Gut health and glucose

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Background 

  1. What is the gut? 
    1. The gut is a long hollow tube that starts at the mouth and ends at the rectum.  
    2. Think of the gut like a row of dominos.  If the first does not fall, the others will not either.  
  1. Why care? 
    1. Digestion 
      1. The gut processes the food into simple nutrients that can enter the bloodstream.  These nutrients are delivered throughout the body.  
      2. If something is wrong with our gut, food will not be absorbed properly. 
      3. 70 million people in the US have digestive issues.  
        1. This includes a variety of gut issues.  The most common are: Abdominal wall hernia, chronic constipation, diverticular disease, gallstones, gastroesophageal reflux disease, gastrointestinal infection, inflammatory bowel disease, ulcerative colitis, IBS, Pancreatitis, Peptic Ulcer disease, Viral Hepatitis   
        2. Abdominal pain, bloating, loose stools, constipation, heartburn nausea are all signs that there is an issue with the gut. 
    2. Immunity  
      1. Gut and immune system are strongly connected.
      2. Over 70% of the body’s immune cells reside in the gut
      3. The gut is the first line of defense against viruses.  We can think of the interior of the gut as being outside of the body 
      4. The gut contains immune cells to ward off infections from bacteria, viruses and fungi.  
      5. Gut microbiome and immune system and deeply connected.  Gut dysbiosis can negatively impact the immune system. 
    3. Chronic condition connection
      1. Leaky gut and dysbiosis are gut issues that have been linked to a variety of chronic conditions.  
      2. Leaky gut is when there is increased permeability in the intestinal barrier.  Dysbiosis is an imbalance of microbes in the gut.  
      3. Obesity, diabetes, cardiovascular disease, cancer, metabolic syndrome and diabetes, neurological disease, overall cognitive health, psychiatric conditions, autoimmune disease, skin health and more are all correlated to poor gut health.  
      4. More than just correlational through fecal transplant studies.
        1. Alterations to mice microbiomes resulted in development of chronic disease.  
        2. Obesity– Animal studies– germ-free mice were colonized with obese microbiome they developed more body fat then the germ-free mice that were colonized with lean microbiome.  
        3. Metabolic/immune dysfunction- Laboratory mice raised to be completely free of any microorganisms show impairment in various metabolic and immune functions, demonstrating that the microbiome is crucial in developing and maintaining normal physiology.
        4. Insulin sensitivity:   Human study – when fecal implant was transferred from lean donor to person with metabolic syndrome, there was an improvement in insulin sensitivity.  

What is the gut?  What makes a good gut 

Long hollow tube that starts at the mouth and ends at the rectum.  The digestion process really starts in the brain.

