Rewilding the Human Gut: Reintroduction of the Species Limosilactobacillus Reuteri

NCT03501082 | Completed

• 1 other identifier: Pro00077565
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 1

Brief Summary

The large intestine is home to trillions of microbes, known as the gut microbiome, which perform essential functions, such as digesting food and fighting disease. The diversity of microbes present in our gut microbiome is influenced by lifestyle factors, such as dietary patterns, medication usage, and sanitation practices. Research shows that the diversity of the human gut microbiome decreases as societies undergo industrialization. For example, fecal samples from rural Papua New Guineans contain an additional 50 microbial species, such as Limosilactobacillus reuteri, not found in people living in the United States. What has caused the disappearance of L. reuteri in industrialized countries is currently unknown. However, diet is a major factor influencing the composition of the gut microbiome. Microbiota-accessible carbohydrates (MACs) are indigestible carbohydrates that are a primary source of energy for gut microbes. North Americans consume far less of these carbohydrates (which are contained in foods such as beans, yams, and artichokes) than rural Papua New Guineans. The overall aim of this controlled feeding study is to determine if a strain of L. reuteri isolated from rural Papua New Guinea can be established in the gut of Canadians when taken as a probiotic alongside a non-industrialized-type diet designed to promote its growth. Furthermore, the study will determine: (i) the physiological and immunological effects of both L. reuteri and the non-industrialized-type diet, and (ii) the effects of both L. reuteri and the non-industrialized-type diet on gut microbiome ecology.

Conditions

Microbial Colonization

Keywords

Gut microbiome

Outcome Measures

Primary Outcomes (2)

• Establishment of L. reuteri (PB-W1 & DSM20016T strains) in the gut of Canadian individuals

  The primary outcome of this study is to measure L. reuteri (PB-W1 and DSM20016T strains) establishment in the gut of Canadian individuals. This will be measured by selective bacterial culture from fecal samples and quantified through quantitative PCR using species specific primers.

  21 days

• Enhanced persistence of colonization of L. reuteri (PB-W1 & DSM20016T strains) following consumption of non-industrialized-type diet designed to provide growth substrates for L. reuteri

  We will measure if the persistence of L. reuteri in the gut of Canadian individuals is enhanced by the consumption of a non-industrialized-type diet specifically designed to provide growth substrates (MACs) for L. reuteri. This will be measured by selective bacterial culture from fecal samples and quantified through quantitative PCR using species specific primers.

  21 days

Secondary Outcomes (16)

• Effect of L. reuteri strains and the non-industrialized-type diet on cardiometabolic surrogate endpoints: fasting glucose and lipid panel.

  21 days

• Effect of L. reuteri strains and the non-industrialized-type diet on cardiometabolic surrogate endpoints: fasting insulin levels.

  21 Days

• Effect of L. reuteri strains and the non-industrialized-type diet on cardiometabolic surrogate endpoints: homeostatic model assessment of insulin resistance and quantitative insulin sensitivity check index.

  21 Days

• Effect of L. reuteri strains and the non-industrialized-type diet on cardiometabolic surrogate endpoints: fasting C-reactive protein levels.

  21 Days

• Effect of L. reuteri strains and the non-industrialized-type diet on cardiometabolic surrogate endpoints: body weight.

  21 Days

Study Arms (6)

L. reuteri PB-W1, Non-Industrialized-Type Diet Start

EXPERIMENTAL

Participants will receive the non-industrialized-type diet for 3 weeks, followed by a crossover to 3 weeks of consuming their usual diet after a 3-week washout period. Participants will be provided with a one-time dose of L. reuteri PB-W1 strain on day 4 of each diet period. The L. reuteri PB-W1 strain will be provided as a drinkable solution (approximately 2.25x10\^10 viable cells will be provided in 50 ml of water).

Other: L Reuteri PB-W1 Strain; Other: Non-Industrialized-Type Diet

L. reuteri DSM20016T, Non-Industrialized-Type Diet Start

EXPERIMENTAL

Participants will receive the non-industrialized-type diet for 3 weeks, followed by a crossover to 3 weeks of consuming their usual diet after a 3-week washout period. Participants will be provided with a one-time dose of L. reuteri DSM20016T strain on day 4 of each diet period. The L. reuteri DSM20016T strain will be provided as a drinkable solution (approximately 2.25x10\^10 viable cells will be provided in 50 ml of water).

Other: L. Reuteri DSM20016T Strain; Other: Non-Industrialized-Type Diet

Placebo, Non-Industrialized-Type Diet Start

PLACEBO COMPARATOR

Participants will receive the non-industrialized-type diet for 3 weeks, followed by a crossover to 3 weeks of consuming their usual diet after a 3-week washout period. Participants will be provided with a one-time dose of a placebo solution on day 4 of each diet period. The placebo solution will be provided as a drinkable solution (2 g maltodextrin dissolved in 50 ml water in food grade conditions).

