Functional Research of Emulsifiers in Humans

Not Applicable

Completed

• Conditions: Healthy
• Interventions: Other: Emulsifier-containing diet

• Registration Number: NCT03440229
• Lead Sponsor: University of Pennsylvania

Brief Summary

A randomized double-blind study of the effect of carboxymethylcellulose (CMC) on stool microbiota composition, microbiota localization, and metabolic parameters in healthy subjects. It includes a 11-day in-patient stay, randomization to an emulsifier-free group or a CMC group with the same diet except baked goods/sorbet with added CMC at 15g/person/day.

Detailed Description

This is a randomized double-blind, controlled feeding experiment examining the effect of CMC on the stool microbiota composition, gene expression, and microbiota localization with respect to the epithelium. In addition, the investigators will assess the impact of CMC exposure in the diet on markers of metabolic syndrome including response to oral glucose tolerance testing and other plasma metabolite measurements.

Sixteen healthy volunteers were be recruited. 3 were admitted for 17 days and 13 participants were admitted for an 11-day in-patient study. All participants received 3 full days of freshly prepared emulsifier-free food to begin the study. This will be called the "washout period". Those will a 17 day stay received the wash out diet while inpatient and those with an 11 day stay received the wash out dies while out patient. Participants will then be randomized into an "emulsifier-free" arm and a "CMC" arm in a 1:1 ratio. Both arms will continue the same diet except that the "CMC" arm's brownie and sorbet will have CMC added to achieve a level of 15 gm per person per day consumption. Serial collection of fecal, plasma, urine and mucosal biopsy samples will be performed to investigate the extent to which CMC consumption by humans impacts the gut microbiota and its interaction with the host parameters related to inflammation and metabolism. Participants will have daily urine and stool collections. Sigmoidoscopies and glucose tolerance testing will be completed on the day prior to the start of the intervention and the last day of the inpatient stay (Days 4 and 17 for the 3 participants with a 17 day stay and days 1 and 11 for participants with an 11 day stay. Blood samples were collected on days 1-4, 5, 8, 10, 12, 15, and 17 for those with a 17 day inpatient stay and 1-4, 8, 10, and 11 for those with an 11 day stay.

Study Timeline

• Study First Submitted: 2018-02-05
• Study First Submitted QC: 2018-02-13
• Study First Posted: 2018-02-22
• Study Start: 2018-04-06
• Primary Completion: 2019-05-13
• Study Completion: 2019-05-13
• Results First Submitted: 2021-06-21
• Results First Submitted QC: 2021-08-18
• Status Verified: 2021-09
• Results First Posted: 2021-09-16
• Last Update Submitted: 2021-09-30
• Last Update Posted: 2021-10-19

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 29

Inclusion Criteria

1. Participant is capable of giving informed consent
2. Participant is age 18 to 60 years

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Exclusion Criteria

1. Diagnosis with Inflammatory Bowel Disease (IBD), celiac disease, or other chronic intestinal disorders. Since we are interested in assessing the impact of diet on the microbiome in the absence of pathologic inflammation, we will exclude participants with chronic intestinal abnormalities.

2. Baseline bowel frequency less than every 2 days or greater than 3 times daily. Normal bowel frequency is every 3rd day to 3 times per day.20-23 Although unknown, stool frequency could be related to the microbiome composition.24-26 Furthermore, change in diet could alter baseline stool frequency, potentially causing diarrhea, particularly in those with high baseline stool frequency, or severe constipation in those with low stool frequency. To avoid the need for use of antidiarrheal medications or laxatives, which themselves could alter the microbiome composition, these patients will be excluded.

3. Current smoker. What effect smoking has on the microbiome of the gut is unknown. Furthermore, because our hospital is a smoke-free environment, volunteers will not be able to smoke. Thus, inclusion of smokers would increase the risk of early withdrawal from the study.

4. Body Mass Index (BMI) <18.5 or >40 at screening. Volunteers with BMI below normal27 will be excluded to prevent inclusion of participants with a subclinical systemic disease that may influence the gut microbiome. Volunteers with severe obesity will be excluded as obesity may be associated with altered gut microbiome composition.

5. More than two of the criteria for metabolic syndrome:

   • A waist circumference greater than 35 inches (89 centimeters) for women and 40 inches (102 centimeters) for men at screening.
   • A diagnosis of diabetes mellitus or baseline HbA1c > 6.4% or a fasting glucose level of greater than 100mg/dL
   • Systolic blood pressure >130 mmHg or diastolic blood pressure >85 mmHg or treated with medications for hypertension at screening.
   • Fasting triglycerides >149 mg/dl or treated with medications for hypertriglyceridemia
   • Fasting HDL cholesterol <40 mg/dl in men or <50 mg/dl in women or treated with medications for hypercholesterolemia

6. Known substance abuse disorder or consumption of illicit drugs or alcohol in the 24 hours prior to admission to the Center for Human Phenomic Science (CHPS).

7. Prior bowel resection surgery other than appendectomy. It is unknown how prior bowel resection surgery may influence the microbiome composition, hence we will exclude these participants.

8. Contraindication to flexible sigmoidoscopy and biopsies. Patients with suppressed white blood count may be at increased risk of systemic infection following sigmoidoscopy with biopsies. As such, participants with a white blood cell (WBC) less than 3,500 or an absolute neutrophil count of less than 1,000 will be excluded. Patients with thrombocytopenia or with a coagulopathy may be at increased risk of bleeding complications after colonoscopic biopsies. As such, patients with a platelet count of less than 100,000 or an international normalized ratio (INR) greater than 1.2 will be excluded from the study.