  1. Gastrointestinal system
    1. Brain
      1. Most Important organ outside of the digestive tract.  The brain and gut are in constant communication.  
      2. The two organs are connected both physically and biochemically.  Connected via nerves.  Microbes in the gut also produce substances that impact the brain.  
      3. Stress 
        1. Autonomic nervous system is the part of our nervous system that controls involuntary actions. 
        2. Parasympathetic (rest and digest) and sympathetic (fight or flight) are 2 or the 3 main components of this.  
        3. The 3rd component is the enteric nervous system which helps regulate digestion.  
        4. If the sympathetic is chronically activated, less energy is put towards digestion.  
        5. Stressful  events are associated with onset of symptoms in several digestive conditions such as IBD, IBS, GERD, peptic ulcer.  
        6. Important to reduce stress before eating!
      4. Vagus nerve 
        1. Gut contains 500 million neurons that are connected to the brian through nerves.  
        2. Vagus nerve is one of the biggest nerves that connect the gut to the brain. Signals are sent in both directions. 
        3. Animal studies show that stress inhibits signals from the vagus nerve, resulting in gastrointestinal problems. 
        4. One study in humans with IBS and Crohn’s had reduced vagal tone, indicating reduced function of the vagus nerve.  
      5. Neurotransmitters
        1. Neurotransmitters are the body’s chemical messengers.  Many neurotransmitters that have to do with mood are produced in the gut.  When the gut is healthy, more neurotransmitters are produced.  When there is dysfunction, less is produced.   
        2. Serotonin
          1. It is estimated that the gut produces 90% of the body’s serotonin. Serotonin is a hormone and neurotransmitter that is responsible for sending chemical messages between cells to help stabilize mood and control body clock.  In the brain, serotonin allows neurons to communicate with one another.  When too little serotonin is produced, we can experience anxiety, depression and other mental issues.    
            1. Gut microbes may be involved in this production 
              1. Study- Germ free mice produced 60% less serotonin in their guts compared to their peers with conventional microbiomes.  
              2. So even though a large proportion of serotonin is produced in the gut, the exact mechanisms for production is still unknown.  Also all studies are conducted on mice.  
      6. GABA
        1. Gut microbiota produce GABA which helps control fear and anxiety. 
        2. Lab mice- shown that certain probiotics can increase GABA and improve mood.  
  2. Gut microbiome 
    1. The microbes in the gut produce chemicals that impact how your brain works.  
    2. SCFA
      1. Gut microbes produce SCFA (butyrate, propionate, acetate) by consuming fiber.  These chemicals can impact the amount of food we eat.  
      2. Study- increased propionate reduced food intake and reduced activity in the brian related to reward for high energy foods.   
    3. Inflammation 
      1. Gut-brain is also connected through the immune system.  
      2. Gut microbiome plays an important role in regulating our immune system and inflammation.  
      3. If the immune system is on for too long, it can lead to inflammation that is associated with brain disorders like depression and Alzheimers.  
      4. LPS is an inflammatory toxin produced by gut microbes that can cause inflammation if it passes from the gut to bloodstream.  This happens when the gut becomes leaky.  
      5. Inflammation and high LPS are associated with brain disorders such as depression, dementia, schizophrenia.  
  3. Mouth
    1. Digestion begins.  
    2. Start of mechanical breakdown of food 
      1. Teeth and tongue help chew. 
    3. Chemical breakdown
      1. Chemicals like saliva and enzymes break down food.  
      2. Mouth produces salivary amylase for carbs and lingual lipase for fats.  
    4. Signals stomach to produce stomach acid. Signals pancreas to produce pancreatic enzymes. 
      1. Study- slowing down eating reduces total intake.  
      2. Study- Increasing chews per bite increased gut hormone releases that relate to satiety.   
      3. Study- Iranian girls.  Shown that those with less teeth had increased IBS symptoms. Implying that less chewing may lead to IBS.  
  4. Esophagus 
    1. This is also called the food pipe.  It transports food from the mouth to the stomach.  
  5. Stomach
    1. Hollow pouch surrounded by muscles.  
    2. Further mechanical breakdown 
      1. Muscles are responsible for further mechanical breakdown.  
      2. Churning of the stomach allows food to be transformed into chyme.  
    3. Chemical breakdown 
      1. Further broken down by producing hydrochloric acid (HCL). 
      2. The HCL helps sterilize the food so we do not get sick. HCL also helps break down protein and other nutrients.  Gastric lipase is produced to break down fat.  
    4. Washing machine 
      1. Think of the stomach like a washing machine.  Chewed up food mixes with HCL just like clothes mix with soap.  The more work you do with chewing, the less work the stomach has to do.   The more chewing, the more surface area for HCLand enzymes to do their job.  
    5. Low HCL 
      1. May experience digestive issues, nutritional deficiencies, GI infections
      2. Digestive symptoms
        1. Indigestion, gas, bloating, constipation, diarrhea, undigested food in stool.  
      3. Reduced absorption of nutrients
        1. Reduced absorption of nutrients such as calcium, iron, folic acid, vitamin B6 and vitamin B12. 
      4. Increase risk of SIBO 
        1. Article that goes into this connection more
      5. Factors that can lower stomach acid
        1. Age, stress, vitamin deficiency (zinc or b vitamins), medications, H. Pylori and Surgery can all lead to lower HCl.  
      6. Diagnosis 
        1. Fasting gastric pH less than 3 is normal.  Values over 3 or hypochlorhydria.   
  6. Pancreas, liver and gallbladder
    1. Solid organs that add compounds to the mix to help aid digestion.  
    2. Pancreas
      1. 6-inch long gland located near the liver and part of the small intestine.  Involved in 2 systems.  
      2. Exocrine system
        1. Secretes digestive enzymes into the small intestine through duct of duodenum.  
        2. Lipase for fats, amylase for carbs, chymotrypsin and trypsin for digesting proteins
      3. Endocrine system
        1. Produces hormones such as blood-sugar regulating insulin and glucagon.
      4. Part of larger system
        1. Starts producing enzymes as soon as food hits the stomach.  
