 6=urgent with pain, 7=incontinent, also summarized on the level of bowel movements. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Energy | 24 hours | Optional 24-hour dietary intake will be submitted using web-based Automated Self-Administered Dietary Assessment Tool developed by the National Cancer Institute (https://epi.grants.cancer.gov/asa24/). Dietary intake within a 24-hour period in 30-90 days after study enrollment were collected. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Healthy Volunteers Adults ages 18-65 years with no prior history of gastrointestinal diseases or symptoms.
Inulin: Inulin ingestion is not being used to diagnose, treat, or prevent IBS. Inulin is being used to study an individual's ability to ferment dietary fiber. | 17 |
| Irritable Bowel Syndrome Patients With Constipation Patients with irritable bowel syndrome (IBS) with constipation, ages 18-65 years fulfilling Rome IV criteria for IBS
Inulin: Inulin ingestion is not being used to diagnose, treat, or prevent IBS. Inulin is being used to study an individual's ability to ferment dietary fiber. | 3 |
| Irritable Bowel Syndrome Patients With Diarrhea Patients with irritable bowel syndrome (IBS) with diarrhea, ages 18-65 years fulfilling Rome IV criteria for IBS
Inulin: Inulin ingestion is not being used to diagnose, treat, or prevent IBS. Inulin is being used to study an individual's ability to ferment dietary fiber. | 9 |
| Total | 29 |
Baseline characteristics
| Characteristic | Total | Healthy Volunteers | Irritable Bowel Syndrome Patients With Constipation | Irritable Bowel Syndrome Patients With Diarrhea |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 28 Participants | 16 Participants | 3 Participants | 9 Participants |
| Age, Continuous | 35.2 years STANDARD_DEVIATION 12.8 | 36.3 years STANDARD_DEVIATION 14.9 | 26.4 years STANDARD_DEVIATION 6 | 36.1 years STANDARD_DEVIATION 9.5 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 29 Participants | 17 Participants | 3 Participants | 9 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 10 Participants | 9 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 18 Participants | 8 Participants | 2 Participants | 8 Participants |
| Sex: Female, Male Female | 21 Participants | 12 Participants | 2 Participants | 7 Participants |
| Sex: Female, Male Male | 8 Participants | 5 Participants | 1 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 16 | 0 / 2 | 0 / 6 |
| other Total, other adverse events | 0 / 16 | 0 / 2 | 0 / 6 |
| serious Total, serious adverse events | 0 / 16 | 0 / 2 | 0 / 6 |
Outcome results
Primary
Fecal Inulin
Fecal inulin content will be measured using short acid hydrolysis and high-performance liquid chromatography
Time frame: 48 hours
Population: Measures of inulin evolved over time and many subjects did not have inulin measured as a fraction.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Healthy Volunteers | Fecal Inulin | 3.6 % of fructose from inulin/total fructose |
| Irritable Bowel Syndrome Patients With Diarrhea | Fecal Inulin | 17.1 % of fructose from inulin/total fructose |
p-value: 0.03Kruskal-Wallis
Primary
Fecal Microbial Population
Stool samples will be be collected from participants for nucleic acid extraction, shotgun sequencing is used to measure microbial communities and profiles of specimens. Shannon index is calculated to measure the diversity of species. The minimum value is 0. There is no upper limit. The higher the Shannon index is, the greater the diversity of species is.
Time frame: 48 hours
Population: Microbiome sequencing was completed on all collected specimens.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Healthy Volunteers | Fecal Microbial Population | 3 units on a scale |
| Irritable Bowel Syndrome Patients With Diarrhea | Fecal Microbial Population | 3.6 units on a scale |
Primary
Individual Fecal Short Chain Fatty Acids - Acetate
Stool samples will be collected for measurement of measurement of short chain fatty acids (mmol/kg) by liquid chromatography-mass spectrometry
Time frame: 48 hours
Population: One subject in the group of Irritable Bowel Syndrome Patients with Constipation had missing data in short chain fatty acids
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Healthy Volunteers | Individual Fecal Short Chain Fatty Acids - Acetate | 255.7 mmol/kg |
| Irritable Bowel Syndrome Patients With Constipation | Individual Fecal Short Chain Fatty Acids - Acetate | 113.9 mmol/kg |
| Irritable Bowel Syndrome Patients With Diarrhea | Individual Fecal Short Chain Fatty Acids - Acetate | 202.5 mmol/kg |
p-value: 0.17Kruskal-Wallis
Primary
Individual Fecal Short Chain Fatty Acids - Butyrate
Stool samples will be collected for measurement of measurement of short chain fatty acids (mmol/kg) by liquid chromatography-mass spectrometry
Time frame: 48 hours
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Healthy Volunteers | Individual Fecal Short Chain Fatty Acids - Butyrate | 57.5 mmol/kg |
| Irritable Bowel Syndrome Patients With Constipation | Individual Fecal Short Chain Fatty Acids - Butyrate | 20.5 mmol/kg |
| Irritable Bowel Syndrome Patients With Diarrhea | Individual Fecal Short Chain Fatty Acids - Butyrate | 37.6 mmol/kg |
p-value: 0.47Kruskal-Wallis
Primary
Individual Fecal Short Chain Fatty Acids - Propionate
Stool samples will be collected for measurement of measurement of short chain fatty acids (mmol/kg) by liquid chromatography-mass spectrometry
