Microbial ColonizationNCT03501082
Rewilding the Human Gut: Reintroduction of the Species Limosilactobacillus Reuteri
A study testing L Reuteri PB-W1 Strain, L. Reuteri DSM20016T Strain and Non-Industrialized-Type Diet in people with Microbial Colonization, run by University of Alberta at 1 site in Canada.
Trial 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… Read more about this study
- Who is it for?
- Ages 18 to 45 yearsHealthy volunteers can take part
- Conditions the study is for
- Microbial Colonization
- What is being tested?
- L Reuteri PB-W1 Strain, L. Reuteri DSM20016T Strain and Non-Industrialized-Type Diet
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 30 participants
- Where
- 1 siteCanada
- Study dates
- 21 Feb 2019to 31 Jan 2020
- Phase
- Interventional
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 45 years
- All sexes
- Healthy volunteers accepted
- Adult
Who may be able to join
- 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
Who cannot join
- 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)
Trial locations and contacts
1 site in 1 country.
About this study
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.
Read more
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.
Read the detailed description
There is now consistent evidence that industrialization has substantially decreased the bacterial diversity of the gut microbiota (Segata, 2015), likely due to a combination of factors such as use of antibiotics, modern clinical practices, sanitation, and changes in dietary habits. However, the only factor for which empirical evidence exists is the low content of Microbiota-Accessible Carbohydrates (MACs) in Western diets, which are indigestible dietary carbohydrates that become available to the microbes colonizing the intestine (Sonnerburg et al., 2015).
Previous work has confirmed the overall premise of 'microbiome depletion' by demonstrating higher diversity in the fecal microbiota of individuals from rural tribes in Papua New Guinea, which contain an additional of 50 species completely undetectable in North Americans (Martínez et al., 2015). One species detectable in every Papua New Guinean individual by 16S rRNA sequencing but not in a single US control was Limosilactobacillus reuteri (L. reuteri). Interestingly, this species, which is also used as a probiotic, was regularly detected in humans in studies conducted around 1960, but is very rarely found in contemporary humans, suggesting a recent decline of the L. reuteri population in Westerners (Walter et al., 2011). Most importantly, L. reuteri is a member of the gut microbiota in many vertebrate species and exerts benefits towards host immune functions and development, as demonstrated in a number of highly cited publications (Zelante et al. 2013; Buffington et al. 2016; Lamas et al. 2016; He et al. 2017).
It is currently unclear what caused the drop in the L. reuteri population. However, it is likely due to the importance of non-digestible carbohydrates that are present at very low amounts in Western diets, while being abundant in the diet of rural Papua New Guineans, a population that consumes a predominantly plant-based diet.
The goal of this study is to demonstrate that a bacterial species dominant in the non-westernized microbiome can be 'reintroduced' in the gut of Canadians fed a non-industrialized type diet designed to promote the growth of gut bacteria. This study will also determine how this 'reintroduction' and the non-industrialized-type diet influences immune function of the host and host-diet-microbiome metabolic interactions, and explore associations between them. It will further explore the effects of the microbial treatment and the diet on gut microbiome ecology. The central hypothesis is that an isolate of L. reuteri, originating from rural Papua New Guinea, can be established in the gut of Canadians fed a diet containing the carbohydrates known to facilitate the growth of this microbe. It is also hypothesized that this 'reintroduction' and consuming the non-industrialized type diet will be associated with immunological and metabolic benefits to the host. To achieve these goals, the following aims are proposed:
- To conduct a human trial to determine if a Limosilactobacillus reuteri strain isolated from rural Papua New Guinea (PNG) can be established in the gut of healthy Canadians.
- To determine if colonization can be improved by feeding a diet specifically designed to provide growth substrates for L. reuteri.
- To determine how both L. reuteri and the non-industrialized-type diet change the human microbiome, metabolome, cardiometabolic surrogate endpoints, and immune biomarkers of inflammation.
This study will establish if a 'lost species' of bacteria can be reintroduced into the human gut and may provide mechanistic insight to inform how such dietary modulation may be applied to reduce the risk of chronic diseases. Since the L. reuteri strain isolated from rural Papua New Guineans is functionally different from western strains, evidenced by different growth rates on substrates of MACs, this study will further identify potential probiotic strains that were previously uncharacterized due to their overall absence from the industrialized gut microbiome.