        2. Main pancreatic duct meets with the common bile duct.  The common bile duct is where the gallbladder meets with the duodenum.  
    3. Liver 
      1. Largest solid organ. Vital in metabolic and immune function.  Right upper portion of the stomach.  
      2. How it aids in digestive process: 
        1. Break down and convert energy- example protein and alcohol. 
        2. Stores vitamins and releases as needed 
        3. Produces bile that is secreted out of gallbladder
    4. Gallbladder 
      1. Small organ located below the liver.  Stores bile that is produced in the liver and releases into the small intestine.  
  7. Small intestine
    1. Made of duodenum, jejunum and ileum.  Measures 6-7 meters.  Surface area of 200 meters.  
    2. Nutrients are absorbed and packaged to the rest of the body.  Because so many nutrients are absorbed here, the SI requires massive surface area.  21 feet in length.  Inner lining has a villi.  These increase surface area of absorption.
  8. Large intestine 
    1. Posterior section of intestine.  Consists of the cecum, colon, rectum and anus.  
    2. Functions of large intestine:  
      1. Reabsorption of water and mineral ions 
        1. Colon acts as a guts dryer.  Continue to absorb out water and electrolytes.  Passes any remaining waste out of the body.  
      2. Formation and temporary storage of feces
      3. Maintain microbiome. 
  9. Gut microbiome 
    1. What is it?  
      1. The microbiota is the community of microorganisms that live in and on the human body. This includes trillions of bacteria, along with archaea, fungi, viruses, and eukaryotes that have co-evolved with humans over thousands of years. Of these, the bacteria are the most abundant and well characterized.
      2. The microbiome is all of the collective genes. Often the terms “microbiota” and “microbiome” are used interchangeably, but the technical distinction is that “microbiota” is referring to the microbes, and “microbiome” is referring to their genes.
      3. When most people refer to the microbiome, they are referring to the gut microbiome.  However, we do have a microbiome in the skin, nose, mouth, etc. 
    2. Brief History/fast facts
      1. Hippocrates once said “all disease begins in the gut.” 
      2. The microbiome was not recognized by modern science until the late 90s.  
      3. In 2001, Dr. Jeff Gordan and his lab produced the first paper on gut-microbe relationship in the gut.  
      4. Very new science.  
      5. We have 38 trillion bacterial cells in the gut.  1.3 bacterial cells for every human cell.  
      6. Microbes in the gut have 3.3 million genes.  100 times human genes.  
      7. Each person has 300-1000 unique species.  
    3. When do we develop a microbiome? 
      1. We develop the microbiome at birth.  But some suggest we start the microbiome in the mother’s womb.
      2.  Our delivery method at birth, our initial feedings, and our early hygiene can all dynamically shape our infant gut microbiome.
    4. How does the microbiome impact our health? 
      1. Digestion/metabolism/synthesizing vitamins
        1. Overview of Digestion: 
          1. The microbiome breaks down complex carbs, fats and proteins.
          2. Breakdown of these nutrients creates metabolites that can act both locally or systemically after being absorbed into the bloodstream.   
          3. Metabolites can be both beneficial or toxic.  
          4. Factors that influence digestive efficiency:  
            1. Form and size of the food particles (affected by cooking and processing)
            2. The composition of the meal (affected by the relative ratios of macronutrients and presence of anti-nutrients such as α-amylase inhibitors)
            3. Transit time.  Transit time can be impacted by diet, physical activity, genetics, drugs (e.g., caffeine and alcohol), and psychological status.
          5. Colon is the major site of fermentation.  This is because there is a relatively high transit time, pH is favorable for gut bugs, low cell turnover and more redox potential.   
        2. Carbohydrates
          1. Key bacterial fermentation products are SCFA and gases. 
          2. SCFA
            1. Acetate, propionate, butyrate are the main one.
            2. Butyrate is the most important for human health. Key energy source for colonic cells and has potential anti-cancer properties
          3. Gases
            1. Gas is a byproduct of anaerobes.  
            2. Healthy human produces several liters a day.  The majority is Hydrogen, carbon dioxide and methane- all odorless! 
            3. The gases that have an odar constitute 1% of gases. NH3, hydrogen sulphide, indole, skatole, and volatile amines.
            4. Excessive gas production by microbes can have negative consequences on the host.  
            5. The presence of methane in the colon has been linked with colorectal cancer, although the association may be a consequence of the disease rather than causal, since patients with the condition have slower colonic transit times.
            6. Individuals with lactose intolerance have increased gas production, since the defective absorption of lactose in the upper GIT means that lactose reaches colonic bacteria, and is fermented forming gas.
        3. Digests protein.  
          1. Breaks down into ammonia, branched-chain fatty acids, amines, sulfur compounds, phenols, and indoles.
          2. Also produces SCFA but accompanied by other compounds listed above
          3. Protein catabolism in the gut generally has a negative connotation, as compounds that are toxic to the host can result from this process, including amines, phenols/indoles, and sulfurous compounds.  However, it is important to note that not all amino acids are fermented to toxic products as a result of gut microbial activity; in fact, the most abundant end products are SCFAs
          4. It may not be protein catabolism per se that negatively impacts the host, but instead specific metabolisims or overall increased protein fermentation activity.
        4. Digests fat.  
          1. Breaks down into glycerol and choline.
        5. Makes polyphenols more bioavailable:
          1. Biotransformation of exogenous plant-derived polyphenols that have antioxidant, anti-cancer, and/or anti-inflammatory properties by the gut microbiota, which improves their uptake by the host.
          2. Polyphenols are a group of compounds found in plants, fruits, vegetables, cereals, tea, coffee and wine.  
          3. Basically the gut breaks down these polyphenols so that we can obtain the benefits.  90% of polyphenols are broken down by the gut microbiome. 