9. Estimated glomerular filtration rate (GFR)<60ml/min/1.73m2 based on measured serum creatinine concentration

10. Pregnant and lactating women. To avoid any risk to an unborn fetus or new born baby from changing the mother's diet, pregnant and lactating women will be excluded.

11. Use of antibiotics in the 6 months prior to Visit 2. A small proportion of bacteria may require 6 months to recover after treatment with antibiotics.28

12. Use of antacids, NSAIDs, or dietary supplements in the week prior to Visit 2. NSAIDs have been associated with C. difficile colitis, although whether this is causative and whether this is mediated through changing the fecal microbiota composition is unknown.29 Antacids could potentially alter the gut microbiota by changing the acid milieu or by altering fecal transit time. For our study purposes, multivitamins will not be considered dietary supplements.

13. Use of laxatives or anti-diarrhea medications in the two weeks prior to Visit 2.

14. Use of anticholinergics in the week prior Visit 2.

15. Use of narcotics in the week prior to Visit 2.

16. HIV infection, AIDS, or other known conditions resulting in immunosuppression - we will determine this by direct participant query; no formal testing will be done.

17. Allergies or intolerance to the components of the study diets.

18. Participant has experienced diarrhea within the two weeks prior to Visit 2. Diarrhea is defined as a change in bowel habits with an increased frequency or loose stools such that the stool could not be lifted with a fork.

19. Refusal to use a medically accepted method of birth control while participating in this study, such as a barrier method, hormonal contraceptives, implanted birth control devices, permanent methods (such as a vasectomy), and/or abstinence.

20. Vegans and Vegetarians.

21. Student or employee of any one of the investigators.

22. Anyone who cannot receive study payment (ie: visa)

23. Any condition that the investigator feels may limit the volunteer's ability to complete the study protocol.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Emulsifier-containing diet	Emulsifier-containing diet	This is a western style diet prepared without any emulsifiers with the exception of the CMC that is included in brownies and sorbet that are provided daily.

Primary Outcome Measures

Name	Time	Method
Distance of Nearest Bacteria to the Epithelium	last day of inpatient stay (either day 17 for the 3 participants with a 17 day inpatient stay or day 11 for the 13 participants with an 11 day inpatient stay.)	Measured distance from the epithelium to the nearest bacteria under high powered microscopy; The measurements were taken on the last day of the diet intervention. An average of 3 measurements was taken.

Secondary Outcome Measures

Name	Time	Method
Area Under Insulin Concentration Curve	For 3 pts. with 17 day stays, area under the curve was measured on days 4 and 17 of the inpatient stay. For 13 pts. with 11 day stays, area under the curve was measured on days 1 and Day 11 of the inpatient stay.	Area under the insulin concentration curves during the oral glucose tolerance test. These measurements were obtained by subtracting the pre from the post net incremental area under the curve. This is measured in microliter international units/milliliter. For 3 participants with a 17 day stay, area under the insulin concentration curve from day 4 of the inpatient stay was substracted from day 17. For 13 participants with an 11 day stay, area under the insulin concentration curve from Day 1 of the inpatient stay was substracted from Day 11
Change in Weight	For 3 participants with a 17 day stay, weight was measured on Day 4 and Day 17 of the inpatient stay. For 13 participants with an 11 day stay, weight was measured on Day 1 and Day 11 of the inpatient stay.	Comparison of weight change during the study period - pre and post intervention. Weight on the last day of the inpatient stay was substracted from weight after the washout period but before the start of the intervention.For 3 participants with a 17 day stay, weight from day 4 of the inpatient stay was substracted from day 17. For 13 with an 11 day stay, weight from Day 1 of the inpatient stay was substracted from Day 11
Area Under Glucose Concentration Curve	For 3 participants with a 17 day stay, area under the glucose curve was measured on days 4 and 17 of the inpatient stay . For 13 participanst with an 11 day stay, area under the glucose curve was measured on days 1 and Day 11 of the inpatient stay.	Area under the glucose concentration curves during the oral glucose tolerance test. These measurements were obtained by subtracting the pre from the post net incremental area under the curve. For 3 participants with a 17 day stay, area under the glucose curve from day 4 of the inpatient stay was substracted from day 17. For 13 participants with an 11 day stay, area under the glucose curve from Day 1 of the inpatient stay was substracted from Day 11
Visual Analog Scale Measurements - Satiety/Hunger - Change From Baseline	Measured at end of inpatient stay (Day 17 for 3 participants and Day 11 for 13 participants) comparing it to the study start (prior to diet intervention; either day 4 for the 3 participants or day 1 for 13 participants.	Desire to eat, hunger, fullness, and prospective food consumption were rated on a 150-mm visual analog scale (VAS) that was adapted from Hill and Blundell in Doucet et al.(see references) The Satiety questionnaire was given before a meal (preprandial) and after the meal (postprandial). The minimum score is 0mm and the maximum score is 150mm for each question. The score prior to the intervention was subtracted from the post intervention score measured on the last day of the inpatient stay. Each question is scored individually. Higher score means more of the characteristic being measured. There are no better or worse outcomes based on these scores.
Fecal Lipocalin-2	For the 3 participants with a 17 day inpatiet stay, this was measured on Day 17. For the 13 participants with an 11 day stay, this was measured on Day 11	Fecal lipocalin-2 by Elisa

Trial Locations

Locations (1)

Hospital of the University of Pennsylvania; 🇺🇸 Philadelphia, Pennsylvania, United States