Luxembourgish Fiber Cohort
Condition: Dietary Fiber; Gastrointestinal Microbiome; Healthy Volunteers
Study type: Interventional

Summary: 
      Many human populations across the world are deficient in the intake of dietary fiber. This
      decline in fiber consumption parallels an increase in prevalence of a multitude of diseases
      (e.g. colorectal cancer, multiple sclerosis). A possible link for this association between
      dietary changes and the diseases could rest in the trillions of commensal gut microbes that
      digest dietary fibers, provide energy for colonic cells, and modulate the immune system.
      However, the molecular mechanisms that link fiber deficiency via the activities of the gut
      microbiome to various diseases have been poorly understood. The investigators previously
      showed that, in a mouse model with a defined human gut microbiota, removal of fiber from the
      diet favors proliferation of bacteria that degrade the gut's protective mucus lining. In the
      proposed project, the investigators aim to translate our findings from mouse studies to
      humans using a 2x2 crossover study among healthy adults. Forty participants will be randomly
      assigned to a low- or high-fiber dietary intervention and then, following a washout period to
      reverse any changes, switched to the other diet type. By employing longitudinal sampling of
      stool collections, the investigators envision that participants will exhibit increased
      abundance and activities of mucolytic bacteria when fed a low-fiber diet. The unique selling
      point of the proposed study involves setting up high-throughput culture collections of
      mucus-degrading bacteria, whose abundances and activities will be investigated by sequencing
      and enzymatic assays in stool. Additionally, the investigators will measure inflammatory
      markers in blood using CyTOF to assess whether short-term fiber deficiency exerts detectable
      changes in the host immune function. Thus, the proposed dietary intervention clinical trial
      will help elucidate the role of fiber deficiency in various chronic diseases.
    

Detailed description: 
      Industrialized nations tend to consume less dietary fiber and, in many nations with a
      Western-style diet, average consumption is half the recommended daily intake of 25-38 g/day.
      Dietary fiber is an important component of a healthy diet because it increases fecal bulking
      and laxation, lowers cholesterol and regulates levels of blood glucose. The connection
      between low fiber-intake and disease may rest with the gut microbiota, the trillions of
      commensal microorganisms that inhabit the gastrointestinal tract. Bacteria found in the gut
      are responsible for an array of functions that support human health, including conversion of
      host-indigestible fibers into short chain fatty acids (SCFAs), which provide energy for
      colonic cells, support mucus production, and modulate the immune system.

      The investigators have recently investigated the effects of a fiber-free diet in a
      gnotobiotic mouse model with a 14-member synthetic microbial community showing that
      mucus-degrading bacteria outcompete fiber-degrading bacteria, causing degradation of the
      colonic mucus layer. One member of this synthetic community, Akkermansia muciniphila, is a
      commensal bacterium found at 1-4% relative abundance in the human gut and feeds specifically
      on the host-secreted mucins. However, this bacterium is significantly enriched in the gut of
      patients with multiple sclerosis and colorectal cancer, suggesting that its mucolytic
      capabilities may play a role in these diseases. A microbial shift toward enrichment of
      mucolytic bacteria could be an important precursor to gut-linked diseases. While
      observational studies have identified a lower risk of irritable bowel diseases (IBD) in
      people who consume diets high in fiber, fruits, and vegetables, no study has explicitly
      investigated the effects of fiber on the functional capacity of the human gut microbiome in
      the context of effects on the mucus-degrading microbiome. Based on our published work in
      mice, for the current project, the investigators hypothesize that deficiency of dietary fiber
      in humans promotes increased activities of mucus-degrading bacteria, thereby reducing the
      mucus lining in the intestine. The investigators request pump priming to initiate this pilot
      project, as it will generate foundational datasets to inform numerous follow-up studies.