          4. Two way streak. Polyphenols can act a prebiotic to the microbiome, benefiting good gut microbes.  
        6. Synthesize nutrients
          1. The gut microbiota can synthesize certain vitamins, notably vitamin K, and B group vitamins including biotin, cobalamin, folates, nicotinic acid, pantothenic acid, pyridoxine, riboflavin, and thiamine.
          2. Study- human subjects on low vitamin K diets for 3–4 weeks did not develop vitamin deficiency, but those treated with a broad-spectrum antibiotic to suppress the microbiota showed a significant decrease in plasma prothrombin levels
      2. Immune health
        1. What is it?  
          1. The immune system is a group of cells and molecules that protect us from disease by monitoring our body and responding to foreign substances that are perceived as threats
        2. Mutualistic relationship between microbiome and immune system
          1. Immune system and microbiome have mutualistic relationships.  They regulate one another and support one another.  Our immune system has co-evolved along with the microbiome to develop defenses to pathogens and support beneficial bacteria.  70-80% of immune cells in the gut.   
          2. Relationship between the microbiome and the immune system starts at birth.  As we grow, the microbiome shapes the immune system.  The immune system shapes the microbiome.  Communication and mutual regulation is maintained throughout life.  
          3. The immune system promotes the growth of beneficial microbes.  Healthy microbes produce molecular signals that support immune cells.  
          4. Healthy intestinal barrier function allows certain gut-derived molecules to get into the body, while keeping others out. This supports better immune performance.
        3. How the microbiome impacts immunity 
          1. SCFA 
            1. SCFA are metabolites produced by microbes
            2. promote activity of T cells.  T cells prevent inflammatory reactions from harmless microbes by suppressing abnormal activation of other immune cells.  
            3. Support the integrity of the endothelial layer.  
          2. Immunoglobulin A 
            1. IgA is a type of antibody produced by B cells.  Can bind to microbes, dietary compounds and other antigens in the intestine.  This creates an additional layer that prevents harmful interactions with the immune system.
            2. There is a two way relationship between IgA and microbiome.  
            3. Immunoglobulin A supports a healthy gut microbiome.  Supports diversity, controls microbiota gene expression, enhances mutualism between gut microbiome and host.  
            4. A  healthy gut microbiome supports more IgA production.  Increase plasma cells, diversity of IgA response
          3. TH17
            1. TH17 is a helper of T cells.  Located in the intestinal walls.  Stimulate antimicrobial proteins, including IgA, and enhance mucosal barrier.  Therefore, reduce infection. 
            2. Dysbioisis can cause dysfunction with TH17.  Can cause it to produce inflammatory cytokines.  Harmful TH17 can migrate to the lymph nodes promoting immune reactions.  This can exacerbate autoimmune symptoms.    
      3. SCFA Benefit brain
        1. SCFA butyrate (produced from microbes) may benefit the brain.
        2. Study- Mice given sodium butyrate of butyrate producing microbes showed increased neurogenesis, reduced oxidative stress, and improved recovery following ischemic brain injury.
      4. SCFA may prevent against colon cancer
        1. SCFA like butyrate (produced from microbes)inhibits the enzyme that is important in tumor development 
        2. Inhibits histone deacetylase (HDAC), which leads to alterations of several important tumor development pathways such as JAK2/STAT3, VEGF. 
      5. Butyrate has anticancer activity in: 
        1. Tongue cancer
        2. Prostate cancer
        3. Liver cancer
        4. Breast cancer 
        5. Lung cancer 
        6. Neuroblastoma
      6. SCFA alter gene expression
        1. Epigenetcs, the expression of our genes, is malleable.  
        2. Butyrate positively influences these genes
        3. In the nucleus of the cell, DNA is wound around histone proteins.  
        4. When histones are acetylated, histones and their associated DNA pack more loosely.  This allows enzymes to bind to the promoter region of the gene and initiate transcription.  First step towards making functional protein.  
        5. Butyrate increases acetylation, making it easier for our genes to produce proteins.  
        6. This impact on gene expression is important against cancer. 
        7. Check out this article to learn more.  
      7. Helps provide energy for colonocytes/keep oxygen low in gut
        1. Colonocytes are cells that line the colon and form gut barriers.  
        2. Colocytes uptake butyrate and other SCFA for energy through a process called beta oxidation.  Provide 70% of energy.
        3. Butyrate and other SCFA are needed to keep oxygen low in gut “physiologic hypoxia.”  
        4. When oxygen is high, gut dysbiosis increases.  
      8. Cardiovascular health
        1. Acetate, another SCFA produced by microbes, may be important for cardiovascular health- hypertension. 
        2. TMAO- TMAO is created after certain microbes in the gut break down choline and carnitine (nutrients predominantly in animal/fish products) that can increase cardiovascular risk.  May contribute to narrowing of arteries.  
          1. Study- High levels of TMAO have been shown to increase risk of clot-related events such as heart attack and stroke.
          2. Studies have shown that fish can reduce cardiovascular risk.  Studies on carnitine supplementation have shown to decrease cardiovascular risk.  So I am thinking that the impact of TMAO on heart health is not super important.  Check out this article to learn more why I think this.      
      9. Weight control 
        1. Metabolites produced by microbes may impact satiety.  
        2. Study- one study on 60 adults showed that taking propionate (metabolite of microbes) for 24 weeks increased levels of PYY and GLP-1 which influence hunger.  They had reduced intake and hunger.  
    5. What does a healthy gut microbiome look like?
      1. Generally believed that community stability and diversity are key components but even this has been associated with disease
        1. Example- depressed individuals had a more diverse microbiome than non-depressed individuals. 
      2. Some beneficial bacteria such as bifidobacteria that are recognized as healthy are absent from the Hadza.   
      3. Healthy microbiome is the microbiome you have when you are healthy.