- Conditions
- Microbial Colonization
- Being tested
- L Reuteri PB-W1 Strain, L. Reuteri DSM20016T Strain, Placebo, Non-Industrialized-Type Diet
- Keywords
- Gut microbiome
- Medical subject headings
- Communicable Diseases
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
L Reuteri PB-W1 StrainOther
Also called Probiotic
- Reuteri PB-W1 strain will be prepared in accordance to the standardized operating procedures to prepare Limosilactobacillus reuteri in food grade conditions
L. Reuteri DSM20016T StrainOther
Also called Probiotic
- Reuteri DSM20016T strain will be prepared in accordance to the standardized operating procedures to prepare Limosilactobacillus reuteri in food grade conditions
PlaceboOther
2 g of maltodextrin will be dissolved in 50 ml water in food grade conditions
Non-Industrialized-Type DietOther
Also called Controlled Diet
Non-industrialized-type diet will be prepared in a metabolic kitchen, with all meals and snacks provided to participants for three weeks.
| Study group | Role | What they receive |
|---|---|---|
| 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). Receives: 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). Receives: 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). Receives: 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). Receives: 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). Receives: 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). Receives: Other: Placebo; Other: Non-Industrialized-Type Diet |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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.
Measured: 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.
Plasma from blood samples will be analyzed for changes in glucose, triglycerides, low density lipoprotein (LDL) cholesterol, high density lipoprotein (HDL) cholesterol, non-HDL cholesterol, and total cholesterol (mmol/L).
Measured: 21 days
Effect of L. reuteri strains and the non-industrialized-type diet on cardiometabolic surrogate endpoints: fasting insulin levels.
Plasma from blood samples will be analyzed for changes in insulin (µIU/L).
Measured: 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.
Homeostatic model assessment of insulin resistance and quantitative insulin sensitivity check index will be calculated based on fasting glucose and insulin levels.
Measured: 21 Days
Effect of L. reuteri strains and the non-industrialized-type diet on cardiometabolic surrogate endpoints: fasting C-reactive protein levels.
Plasma from blood samples will be analyzed for changes in C-reactive protein (mg/L).
Measured: 21 Days
Effect of L. reuteri strains and the non-industrialized-type diet on cardiometabolic surrogate endpoints: body weight.
Body weight will be measured in kilograms.
Measured: 21 Days
Effect of L. reuteri strains and the non-industrialized-type diet on inflammatory bowel disease surrogate endpoint: fecal calprotectin levels.
Fecal samples will be analyzed for changes in calprotectin (ng/mg).
Measured: 21 Days
Effect of L. reuteri strains and the non-industrialized-type diet on biomarkers of gut barrier function: lipopolysaccharide binding protein.
Plasma from blood samples will be analyzed for changes in lipopolysaccharide binding protein (µg/mL).
Measured: 21 Days
Effect of L. reuteri strains and the non-industrialized-type diet on biomarkers of gut barrier function: fecal zonulin levels.
Fecal samples will be analyzed for changes in zonulin (ng/mg).
Measured: 21 days
Effect of L reuteri strains and the non-industrialized-type diet on the composition of the fecal microbiome.
- Fecal samples will be analyzed using 16S rRNA-sequencing to measure changes in the fecal microbiome at the phylum, class, order, family, genus, and amplicon sequencing variant levels. Fecal microbiome composition will also be analyzed using whole metagenome sequencing to measure changes at the phylum, class, order, family, genus, species, and species-level genome bin levels.
Measured: 4-21 days
Effect of L reuteri strains and the non-industrialized-type diet on the function of the fecal microbiome: enzyme levels.
Fecal samples will be analyzed using whole metagenome sequencing to measure changes in enzymes encoded by gut microbiota.
Measured: 8 days
Effect of L reuteri strains and the non-industrialized-type diet on the function of the fecal microbiome: short-chain fatty acid levels.
Short-chain fatty acids (acetate, propionate, butyrate, valerate) and branched-chain fatty acids (isovalerate, isobutyrate) will be measured in fecal samples using gas chromatography mass spectrometry (µmol/g).
Measured: 8 & 21 days
Effect of L reuteri strains and the non-industrialized-type diet on the function of the fecal microbiome: pH.
Fecal pH will be measured using a pH meter.
Measured: 8 & 21 days
Effect of L. reuteri strains and non-industrialized-type diet on the metabolome.
Plasma metabolome will be assessed to determine changes in molecules with known immunological functions such as indole derivatives of tryptophan and bile acids following the provision of the intervention. This will be measured via high performance chemical isotope labeling liquid chromatography mass spectrometry platform.
