Rewilding the Human Gut: Reintroduction of the Species Limosilactobacillus Reuteri
Condition: Microbial Colonization
MeSH terms: Communicable Diseases; Infections
Study type: Interventional

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.
    

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:

        1. 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.

        2. To determine if colonization can be improved by feeding a diet specifically designed to
           provide growth substrates for L. reuteri.

        3. 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.
    

Intervention name(s): L Reuteri PB-W1 Strain; L. Reuteri DSM20016T Strain; Placebo; Non-Industrialized-Type Diet
Intervention type(s): Other; Other; Other; Other
Intervention description(s): L. 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 strain will be prepared in accordance to the standardized operating procedures to prepare Limosilactobacillus reuteri in food grade conditions; 2 g of maltodextrin will be dissolved in 50 ml water in food grade conditions; Non-industrialized-type diet will be prepared in a metabolic kitchen, with all meals and snacks provided to participants for three weeks.
Other intervention name(s): Probiotic; Probiotic; Controlled Diet
Allocation: Randomized
Intervention model: Crossover Assignment
Intervention 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 (Participant, Investigator)
Primary purpose: Other
Keywords: Gut microbiome