Gut problems

Dysbiosis 

  1. What is it?
    1. Disruption in gut bacteria homeostasis.  Caused by imbalance of microflora, changes in functional composition, or shift in distribution. 
    2. There is no perfect microbiome and each human is unique.  Dysbiosis is when the relation between the quantity of microbes is skewed. 
    3. An imbalance of microbial composition, changes in microbial metabolic activity and changes in distribution through the gut.  
  2. Types of dysbiosis:
    1. Overgrowth of potentially pathogenic bacteria
    2. Absence of bacteria that benefit the host
      1. No definitive answer to what specific mircoes are beneficial and which are not.  What is beneficial for one may not be for someone else.  Highly context dependent.  
    3. Loss of overall diversity
      1. Phylogenetic diversity is a measure of diversity that measures phylogenetic diversity among species.  60 is high and 20 is low.  I used this study comparing diversity of US people vs. un-westernized population.   
  3. What can cause this?  
    1. Antibiotics
      1. Cause a profound loss of diversity and a shift in composition of gut flora. 
      2. Study- after 3 days of antibiotics, butyrate (SCFA produced by microbes) dropped and gut oxygen rose.  
    2. C-section
      1. Microbial composition of a C-section baby is different from vaginal birth.  
      2. During vaginal birth, the contact with the mothers vagina and intestinal flora is the most important source of microbial infant microbial colonization favouring the colonization mainly of Lactobacilli, Prevotella and Bifidobacteria.  
      3. During C-section, colonization of the baby’s microflora is less diverse and resembles skin surface microbes and delayed intestinal colonization by Lactobacillus, Bifidobacterium and Bacteroides.  Even up to 2 years later.   
      4. Asthma, type-1 diabetes and food allergies are more prevalent in infants after C-section than after vaginal delivery 
    3. Bottle-fed babies
      1. Study- children who were breast-fed for at least 6-months had more beneficial bacteria than those who were bottle-fed.  
    4. Poor diet
      1. A diet high in fat and sugar and low in fiber can cause dysbiosis.  
      2. Study in 2010- Comparative study of urban kids in Europe compared to kids from rural Africa.  Children from Burkina Faso had a significant amount of bacteria that assist in the degradation of cellulose, xylans, and other complex polysaccharides in their high-fiber diet. Meanwhile, European children had higher levels of Enterobacteriaceae, a family of bacteria that has been associated with several chronic inflammatory diseases and reflects their Western diet much lower in fiber.  Enterobacteriaceae is considered a microbial signature of dysbiosis.  
      3. Study in 2009 on mice– Germ free mice were colonized with human fecal material. First on high fiber diet.  Then shift to western diet.  After a single day on Western diet (high fat & sugar, low fiber), significant changes to the composition, metabolic pathways and gene expression.  
      4. Study on humans– Regardless of diet (vegan, vegetarian, omnivore) individuals who consumed more than 30 different types of plants each week had higher microbial diversity then those who consumed less than 10.  The people who ate more diverse plants had more of the microbes that produced beneficial butyrate. 
  1. Emulsifiers 
    1. Study- Found that by feeding mice carboxymethylcellulose and polysorbate-80, two emulsifiers commonly used in processed foods, for 12 weeks reduced microbial diversity and resulted in increased mucosa-associated Proteobacteria.
  2. Non-caloric sweeteners 
    1. Study- feeding rats the non-caloric sweetener Aspartame for 8 weeks resulted in increased Enterobacteriaceae.  This is potentially a pathogenic bacteria.  
  3. Not getting enough activity as a youth.
    1. Study- exercise earlier in life was able to shift the microbiome better than exercise in adulthood.   
  4. Hygiene hypothesis
    1. Early exposure to certain microbes can help with the immune system.  Reducing chance of developing autoimmune disease. A too clean environment may hinder the development of the immune system.  
    2. Study-  Looked at 9,000 kids.  Kids in a household that used bleach had a higher incidence of sinusitis, bronchitis, pneumonia.  
    3. Study- 2 farming groups (Amish and Hutterite).  Amish used traditional farming with hand-held tools.  Hutterite used tractors.  Amish had a lower incidence of asthma.  The Amish had more white blood cells.  Author theorized it was due to exposure of more microbes.  
  5. Poor sleep
    1. Diversity of the microbiome decreased with sleep deprivation. 
  1. Associated with
    1. Autoimmune disease
      1. Patients with MS have reduced levels of bacteria that produce butyrate.  
      2. Patients with lupus and Type 1 diabetes have lower levels of bacteria in the phylum Firmicutes and more bacteria in the phylum Bacteroidetes.
  2. We do not know if the dysbiosis is causing the issues or is the result of being sick.  

Poor gut integrity 

  1. What is it? 
    1. Dysfunctions in the intestinal barrier alter permeability and lead to leaky gut. 
    2. Leaky gut is when macromolecules pass through cell membranes due to changes in transport mechanisms and loosening of tight junctions.
    3. When the intestinal barrier opens up, 
    4. harmful substances like bacteria, toxins and undigested food particles can enter the system.  
    5. Certain practitioners believe that leaky gut triggers widespread inflammation, leading to an immune response which can cause a variety of health conditions.  
  2. What can cause this?
    1. Exact cause is unknown.
    2. Unclear if it is a symptom or cause of disease.    
    3. Gluten and zonulin
      1. Research has shown high levels of protein zonulin may loosen tight junctions and increase intestinal permeability. 
      2. Gluten has been shown to increase zonulin in those with celiac.  
      3. Mixed results in healthy people or those with non-celiac gluten sensitivity.  
        1. Study- Test-tube studies show that gluten activates zonulin, which leads to intestinal permeability in non-celiac and celiac people.  
        2. Study- One clinical study found that gluten increases intestinal permeability in those with IBS.  
        3. Study- Gluten did not cause changes in intestinal permeability in those with non-celiac gluten sensitivity. 
    4. Excessive sugar intake.  Particularly fructose damages intestinal permeability
    5. NSAIDs like ibuprofen
    6. Excessive alcohol intake
      1. The byproduct of ethanol metabolism, acetaldeyde and nutric oxide play a role in the dysfunction. 
      2. Increased acetaldehyde was associated with increased intestinal permeability and endotoxin translocation
    7. Nutrient deficiencies.  
      1. Deficiencies in vitamin A, vitamin D and zinc have each been implicated in increased intestinal permeability
    8. Inflammation
    9. Chronic stress
    10. Gut dysbiosis
    11. Yeast overgrowth 
    12. Too much intense exercise – READ ARTICLE 
  3. Associated with 
    1. Autoimmune disease (type 1 diabetes, Crohn’s, Inflammatory skin disorders)
    2. So closely associated with food allergies and food hypersensitivities.  
    3. Some think intestinal permeability is a prerequisite to developing autoimmune disease.  

Gut and glucose relationship

Why is it important for metabolic health?  