Measured: 8 & 21 days
Effect of L. reuteri strains and the non-industrialized-type diet on host immune response.
Host immune responses will be measured in blood samples by quantifying IgA, selected cytokines, and white blood cell phenotyping using flow cytometry. Mononuclear cells will be isolated from whole blood on ficoll gradients and the ability of cells to respond to challenges (peptidoglycan, phytohemagglutinin, and lipopolysaccharide) will be determined ex vivo.
Measured: 8 & 21 days
Effect of L. reuteri strains and the non-industrialized-type diet on changes in psychological mood state.
Changes in individual mood state will be measured by the profile of mood states questionnaire (scored between -32 and 200; lower scores indicate more stable mood profiles).
Measured: 21 days
Effect of L. reuteri strains and the non-industrialized-type diet on changes in gastrointestinal symptoms.
Changes in individual gastrointestinal symptoms will be measured by a gastrointestinal symptom questionnaire (scored on a scale of 0-5; higher scores indicating more symptoms).
Measured: 21 days
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted18 Apr 2018
- Study start21 Feb 2019
- Primary completion31 Jan 2020
- Study completion31 Jan 2020
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (8)Papers the sponsor has linked to this study.
- Other trials for Microbial ColonizationStudies of the same condition, open and under way.
- More trials run by University of AlbertaThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Other
- Allocation
- Randomised
- Intervention model
- Crossover
- Model description
- 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).
- Masking
- Double blind
- Who is masked
- Participant, Investigator
- Enrolment
- 30 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Alberta
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Jens Walter, PhD, Principal investigator, University College CorkAndrea Haqq, MD, Principal investigator, University of Alberta
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03501082
- Sponsor's protocol ID
- Pro00077565
- Status last verified
- May 2020
- First submitted
- 21 Nov 2017
- Last updated
- 19 Sep 2024
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes: Individual participant data will be shared that underlies the results reported after deidentification (text, tables, figures, and appendices). Data will be made available through a safe and secure publicly available data sharing repository.
Publications
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.
PubMed 26196489Sonnenburg 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.
PubMed 25156449Martinez 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.
PubMed 25892234Walter 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.
PubMed 20615995Zelante 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.
PubMed 23973224Buffington 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.
PubMed 27315483Lamas 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.
PubMed 27158904He 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.
PubMed 27994068
Study at a glance
From the registry record, last updated by the sponsor on 19 Sep 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Rewilding the Human Gut: Reintroduction of the Species Limosilactobacillus Reuteri
- ClinicalTrials.gov ID
- NCT03501082
- Acronym / sponsor ID
- Pro00077565
- Conditions
- Microbial Colonization
- Keywords
- Gut microbiome
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 30 participants (actual)
- Lead sponsor
- University of AlbertaUniversity, hospital or other
- Study start
- 21 Feb 2019 (actual)
- Primary completion
- 31 Jan 2020 (actual)
- Study completion
- 31 Jan 2020 (actual)
- First posted
- 18 Apr 2018 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
There is now consistent evidence that industrialization has substantially decreased the bacterial diversity of the gut microbiota (Segata, 2015), likely due to a combination of factors such as use of antibiotics, modern clinical practices, sanitation, and changes in dietary habits. However, the only factor for which empirical evidence exists is the low content of Microbiota-Accessible Carbohydrates (MACs) in Western diets, which are indigestible dietary carbohydrates that become available to the microbes colonizing the intestine (Sonnerburg et al., 2015).
Previous work has confirmed the overall premise of 'microbiome depletion' by demonstrating higher diversity in the fecal microbiota of individuals from rural tribes in Papua New Guinea, which contain an additional of 50 species completely undetectable in North Americans (Martínez et al., 2015). One species detectable in every Papua New Guinean individual by 16S rRNA sequencing but not in a single US control was Limosilactobacillus reuteri (L. reuteri). Interestingly, this species, which is also used as a probiotic, was regularly detected in humans in studies conducted around 1960, but is very rarely found in contemporary humans, suggesting a recent decline of the L. reuteri population in Westerners (Walter et al., 2011). Most importantly, L. reuteri is a member of the gut microbiota in many vertebrate species and exerts benefits towards host immune functions and development, as demonstrated in a number of highly cited publications (Zelante et al. 2013; Buffington et al. 2016; Lamas et al. 2016; He et al. 2017).