Time frame: 48 hours
Population: One subject in the group of Irritable Bowel Syndrome Patients with Constipation had missing short chain fatty acids
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Healthy Volunteers | Individual Fecal Short Chain Fatty Acids - Propionate | 59.7 mmol/kg |
| Irritable Bowel Syndrome Patients With Constipation | Individual Fecal Short Chain Fatty Acids - Propionate | 22.8 mmol/kg |
| Irritable Bowel Syndrome Patients With Diarrhea | Individual Fecal Short Chain Fatty Acids - Propionate | 39.1 mmol/kg |
p-value: 0.079Kruskal-Wallis
Primary
Total Fecal Bile Acids
Stool samples will be collected over 2 days for measurement of fecal bile acids (mcmol/48h) by high performance liquid chromatography-mass spectometry
Time frame: 48 hours
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Healthy Volunteers | Total Fecal Bile Acids | 471.5 mcmol/48 hours |
| Irritable Bowel Syndrome Patients With Constipation | Total Fecal Bile Acids | 347 mcmol/48 hours |
| Irritable Bowel Syndrome Patients With Diarrhea | Total Fecal Bile Acids | 329.5 mcmol/48 hours |
p-value: 0.62Kruskal-Wallis
Primary
Total Fecal Short Chain Fatty Acids
Stool samples will be collected for measurement of measurement of short chain fatty acids (mmol/kg) by liquid chromatography-mass spectrometry
Time frame: 48 hours
Population: One subject in the group of Irritable Bowel Syndrome Patients with Constipation had missing data in short chain fatty acids.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Healthy Volunteers | Total Fecal Short Chain Fatty Acids | 359.8 mmol/kg |
| Irritable Bowel Syndrome Patients With Constipation | Total Fecal Short Chain Fatty Acids | 157.1 mmol/kg |
| Irritable Bowel Syndrome Patients With Diarrhea | Total Fecal Short Chain Fatty Acids | 276.9 mmol/kg |
p-value: 0.17Kruskal-Wallis
Secondary
Percent Primary Fecal Bile Acids
Stool samples will be collected over 2 days for measurement of fecal bile acids (mcmol/48h) by high performance liquid chromatography-mass spectrometry. Percent primary bile acids is then calculated as primary bile acids divided by total bile acids multiplied by 100.
Time frame: 48 hours
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Healthy Volunteers | Percent Primary Fecal Bile Acids | 2.7 % of primary/total fecal bile acids |
| Irritable Bowel Syndrome Patients With Constipation | Percent Primary Fecal Bile Acids | 0.4 % of primary/total fecal bile acids |
| Irritable Bowel Syndrome Patients With Diarrhea | Percent Primary Fecal Bile Acids | 2.1 % of primary/total fecal bile acids |
p-value: 0.14Kruskal-Wallis
Secondary
Stool Characteristics - Ease of Passage
Stool characteristics will be measured using a 4 day bowel diary. Ease of passage is on a scale from 1 to 7, where 1=manual disimpaction, 2=enema needed, 3=straining needed, 4=normal, 5=urgent without pain, 6=urgent with pain, 7=incontinent, also summarized on the level of bowel movements.
Time frame: 4 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Healthy Volunteers | Stool Characteristics - Ease of Passage | 4 score on a scale |
| Irritable Bowel Syndrome Patients With Constipation | Stool Characteristics - Ease of Passage | 3 score on a scale |
| Irritable Bowel Syndrome Patients With Diarrhea | Stool Characteristics - Ease of Passage | 4 score on a scale |
p-value: 0.17Kruskal-Wallis
Secondary
Stool Characteristics - Stool Form
Stool characteristics will be measured using a 4 day bowel diary. Stool form is on a scale from 1 to 7, where 1=hard lumps, 2=lumps sausage,3=cracked sausage, 4=normal, 5=soft lumps, 6=mushy,7=watery, summarized on the level of bowel movements.
Time frame: 4 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Healthy Volunteers | Stool Characteristics - Stool Form | 4 score on a scale |
| Irritable Bowel Syndrome Patients With Constipation | Stool Characteristics - Stool Form | 1 score on a scale |
| Irritable Bowel Syndrome Patients With Diarrhea | Stool Characteristics - Stool Form | 5 score on a scale |
p-value: 0.004Kruskal-Wallis
Secondary
Stool Characteristics - Stool Frequency in 4 Days
Stool characteristics will be measured using a 4 day bowel diary. Stool frequency is the total number of bowel movements in 4 days summarized on the subject level.
Time frame: 4 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Healthy Volunteers | Stool Characteristics - Stool Frequency in 4 Days | 4.5 Number of bowel movements in 4 days |
| Irritable Bowel Syndrome Patients With Constipation | Stool Characteristics - Stool Frequency in 4 Days | 0.5 Number of bowel movements in 4 days |
| Irritable Bowel Syndrome Patients With Diarrhea | Stool Characteristics - Stool Frequency in 4 Days | 5 Number of bowel movements in 4 days |
p-value: 0.074Kruskal-Wallis
Other Pre-specified
Energy
Optional 24-hour dietary intake will be submitted using web-based Automated Self-Administered Dietary Assessment Tool developed by the National Cancer Institute (https://epi.grants.cancer.gov/asa24/). Dietary intake within a 24-hour period in 30-90 days after study enrollment were collected.
Time frame: 24 hours
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Healthy Volunteers | Energy | 1887.6 kcal |
| Irritable Bowel Syndrome Patients With Constipation | Energy | 2083.8 kcal |
| Irritable Bowel Syndrome Patients With Diarrhea | Energy | 2246.4 kcal |
p-value: 0.98Kruskal-Wallis