  1. Issue with the gut = poor glucose regulation.
  2. Leaky gut creates inflammation which reduces insulin sensitivity.
    1. Increased inflammation associated with metabolic disease. 
  3. The microbiome plays a role in our metabolic health.
    1. Microbes produce SCFA such as butyrate that help with metabolic health. 
    2. Metabolic dysfunction has been correlated with dysbiosis.   
    3. Dysbiotic gut with less butyrate-producing microbes can reduce insulin sensitivity.
  4. Not just correlational!  
    1. Germ free mice have shown to have metabolic dysfunction. 
  5. Good review that goes over the mechanisms of this. Same here.  

How the gut impacts metabolic health 

  1. Promotes secretion of gut-derived metabolic hormones
    1. The Gut Microbiome affects GLP-1, an incretin (hormone) that signals the release of insulin. 
    2. What is GLP-1?  
      1. Incretins are sensor hormones that our gut harbors.  They detect incoming food and signal our body to absorb, metabolize and store nutrients.  GLP-1 signals the release of insulin.  
      2. Within minutes of eating, the lining of our cells (L-cells) release GLP-1.  This slows down the release of food out of the stomach, decreases appetite and improves insulin sensitivity.  
      3. Study– GLP-1 decreases inflammation in the fat tissue.  This improves fat tissue metabolic function and insulin sensitivity.  People with diabetes and obesity suffer from poor GLP-1 signaling. 
    3. How does the gut microbiome impact GLP-1 signalling?  
      1. Certain bacterial metabolites directly stimulate GLP-1 signalling from L-cells.  
      2. SCFA have been shown in animals to increase GLP-1 AND improve glucose metabolism.
      3. Study in humans– eating more dietary fiber promoted more SCFA producing microbes and improved glucose control.  
      4. Microbes break down bile acids and can stimulate GLP-1 secretion.  
      5. So disruption in microbes that produce SCFA or break down bile acids may cause a disruption in GLP-1 signalling.  This can negatively impact our ability to regulate glucose.  
  2. Strengthening the gut barrier 
    1. Why does this relate to good metabolism?    
      1. Chronic inflammation underlies many metabolic disorders.  One pathway to inflammation is through the gut.  Compromised gut leads to inflammation which can exacerbate metabolic disorders.  
      2. Endotoxemia is when elements of the gut leak through the gut lining and enter into our system.  LPS (lipopolysaccharide) is a triggering factor of this inflammation.  LPS is an endotoxin found on the outer membrane of gram-negative bacteria.  
      3. Adipose tissue, other organs and tissues (liver, pancreas, heart) can be impacted by this inflammation consequently impacting glucose metabolism.  
    2. What keeps our gut lining healthy? How does the microbiome impact our gut lining?
      1. Good mucus layer
        1. Gut barrier is lined with epithelial cells.  Layer of mucus is on the inside to coat and protect epithelial cells from microbes and digestive enzymes.  Also contains antibodies as an extra layer of protection.  
        2. Germ-free mice have a thinner mucosal layer and fewer antimicrobial agents.  
        3. Mouse study- fiber deprived diet caused shift in microbiome to consume rather than build mucus.  This caused a compromised gut.  
          1. Caveat- the diet was high in sugar and fat.  Not sure if it is the fiber perse or the sugar/fat combo causing the issue.
      2. Tight junctions
        1. Epithelial cells are bound together by tight junction proteins.  
        2. If tight junctions are compromised, LPS can leak out causing inflammation.  
        3. Butyrate producing microbes can help support tight junctions. 

Treatments for gut health/glucose regulation

  • Prebiotic into the diet 
    • Addition of oligofructose in the diet has been shown to improve glucose tolerance, insulin response and reduce food intake in rats.  
    • In humans (obese women), improved postprandial glucose response and higher abundance of butyrate-producing microbes was absorbed after 3 months of prebiotic mixture of inulin and oligofructose.  
    • Study in humans– eating more dietary fiber promoted more SCFA producing microbes and improved glucose control.  
      • Randomized 2 groups with isocaloric diets. One group received standard treatment.  The other group had the same calories but more fiber.  After 12 weeks, the high fiber group had a greater reduction in 3 month average glucose, fasting glucose and weight loss. 
    • Meta-analysis:  15 studies showed that a high-fiber diet improved fasting glucose and HgA1C in T2DM. 
    • 3 more studies showed that a high-fiber diet improves insulin sensitivity in health and overweight men and women.  One, two, three.  
  • Probiotics 
    • Addition of probiotics in the diet has been shown to improve postprandial glucose and insulin resistance via increase in GLP-1 in rats.   
    • Prospective randomized controlled trial in humans- 21 glucose-tolerant individuals were given a probiotic for 4 weeks and they saw an increase in GLP-1 by 73% compared to control group.  
    • Inflammation
      • Probiotics have been shown to reduce inflammation, ithereby improving insulin sensitivity.  
      • Study- probiotics shown to reduce hyperglycemia and obesity by lowering the inflammatory state in mice.  Treatment of probiotics for 4 weeks reduced fasting glucose and improved oral glucose tolerance test.  

Gut health testing

Comprehensive stool testing 

Check out this article to learn more.  