Other: Placebo; Other: Non-Industrialized-Type Diet

L. reuteri PB-W1, Usual Diet Start

EXPERIMENTAL

Participants will consume their usual diet for 3 weeks, followed by a crossover to 3 weeks of consuming the provided non-industrialized-type diet after a 3-week washout period. Participants will be provided with a one-time dose of L. reuteri PB-W1 strain on day 4 of each diet period. The L. reuteri PB-W1 strain will be provided as a drinkable solution (approximately 2.25x10\^10 viable cells will be provided in 50 ml of water).

Other: L Reuteri PB-W1 Strain; Other: Non-Industrialized-Type Diet

L. reuteri DSM20016T, Usual Diet Start

EXPERIMENTAL

Participants will consume their usual diet for 3 weeks, followed by a crossover to 3 weeks of consuming the provided non-industrialized-type diet after a 3-week washout period. Participants will be provided with a one-time dose of L. reuteri DSM20016T strain on day 4 of each diet period. The L. reuteri DSM20016T strain will be provided as a drinkable solution (approximately 2.25x10\^10 viable cells will be provided in 50 ml of water).

Other: L. Reuteri DSM20016T Strain; Other: Non-Industrialized-Type Diet

Placebo, Usual Diet Start

PLACEBO COMPARATOR

Participants will consume their usual diet for 3 weeks, followed by a crossover to 3 weeks of consuming the provided non-industrialized-type diet after a 3-week washout period. Participants will be provided with a one-time dose of a placebo solution on day 4 of each diet period. The placebo solution will be provided as a drinkable solution (2 g maltodextrin dissolved in 50 ml water in food grade conditions).

Other: Placebo; Other: Non-Industrialized-Type Diet

Interventions

L Reuteri PB-W1 Strain OTHER

L. Reuteri PB-W1 strain will be prepared in accordance to the standardized operating procedures to prepare Limosilactobacillus reuteri in food grade conditions

Also known as: Probiotic

L. reuteri PB-W1, Non-Industrialized-Type Diet Start; L. reuteri PB-W1, Usual Diet Start

L. Reuteri DSM20016T Strain OTHER

L. Reuteri DSM20016T strain will be prepared in accordance to the standardized operating procedures to prepare Limosilactobacillus reuteri in food grade conditions

Also known as: Probiotic

L. reuteri DSM20016T, Non-Industrialized-Type Diet Start; L. reuteri DSM20016T, Usual Diet Start

Placebo OTHER

2 g of maltodextrin will be dissolved in 50 ml water in food grade conditions

Placebo, Non-Industrialized-Type Diet Start; Placebo, Usual Diet Start

Non-Industrialized-Type Diet OTHER

Non-industrialized-type diet will be prepared in a metabolic kitchen, with all meals and snacks provided to participants for three weeks.

Also known as: Controlled Diet

L. reuteri DSM20016T, Non-Industrialized-Type Diet Start; L. reuteri DSM20016T, Usual Diet Start; L. reuteri PB-W1, Non-Industrialized-Type Diet Start; L. reuteri PB-W1, Usual Diet Start; Placebo, Non-Industrialized-Type Diet Start; Placebo, Usual Diet Start

Eligibility Criteria

• Age: 18 Years - 45 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Healthy individuals with a body mass index between 20-29.9 kg/m²
• Have at least one bowel movement per day
• Willing to consume prepared study foods (breakfast, lunch dinner, snacks) for a period of 3 weeks
• Men and pre-menopausal, non-pregnant or non-lactating women
• Non-vegetarian, non-smoking, and alcohol intake ≤8 drinks/week, and willing to consume 8 drinks per week or less during the course of the study.
• If consuming probiotic containing foods, willing to discontinue eating same, and substitute with non-probiotic containing foods
• ≤5 h/week of moderate-vigorous exercise.
• Quantity of L. reuteri in screening fecal sample below 10\^4 CFU/g

You may not qualify if:

• History of diabetes, acute or chronic GI illnesses, conditions, or history of GI surgical intervention
• antibiotic treatment in the last 3 months
• use of dietary supplements (including prebiotics and probiotics, fiber supplements/bars, digestive enzymes/beano)- if consumed, willing to undergo 4 week pre-intervention washout period, and remain free of supplements for duration of study. Exception: multivitamin or vitamin d supplement (1 week washout period)
• use of antihypertensive, lipid-lowering, anti-diabetic, anti-inflammatory (i.e corticosteroids or chronic NSAID use), or laxative medications
• known food allergies or intolerances (including dairy allergic or lactose intolerant)

Sponsors & Collaborators

• University of Alberta: lead

Study Sites (1)

University of Alberta

Edmonton, Alberta, T6G 2E1, Canada

Location

Related Publications (8)

• Segata N. Gut Microbiome: Westernization and the Disappearance of Intestinal Diversity. Curr Biol. 2015 Jul 20;25(14):R611-3. doi: 10.1016/j.cub.2015.05.040.

