The Alberta FYBER (Feed Your Gut Bacteria morE fibeR) Study
Condition: Overweight and Obesity
MeSH terms: Overweight
Study type: Interventional

Summary: 
      Too much body-fat has been linked to a low-grade inflammation throughout the body. This
      inflammation is thought to then cause different diseases, like heart disease and diabetes. A
      lower amount of inflammation is usually seen in people that follow a high fiber diet. A
      reason for this is the microbes that live in our gut. Fiber is a main food source for these
      microbes. This allows fiber to actually change the type of microbes that live in our gut.
      Also, when fiber gets fermented by these microbes, health-promoting waste products get
      released. We aim to determine how exactly our gut microbes contribute to the health
      properties of fiber.

      We hypothesize that fiber's health properties depend on how the gut microbes respond to the
      fiber. To test this, we plan to add three different fibers to the diets of healthy overweight
      and obese individuals for six weeks. We then will determine how the different fibers affect
      an individuals' health by looking at how established markers of health change from adding the
      fiber. Following this, we will see how an individual's gut microbes respond to the added
      fiber. The response will be decided by looking at changes to the microbe community, as well
      as their ability to ferment the fibers. By connecting health outcomes to the gut microbes'
      response, we can test if the gut microbes' response to the fiber determines the fiber's
      ability to effect health. If we can understand how our gut microbes respond to different
      fibers and the importance of that response. Then we could personalize diets to have a greater
      impact on improving health.
    

Detailed description: 
      Being overweight and obese significantly increases the risk of developing numerous diseases,
      including cardiovascular disease (CVD), type 2 diabetes (T2D), and certain cancers. The
      microbial community (microbiota) that resides within the gut play a notable role in obesity
      and its associated pathologies (e.g. CVD, T2D), and is therefore a potential therapeutic
      target. Diet is known to determine whether the gut microbiota contributions to host
      metabolism are beneficial or detrimental. A westernized diet high in fat and sugar is
      associated with systemic inflammation, while fat intake increases lipopolysaccharide
      translocation through the gut membrane. In addition, gut microbial metabolism of choline and
      L-carnitine can produce trimethylamine, which has been shown to contribute to atherosclerosis
      after being oxidized in the liver to trimethylamine N-oxide (TMAO). In contrast, diets high
      in dietary fiber from fruits, vegetables, and whole grains are inversely associated with
      inflammation and can potentially reverse effects of a high fat diet. Fermentable fiber types
      can resist host digestion, but are then subsequently fermented by the gut microbiota to
      short-chain fatty acids (SCFAs), which are known to have metabolic and immunologic benefits.
      Accordingly, both epidemiologic associations and human intervention trials suggest an inverse
      association between fiber intake, reduced systemic inflammation, and improved lipid and
      glucose metabolism; however, results remain inconsistent. These discrepancies might be partly
      attributable to (I) the low fiber doses used in most studies, and (II) the high degree of
      inter-individual variation in the response to fiber, which may stem from the individualized
      responses of the microbiome to fiber. The emerging evidence that fiber and the gut microbiota
      interact to influence host physiology warrant human clinical research that investigates the
      capacity of chemically distinct fibers to modulate host metabolism and inflammation, and the
      mechanistic role of the gut microbiota in their physiological effects.

      Our long-term goal is to contribute to such a framework through clinical research that
      applies a holistic approach to examining the effect of fiber on both the host and its gut
      microbiota. We hypothesize that fibers show structure-dependent effects on inflammatory,
      metabolic, and hormonal markers of obesity-associated pathologies that can be predicted
      through compositional, functional, and genetic characteristics of an individual's fecal
      microbiome. We propose the following specific aims:

      AIM 1. Perform a parallel-arm exploratory intervention study in overweight and mildly obese
      individuals to determine the impact of high doses of chemically distinct fibers on host
      inflammatory markers, measures of insulin sensitivity, and other clinical outcomes.