Gut pathologies that can be captured in comprehensive stool test

  1. Gut dysbiosis
    1. Imbalance in the composition of the gut microbiome.  Lack of beneficial bacteria and overgrowth of potentially pathogenic bacteria.  
  2. Parasitic infection
    1. A parasite is an organism that lives in or on a host organism and gets its nourishment at the expense of the host.  Protozoa and helminths are the two main classes of parasites.  
  3. Fungal overgrowth
    1. The most common fungal infections are Candida, Geotrichum, Microsporidium, and Rodoturula.
  4. Macronutrient malabsorption
    1. Malabsorption of protein, carbs and fats can result in abdominal pain, bloating gas or skin issues.  Secondary to pathologies above. 
  5.   Immune dysregulation and inflammation
    1. Immune dysregulation can lead to gut dysbiosis and increase risk of gut dysbiosis or increase risk of fungal/parasitic infection. 

Different types of comprehensive stool testing methods

  1. Culture based methodologies
    1. Culture, staining, microscopy
    2. Stool is added to a petri dish in the lab and watched to see which microbes multiply.
    3. Cons:
      1. Favors oxygen loving bacteria and misses anaerobes. 
      2. Tells you nothing about the relative abundance of microbes. 
      3. A certain microbe may only make up 0.0001% of stool samples but rapidly grow in media.  
      4. Can only identify a fraction of microbes in gut and give false idea of which microbes are abundant. 
    4. Doctors Data, Genova (GI effects), BioHealth
  2. Molecular techniques- sequence the DNA or RNA of the microbes in the stool. 
    1. 16S rRNA gene sequencing. Pretty much like a bacterial finger print.  
      1. All bacteria contain a 16S gene that are unique to the bacteria 
      2. Gets down to the genus level.
      3. Most widely used method to accurately and cost effectively characterize the microbiome community. 
      4. Companies- UBiome, Thryve, AmericanGut, Biohm, Atlas BioMed
      5. Cons:  
        1. Can only go down to genus level
        2. No information on fungi and parasites
    2. Targeted PCR
      1. Requires a unique primer for each microbe you want to screen for.  Involves amplification of DNA that has been captured for each primer. 
      2. Advantage to 16S rRNA because it can detect up to species level.
      3.  It’s very accurate in its identification but can’t catch all the microbes, because they don’t have primers for all of them.
      4. Can also detect fungi virus and parasites.  
      5. Tests- GI Effects 
      6. Cons: 
        1. Can not catch all microbes because there are not primers for all of them. 
    3. Quantitative PCR
      1. Similar to targeted PCR but amplifies and quantifies targeted microbial species in real time.  
      2. Significantly improves accuracy, sensitivity and speed of results. 
      3. Tests- GI Map
    4. Metagenomics
      1. Deep genetic sequencing to assess the entire gene content of the microbiome. 
      2. Can identify down to species.  More accurate than 16S rRNA. 
      3. Cons:
        1. More expensive.
        2. In most cases, does not provide sufficient additional information to justify the cost 
      4. Tests- DayTwo, Aperiomics, SmartDNA, Microba
      5. When it might be worth the extra cost:
        1. People with diabetes of glucose dysregulation.  Predicts blood sugar response to certain foods.  DayTwo
        2. For people with an acute or chronic infection not picked up on other tests.  Aperiomics can utilize metagenomics to identify all of the potentially pathogenic bacteria, virus, parasites, and fungi in a sample.
    5. Metabolomics and meta-transcriptomics
      1. Assess the metabolic output of the gut microbiome and the sum total of all of the gene expression of the microbiome. 
      2. Tests- Viome
      3. Cons:
        1. Can not accurately estimate bacterial abundance.
        2. Just because a species has higher metabolic activity does not mean it is more abundant. 

Gut health therapy

First line of defense- Diet!

How to optimize gut health 

  1. Whole foods healthy diet
    1. Avoiding excessive sugar + fat.  
    2. Adequate fiber if you can handle it.  
      1. When we consume fiber, microbes ferment this and produce SCFA that may be beneficial.  
    3. Fermented foods
      1. Study- showed that high fermented food diet for 10 weeks improved diversity and immune response. 
    4. Whole foods for nutrients.    
    5. Polyphenols.  
      1. Berries, herbs, spices, beans, nuts, vegetables, tea
      2. Prebiotic.  Promoting beneficial microbes and butyrate production.  
  2.   Stress management 
    1. If we are in the sympathetic state, we will not digest properly.  
    2. Stress can impact gut physiology through: increased intestinal permeability, alterations in motility, negative impact on microbiome, etc.  
    3. Stressful events are associated with onset of digestive issues.  
  3. Sleep 
    1. More diversity has been linked with better sleep.  
  4. Moderate exercise
    1. Increases microbial diversity
    2. Increases butyrate
    3. Decrease potentially pathogenic microbes including streptococcus. 
    4. Things to watch out for in exercise:
      1. Exercise can lead to a 50% reduction in intestinal blood flow.  Reduced blood flow is a stressor on the gut, leading to leaky gut.  Recommended to not eat 2 hours before and 45 minutes after to reduce GI symptoms.  
  5. More time in nature
  6. Social support
    1. Study on prairie dogs- social isolation impaired gut-brain axis.  Impaired gut microbiome.  
  7. Chew food 
    1. Supports digestion.  
    2. Digestion starts in the mouth.  Our mouth releases enzymes  to break down food.
    3. Signals stomach to produce stomach acid. Signals pancreas to produce pancreatic enzymes. 
  8. Limiting alcohol to no more than 3 drinks. 
    1. Known to affect the GI tract motility, absorption, and permeability.