  PMID: 26196489 BACKGROUND

• Sonnenburg ED, Sonnenburg JL. Starving our microbial self: the deleterious consequences of a diet deficient in microbiota-accessible carbohydrates. Cell Metab. 2014 Nov 4;20(5):779-786. doi: 10.1016/j.cmet.2014.07.003. Epub 2014 Aug 21.

  PMID: 25156449 BACKGROUND

• Martinez I, Stegen JC, Maldonado-Gomez MX, Eren AM, Siba PM, Greenhill AR, Walter J. The gut microbiota of rural papua new guineans: composition, diversity patterns, and ecological processes. Cell Rep. 2015 Apr 28;11(4):527-38. doi: 10.1016/j.celrep.2015.03.049. Epub 2015 Apr 16.

  PMID: 25892234 BACKGROUND

• Walter J, Britton RA, Roos S. Host-microbial symbiosis in the vertebrate gastrointestinal tract and the Lactobacillus reuteri paradigm. Proc Natl Acad Sci U S A. 2011 Mar 15;108 Suppl 1(Suppl 1):4645-52. doi: 10.1073/pnas.1000099107. Epub 2010 Jun 25.

  PMID: 20615995 BACKGROUND

• Zelante T, Iannitti RG, Cunha C, De Luca A, Giovannini G, Pieraccini G, Zecchi R, D'Angelo C, Massi-Benedetti C, Fallarino F, Carvalho A, Puccetti P, Romani L. Tryptophan catabolites from microbiota engage aryl hydrocarbon receptor and balance mucosal reactivity via interleukin-22. Immunity. 2013 Aug 22;39(2):372-85. doi: 10.1016/j.immuni.2013.08.003.

  PMID: 23973224 BACKGROUND

• Buffington SA, Di Prisco GV, Auchtung TA, Ajami NJ, Petrosino JF, Costa-Mattioli M. Microbial Reconstitution Reverses Maternal Diet-Induced Social and Synaptic Deficits in Offspring. Cell. 2016 Jun 16;165(7):1762-1775. doi: 10.1016/j.cell.2016.06.001.

  PMID: 27315483 BACKGROUND

• Lamas B, Richard ML, Leducq V, Pham HP, Michel ML, Da Costa G, Bridonneau C, Jegou S, Hoffmann TW, Natividad JM, Brot L, Taleb S, Couturier-Maillard A, Nion-Larmurier I, Merabtene F, Seksik P, Bourrier A, Cosnes J, Ryffel B, Beaugerie L, Launay JM, Langella P, Xavier RJ, Sokol H. CARD9 impacts colitis by altering gut microbiota metabolism of tryptophan into aryl hydrocarbon receptor ligands. Nat Med. 2016 Jun;22(6):598-605. doi: 10.1038/nm.4102. Epub 2016 May 9.

  PMID: 27158904 BACKGROUND

• He B, Hoang TK, Wang T, Ferris M, Taylor CM, Tian X, Luo M, Tran DQ, Zhou J, Tatevian N, Luo F, Molina JG, Blackburn MR, Gomez TH, Roos S, Rhoads JM, Liu Y. Resetting microbiota by Lactobacillus reuteri inhibits T reg deficiency-induced autoimmunity via adenosine A2A receptors. J Exp Med. 2017 Jan;214(1):107-123. doi: 10.1084/jem.20160961. Epub 2016 Dec 19.

  PMID: 27994068 BACKGROUND

MeSH Terms

Conditions

Communicable Diseases

Interventions

Probiotics

Condition Hierarchy (Ancestors)

Infections; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Dietary Supplements; Food; Diet, Food, and Nutrition; Physiological Phenomena; Food and Beverages

Study Officials

• Jens Walter, PhD

  University College Cork

  PRINCIPAL INVESTIGATOR

• Andrea Haqq, MD

  University of Alberta

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: OTHER
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Crossover design for dietary intervention (non-industrialized-type diet compared to participants' usual diet); parallel design for L. reuteri probiotic (L. reuteri PB-W1, L. reuteri DSM-20016T, and placebo).

Study Record Dates

• First Submitted: November 21, 2017
• First Posted: April 18, 2018
• Study Start: February 21, 2019
• Primary Completion: January 31, 2020
• Study Completion: January 31, 2020
• Last Updated: September 19, 2024

Record last verified: 2020-05

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ANALYTIC CODE
• Time Frame: Immediately following publication, ending 5 years following publication.
• Access Criteria: Anyone who wishes to access the data may do so to achieve aims in the approved proposal and for individual participant data meta-analysis.

Locations

CA (1)