It is currently unclear what caused the drop in the L. reuteri population. However, it is likely due to the importance of non-digestible carbohydrates that are present at very low amounts in Western diets, while being abundant in the diet of rural Papua New Guineans, a population that consumes a predominantly plant-based diet.
The goal of this study is to demonstrate that a bacterial species dominant in the non-westernized microbiome can be 'reintroduced' in the gut of Canadians fed a non-industrialized type diet designed to promote the growth of gut bacteria. This study will also determine how this 'reintroduction' and the non-industrialized-type diet influences immune function of the host and host-diet-microbiome metabolic interactions, and explore associations between them. It will further explore the effects of the microbial treatment and the diet on gut microbiome ecology. The central hypothesis is that an isolate of L. reuteri, originating from rural Papua New Guinea, can be established in the gut of Canadians fed a diet containing the carbohydrates known to facilitate the growth of this microbe. It is also hypothesized that this 'reintroduction' and consuming the non-industrialized type diet will be associated with immunological and metabolic benefits to the host. To achieve these goals, the following aims are proposed:
- To conduct a human trial to determine if a Limosilactobacillus reuteri strain isolated from rural Papua New Guinea (PNG) can be established in the gut of healthy Canadians.
- To determine if colonization can be improved by feeding a diet specifically designed to provide growth substrates for L. reuteri.
- To determine how both L. reuteri and the non-industrialized-type diet change the human microbiome, metabolome, cardiometabolic surrogate endpoints, and immune biomarkers of inflammation.
This study will establish if a 'lost species' of bacteria can be reintroduced into the human gut and may provide mechanistic insight to inform how such dietary modulation may be applied to reduce the risk of chronic diseases. Since the L. reuteri strain isolated from rural Papua New Guineans is functionally different from western strains, evidenced by different growth rates on substrates of MACs, this study will further identify potential probiotic strains that were previously uncharacterized due to their overall absence from the industrialized gut microbiome.
Study design
- Primary purpose
- Other
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Double blind (participant, investigator)
- Number of arms
- 6
- Model description
- 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).
| Arm | Type | Receives |
|---|---|---|
| L. reuteri PB-W1, Non-Industrialized-Type Diet Start | Experimental | Other: L Reuteri PB-W1 Strain, Other: Non-Industrialized-Type DietParticipants 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). |
| L. reuteri DSM20016T, Non-Industrialized-Type Diet Start | Experimental | Other: L. Reuteri DSM20016T Strain, Other: Non-Industrialized-Type DietParticipants 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). |
| Placebo, Non-Industrialized-Type Diet Start | Placebo comparator | Other: Placebo, Other: Non-Industrialized-Type DietParticipants 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). |
| L. reuteri PB-W1, Usual Diet Start | Experimental | Other: L Reuteri PB-W1 Strain, Other: Non-Industrialized-Type DietParticipants 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). |
| L. reuteri DSM20016T, Usual Diet Start | Experimental | Other: L. Reuteri DSM20016T Strain, Other: Non-Industrialized-Type DietParticipants 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). |
| Placebo, Usual Diet Start | Placebo comparator | Other: Placebo, Other: Non-Industrialized-Type DietParticipants 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). |
Who may qualify
- Ages
- 18 to 45 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (8 listed)
- 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.
Key exclusion criteria (5 listed)
- 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)
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| L Reuteri PB-W1 StrainAlso: ProbioticL. Reuteri PB-W1 strain will be prepared in accordance to the standardized operating procedures to prepare Limosilactobacillus reuteri in food grade conditions | Other | L. reuteri PB-W1, Non-Industrialized-Type Diet Start, L. reuteri PB-W1, Usual Diet Start |
| L. Reuteri DSM20016T StrainAlso: ProbioticL. Reuteri DSM20016T strain will be prepared in accordance to the standardized operating procedures to prepare Limosilactobacillus reuteri in food grade conditions | Other | L. reuteri DSM20016T, Non-Industrialized-Type Diet Start, L. reuteri DSM20016T, Usual Diet Start |
| Placebo2 g of maltodextrin will be dissolved in 50 ml water in food grade conditions | Other | Placebo, Non-Industrialized-Type Diet Start, Placebo, Usual Diet Start |
| Non-Industrialized-Type DietAlso: Controlled DietNon-industrialized-type diet will be prepared in a metabolic kitchen, with all meals and snacks provided to participants for three weeks. | Other | 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 |
Primary outcome
Establishment of L. reuteri (PB-W1 & DSM20016T strains) in the gut of Canadian individuals
Time frame: 21 days
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.
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
Time frame: 21 days
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.