      The effect of two physicochemically distinct fermentable dietary fibers (acacia gum and
      resistant starch type 4) on clinical markers of metabolic disease will be compared against a
      relatively non-fermentable dietary fiber (microcrystalline cellulose - control). We will
      employ a three-arm, parallel-design, single-blind, placebo-controlled, stratified randomized
      exploratory trial. Fibers will be administered in relative pure form daily over six weeks
      without any further lifestyle adjustments. Doses used in the trial will be 25 g/day of fiber
      for women and 35 g/day for men (close to Health Canada's dietary recommendations). Although,
      the first two days of treatment will use half the daily treatment dose of fiber (women: 12.5
      g/day; men: 17.5 g/day), to ease the incorporation of the fiber into the diet. Participants
      will be advised on how to incorporate the fibers into their diet, as to improve tolerance and
      compliance.

      The impact of dietary fiber on a comprehensive set of well-established obesity-related
      biomarkers will be determined via quantification at baseline and post-dietary intervention.
      High sensitive C-reactive protein and other inflammatory markers (e.g. interleukin-6,
      interleukin-10), as well as established markers for metabolic syndrome (e.g. fasting glucose
      and triglycerides) will constitute as key endpoints of the exploratory trial. To gain further
      understanding on the mechanisms that mediate metabolic and inflammatory improvements; five
      primary gut hormones, including satiety/hunger signaling hormones (e.g. glucagon-like
      peptide-1, leptin, and ghrelin), will be included. Lifestyle indicators, compliance with
      treatment, and satiation will be further assessed through self-administered questionnaires.

      AIM 2. Evaluate the short- and long-term impacts of chemically distinct types of dietary
      fiber on gut microbiota composition, genetic characteristics, and production of
      anti-inflammatory (SCFA) and pathogenic (TMAO) metabolites.

      We will utilize Illumina 16S rRNA sequencing and whole metagenomic sequencing to characterize
      the fecal microbiota (that will be enriched for large bowel bacteria) of our exploratory
      trial participants at weeks 0, 1, and 6, to explore fiber-induced changes in gut microbiota
      composition and gene content. These methods will be used as a majority of gut microbiota are
      not currently culturable. To further investigate gut microbiota function, we will quantify
      specific bacterial associated metabolites in plasma (TMAO) and in feces (SCFAs and bile
      acids). In parallel, we will quantify the fecal metabolites after in vitro fermentation, to
      account for absorption in the human gut. This will allow us to gain insight into
      fiber-induced changes in gut microbiota composition, metabolism, and functionality that
      coincide with the physiological effects observed in the host.

      AIM 3. Characterize associations between clinical outcomes and microbiome shifts and
      determine how well individual microbiome configurations predict impacts of dietary fiber.

      With the establishment of a robust human exploratory trial, a well-defined set of host
      phenotypes, and participant microbiome characteristics, Aim 3 will statistically integrate
      these data to specifically test for associations between diet, the gut microbiome, and host
      metabolism, and evaluate if microbiome and host phenotypic signatures at baseline can predict
      clinical outcomes of dietary fibers
    

Intervention name(s): Microcrystalline Cellulose Supplementation; Acacia Gum Supplementation; Resistant Starch Type 4 Supplementation
Intervention type(s): Other; Other; Other
Intervention description(s): Fifty overweight and mildly obese subjects will supplement their normal dietary intake with a significant yet tolerable amount of MCC (Females: 25 g; Males: 35 g) daily for six consecutive weeks.; Seventy five overweight and mildly obese subjects will supplement their normal dietary intake with a significant yet tolerable amount of AG (Females: 25 g; Males: 35 g) daily for six consecutive weeks.; Seventy five overweight and mildly obese subjects will supplement their normal dietary intake with a significant yet tolerable amount of RS4 (Females: 25 g; Males: 35 g) daily for six consecutive weeks.
Other intervention name(s): Microcel MC-12; Blanver Farmoquímica Ltda.; Agri-Spray Acacia Fibre; Agrigum International Ltd.; Fibersym RW; MGP Ingredients, Inc.
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Participant)
Primary purpose: Other
Keywords: Dietary Fiber; Gastrointestinal Microbiome; Overweight and Obesity; Personalized Nutrition; Inflammation; Metabolism