      Thus, the current project seeks to translate findings from mouse models to humans, using a
      crossover study among healthy adults. Participants will be randomly assigned to a first
      dietary intervention that is low or high in fiber and then, following a washout period
      intended to reverse any compositional changes, switched to the second diet type. The diets
      will be evaluated by a nutritionist to ensure that they differ in fiber content, but are
      comparable in terms of caloric and macronutrient content. The targeted amount of dietary
      fiber intake from the high-fiber test meals will be around 30 g/d more than the low-fiber
      diet. In addition to dietary records, the investigators will administer questionnaires,
      obtain basic clinical measures (blood pressure, weight, height, waist/thigh circumference),
      collect blood samples for immunological assays and collect stool samples before and at the
      end of each diet intervention for sequencing and functional profiling of bacterial
      communities.

      The investigators will recruit healthy volunteers to participate in a 2x2 crossover design
      controlled-diet study. After statistical consultation, the investigators conclude that the
      investigators require a sample size of n=15 in each sequence group (a total sample size of
      N=30) to have 87.5% power to detect a -0.5 difference in means for alpha diversity (Shannon
      index) under the two diet conditions. Volunteers who meet all inclusion and exclusion
      criteria will be randomly assigned to a high- or low-fiber diet intervention and then, after
      a week-long washout period, will receive the second diet type. High and low fiber meals
      containing a variety of fiber types will be served to participants at a designated drop-off
      site (home or workplace) for one week in order to decrease variance in fiber intake, increase
      adherence to the diet, and maximize knowledge of the nutritional content in participants'
      diet. Nutritionally balanced dietary interventions are designed by a qualified dietitian at
      SERVIOR in conjunction with the LIH study team and delivered by Paul Eischen Traiteur, a
      partner catering service. Participants on both diet interventions will be given multivitamin
      supplements in order to further ensure they receive essential vitamins and minerals.

      At the baseline visit, our team will work with nurses from the Clinical and Epidemiological
      Investigation Center (CIEC, headed by Dr. Manon Gantenbein) to collect demographic data,
      anthropometry, early life history, family medical history, detailed dietary patterns, and
      biological samples (blood, urine, and stool). Participants will use a Participant Diary to
      log their diet throughout the study in the form of daily 24 hour food recalls, except for
      foods or beverages provided during the dietary interventions. After each intervention period,
      a week-long washout period will be employed to reverse any changes that occurred due to the
      diet.

      Mid-way through each intervention and washout period, the investigators will administer a
      brief survey containing questions relevant to our research objective. At each of these
      visits, CIEC nurses will collect biological samples and anthropometric measures. Participants
      will also be asked to drop off a stool sample for the next two days. All participant data
      will be pseudonymized when exported from Research Electronic Data Capture application
      (REDCap) for analysis and will be handled in accordance with the General Data Protection
      Regulation (GDPR). The study has been granted ethical approval by the Luxembourg Ministry of
      Health (Ref# 835x38895) and by Comité National d'Ethique de Recherche (CNER; Ref# 201911/03).
    

Intervention name(s): High Fiber Diet Intervention; Low Fiber Diet Intervention
Intervention type(s): Dietary Supplement; Dietary Supplement
Intervention description(s): Plant-based diet with a targeted quantity of 35 g of dietary fiber per day, from a variety of fiber types. Each meal will be balanced to provide all essential nutrients and portions will be of adequate size to ensure participants are satiated. Participants on both diet interventions will be given multivitamin supplements in order to ensure they are receiving essential vitamins and minerals.; Animal based diet (meat, dairy) with a targeted quantity of 10 g of dietary fiber per day. Each meal will be balanced to provide all essential nutrients and portions will be of adequate size to ensure participants are satiated. Participants on both diet interventions will be given multivitamin supplements in order to ensure they are receiving essential vitamins and minerals.
Allocation: Randomized
Intervention model: Crossover Assignment
Intervention model description: This study involves recruitment of healthy volunteers to participate in a 2x2 crossover design controlled-diet study.
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: Metagenome; Whole Genome Sequencing; Biomarkers; Mucolytic Activity; Mass cytometry; Inflammatory Bowel Diseases