16 secondary outcomes
Effect of L. reuteri strains and the non-industrialized-type diet on cardiometabolic surrogate endpoints: fasting glucose and lipid panel.
Time frame: 21 days
Effect of L. reuteri strains and the non-industrialized-type diet on cardiometabolic surrogate endpoints: fasting insulin levels.
Time frame: 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.
Time frame: 21 Days
Effect of L. reuteri strains and the non-industrialized-type diet on cardiometabolic surrogate endpoints: fasting C-reactive protein levels.
Time frame: 21 Days
Effect of L. reuteri strains and the non-industrialized-type diet on cardiometabolic surrogate endpoints: body weight.
Time frame: 21 Days
Effect of L. reuteri strains and the non-industrialized-type diet on inflammatory bowel disease surrogate endpoint: fecal calprotectin levels.
Time frame: 21 Days
Effect of L. reuteri strains and the non-industrialized-type diet on biomarkers of gut barrier function: lipopolysaccharide binding protein.
Time frame: 21 Days
Effect of L. reuteri strains and the non-industrialized-type diet on biomarkers of gut barrier function: fecal zonulin levels.
Time frame: 21 days
Effect of L reuteri strains and the non-industrialized-type diet on the composition of the fecal microbiome.
Time frame: 4-21 days
Effect of L reuteri strains and the non-industrialized-type diet on the function of the fecal microbiome: enzyme levels.
Time frame: 8 days
Effect of L reuteri strains and the non-industrialized-type diet on the function of the fecal microbiome: short-chain fatty acid levels.
Time frame: 8 & 21 days
Effect of L reuteri strains and the non-industrialized-type diet on the function of the fecal microbiome: pH.
Time frame: 8 & 21 days
Effect of L. reuteri strains and non-industrialized-type diet on the metabolome.
Time frame: 8 & 21 days
Effect of L. reuteri strains and the non-industrialized-type diet on host immune response.
Time frame: 8 & 21 days
Effect of L. reuteri strains and the non-industrialized-type diet on changes in psychological mood state.
Time frame: 21 days
Effect of L. reuteri strains and the non-industrialized-type diet on changes in gastrointestinal symptoms.
Time frame: 21 days
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 19 Sep 2024.
- Background: PubMed 26196489Segata 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.
- Background: PubMed 25156449Sonnenburg 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.
- Background: PubMed 25892234Martinez 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.
- Background: PubMed 20615995Walter 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.
- Background: PubMed 23973224Zelante 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.
- Background: PubMed 27315483Buffington 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.
- Background: PubMed 27158904Lamas 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.
- Background: PubMed 27994068He 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.
- Individual participant dataSharing planned: Yes. Individual participant data will be shared that underlies the results reported after deidentification (text, tables, figures, and appendices). Data will be made available through a safe and secure publicly available data sharing repository.
Related trials for Microbial Colonization
Not yet recruitingPhase 1
Phase I Open-Label Safety Trial of Pembrolizumab for Neurological Post- Acute Sequelae of SARS-CoV-2 (PD1-PASC I)
Post-Acute COVID-19 Syndrome
Not yet recruitingPhase 2/3
A Pivotal Safety and Immunogenicity GBS-NN/NN2 Vaccine Maternal Immunisation Trial
Streptococcus Agalactiae Infection, Neonatal Sepsis
Not yet recruiting
HealthMpowerment Korea: Pilot Testing the Cultural Adaptation of a Digital HIV Intervention for Men Who Have Sex With Men in South Korea
HIV Infections, HIV Prevention and Care
Not yet recruiting
Expanded Diagnostic Strategy in Older Adults Hospitalized With Community-Acquired Acute Respiratory Infection
Acute Respiratory Infection
RecruitingPhase 4
A Study to Compare the Efficacy and Safety of Extended and Intermittent Infusion of Beta-lactams in Critically Ill Paediatric Patients
Infection, Sepsis
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Jens Walter, PhD principal investigator
University College Cork
Andrea Haqq, MD principal investigator
University of Alberta
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing L Reuteri PB-W1 Strain, L. Reuteri DSM20016T Strain and Non-Industrialized-Type Diet in people with Microbial Colonization, run by University of Alberta at 1 site in Canada.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 8 inclusion and 5 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 19 Sep 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Canada. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Establishment of L. reuteri (PB-W1 & DSM20016T strains) in the gut of Canadian individuals (time frame: 21 days). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03501082, which also lists 8 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 19 Sep 2024.