Modification of Gut Microbiota in the Treatment of Insulin Resistance: a Personalized Approach
Condition: Insulin Resistance; Microbiome
MeSH terms: Insulin Resistance
Study type: Interventional

Summary: 
      Gut microbiota may play a key role in many metabolic diseases, including type 2 diabetes
      (T2D). Consumption of high-fat/high-sugar western diet seem to alter human resident
      microbiota towards reduced genetic diversity and to influence its metabolic activity towards
      enhanced energy extraction. Plant-based diets are effective in the treatment of T2D but it is
      not clear whether their effect results solely from diet composition or whether it is
      mediated, at least partly, by different microbiota and its metabolic activity. One possible
      therapeutic approach is replacement of "pro-diabetic" microbiota with its "healthy" variant
      but what the "healthy" microbiota is and under which conditions this microbiota could stay
      stable and functional is not known. The aim of the proposed study is to identify possible
      metagenome/metabolome characteristics in different human cohorts (T2D vs vegans), to assess
      the stability of vegan microbiota in T2D-like environment and to evaluate the possibility to
      influence human T2D microbiota/metabolome towards more protective composition by dietary
      intervention.
    

Detailed description: 
      The aim of this project is to study the possibilities of gut microbiota manipulation in type
      2 diabetes (T2D) towards more beneficial genetic and metabolic profile. This study address
      several issues. First, identification of specific metagenome/metabolome features
      characteristic for human cohorts with different risk of T2D development. Second, the
      resilience of microbiota associated with beneficial metabolic phenotype in pro-diabetogenic
      environment and the possibility to support its survival by prebiotic treatment. Third,
      development of the method for personalized prediction of the effectivity of prebiotic
      treatment in T2D patients and the evaluation of the benefit of long-term prebiotic
      administration in responders´ subpopulation. The project will be realized in three work
      packages.

      WP1: Observation study focused on the description of gut microbiome and metabolome in obese
      type 2 diabetics, vegans and obese but otherwise healthy omnivores and identification of key
      markers specific for these populations.

      WP2: Study focused on the interaction of vegan microbiota and pro-diabetogenic (western-type)
      diet and on the effects of prebiotic supplementation in germ-free animals. In addition, the
      effect of diet-alone and the effect of standardized Schaedler flora will be tested as well.

      WP3: The identification of predictive markers indicative for the benefit of prebiotic
      treatment in the individual context (T2D cohort) and second, long-term human intervention
      study in the selected responders´ group aimed on the possibility of therapeutic modulation of
      gut microbiome/ metabolome by prebiotics. Only WP3 is subjected to clinical trial
      registration.

      In details:

      WP 3: Identification of T2D subpopulations according to their susceptibility to dietary fiber
      intervention Questions:

        1. Are there different subpopulations within T2D subjects that differ in their ability to
           increase SCFA production in response to prebiotic supplementation?

        2. Is it possible to identify these subpopulations ("responders" vs "non-responders") by
           simple intervention test?

        3. Is this phenomenon associated with specific microbiota composition?

        4. Within "responder" subpopulation, is it possible to manipulate fecal
           metabolome/metagenome towards more beneficial composition by long-term prebiotic
           intervention? In order to fulfill this task microbiome characterization of T2D cohort in
           WP1 will be used.

      The aim of WP3 is to provide the proof of concept that a diet enriched with specific
      prebiotics improves the specific (SCFA) metabolite production and that the beneficial effect
      is dependent on pre-existing microbiota composition.

      Acute intervention test ("inulin test") The participants enrolled into T2D cohort will be
      asked to participate in short-term intervention test. They will be provided the prebiotic and
      instructed on the test procedure.

      Step 1: sample the stool ("sample 1"); step 2: take the dose (20 g) of inulin; step 3: during
      following three days collect sample of feces at each defecation. The samples will be analyzed
      by NMR and mass spectrometry with special respect to SCFA content.

      Primary readout: The magnitude of SCFA content elevation after the bolus prebiotic
      administration.

      Secondary readout: The potential association between the response to prebiotic bolus and
      microbiota composition.

      Long-term intervention study Based on the results of acute inulin intervention test, the
      subgroups of most pronounced "responders" and "non-responders" will be selected (defined as
      both extreme tertiles of the group, at least 10 subjects are expected to be enrolled per
      subgroup). Participants from both subgroups will be asked to take part in three months
      intervention study when they will be administered 10 g of inulin prebiotic (FAN s.r.o.,
      Tišice 225, 27715 Tišice) on every-day basis. Prior and at the end of the intervention
      period, the participants will be subjected to metabolic characterization, indirect
      calorimetry and assessment of intestine permeability. Feces samples will be collected before
      the study and then after each month for 16S rRNA sequencing, NMR spectroscopy and mass
      spectrometry.

      Primary readout:

      gut microbiome and fecal, urine and plasma metabolome composition of feces

      Secondary readouts:

        1. metabolic characteristics: basal blood tests (glucose, lipid profile, NEFA, insulin,
           C-peptide); twostep hyperinsulinemic euglycemic clamp; indirect calorimetry with energy
           expenditure and respiratory quotient

        2. intestinal permeability markers: serum content of bacterial endotoxin, D-lactate,
           endotoxin core antibody, iFABP and citrulline.

      Expected outcome: validation of short prebiotic intervention test as a tool for prediction of
      the efficiency and benefit of long-term prebiotic supplementation; evaluation of the benefit
      of long-term prebiotic supplementation in T2D "responder" subgroup.
    

Intervention name(s): Inulin
Intervention type(s): Dietary Supplement
Intervention description(s): Inulin is a dietary fibre. Will be supplemented in a dose 10g/d for a period of 3 moths.
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Intervention model description: single groups assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Insulin resistance; Diabetes; Inulin; Microbiome