How to resolve gut issues: 

  1. Regular eating pattern.  Breakfast, lunch and dinner.  
    1. Some studies have shown that irregular eating can lead to IBS.
  2. Gluten free 
  1. No clinical diagnosis for it, but some people find relief!  
  2. Study in 1980– 6 out of 8 womens GI symptoms resolved after gluten withdrawal.
  3. Study- showed improved IBS symptoms when gluten taken out of diet
  4. Gut dysbiosis likely plays a role in development of sensitivity to gluten.  
  1. Dairy free  
    1. Could be experiencing some lactose intolerance.  Individuals are not able to digest lactose, sugar found in dairy. SI stops producing enzyme lactase to break down dairy.  Can be caused by genes, injury, 
      1. Symptoms: gas, bloating diarrhea. 
    2. Common sensitivity in those who have autoimmune disease.  
      1. In those without lactose intolerance, proteins like casein can often trigger a gut immune response and antibody reaction.  
  2. Paleo
    1. Takes out grains, beans, legumes and lentils, dairy, vegetable oils, artificial sweeteners. 
  3. Autoimmune paleo 
    1. This article does a great job explaining this.  
    2. Anti Inflammatory, nutrient dense diet.  
    3. Thought process is if we can remove foods that are contributing to intestinal permeability and dysbiosis, we can reduce inflammation and restore gut integrity.  
    4. Avoids foods that might trigger intestinal inflammation, promote dysbiosis, or are highly immunogenic, represent sensitivities.  
    5. Eliminates: 
      1. Grains and legumes 
        1. Gliadin in gluten has been shown to increase intestinal permeability in non-celiac intestinal lines.  
        2. Grain free diet has been shown in animals to reduce inflammation.  
        3. Also contains saponins.  These have been shown to increase intestinal permeability.  
      2. Dairy
      3. Nightshades
        1. Tomatoes, hot and sweet peppers, potatoes, eggplant and chili-based substances like spies like cayenne and paprika.  
        2. Can also contain saponins
      4. Eggs 
        1. Lysozyme is an allergenic compound in eggs
      5. Alcohol 
        1. Alcohol increases intestinal permeability
      6. Nuts/seeds (including coffee) 
        1. Not are a common food allergen.  
      7. Refined sugars and food additives 
        1. Feeds pathogenic bacteria. 
    6. Clinical trial– 15 patients with IBD for 19 years.  Clinical remission was achieved by week 6 for 73% of patients.  
  4. Low FOD-MAP diet 
    1. fermentable oligo-, di-, mono-saccharides and polyols
    2. Short chain carbs that are resistant to digestion.  They are not absorbed into the bloodstream and are consumed by the bacteria in the gut.  
    3. FODMAPs produce hydrogen, which can lead to gas, bloating, stomach cramps, pain and constipation. 
    4. Also osmotically active.  Can draw water into the intestines and produce diarrhea.  
    5. Many people with IBS find relief from a low FOD-MAP diet. Some research estimates that 75% with IBS can find relief.  
  5. Low histamine 
    1. Histamine is a biogenic amine.  Some people have histamine intolerance.  This is not so much a sensitivity but indication you have developed too much of it.  
    2. When levels or two high or it can not be broken down, it can cause problems. 
    3. May be a histamine issue if you are getting sinus infections, skin issues, hives, eczema, headaches, worse PMS.  
    4. Study- Has shown to help urticaria, atopic dermatitis
    5. Big culprits- leftover protein, strawberries, spinach and coffee
    6. Minimizing leftovers might be enough! 
  6. Carnivore diet 
    1. Last minute approach if not responding to other treatments.   
    2. Not too many randomized controlled studies.  Some case studies indicating improvement.  
    3. Removes all plants that could be potentially causing inflammation. 
    4. Paleomedicina in Hungry uses a carnivore diet and has shown that the diet improves intestinal permeability.  Not published data tho.  
    5. Good article that goes into the research. 
    6. I would recommend nose-to-tail carnivore to make sure user is receiving adequate nutrition. 
    7. Maybe try carnivore and then add in some veggies.  
  7. Reduced fat intake 
    1. IBS patients may find symptom improvement on a low fat diet.  
      1. Lab-based studies show that duodenal lipids inhibit small bowel motility and impair intestinal gas clearance.  This can induce gas retention and bloating.  The mechanism is upregulated in patients with IBS. 
      2. Not too much research on this.  You could try experimenting with it and see how it works if you have IBS! 
    2. Endoxin
      1. Endoxin is a component of the cell walls of gram-negative bacteria.  
      2. They can leak into the body and cause inflammation. They can be  transported with fat or leaked through tight junctions. When they leak through, they can activate immune cells.  Too small for fever but it can cause chronic inflammation.  
      3. Some studies have shown that high fat diet can increase endoxtin.  
      4. Also, endotoxin that has been attached to chylomicron (through fat absorption) has been shown to be advantageous because it favors clearance of endoxin by the liver.  
      5. Studies that show that high fat increases endoxtin also contain refined carbs.  So we should not generalize this to a high fat low carb diet.  
      6. Some studies show that refined carbs increase endoxin in blood and increase intestinal permeability.  
      7. It may be advantageous to limit refined carbs + fat together to reduce endotoxin. 
  8. Elemental diet 
    1. Nutritionally complete pre-digested.  Comes in liquid or powder form that mixes with water.  Protein, fat and carbs broken down into building blocks. 
    2. Can reduce symptoms in severe digestive issues. Shown to help manage SIBO, EoE, Crohn’s. 
  9. Probiotics 
    1. Living microorganisms that when ingested provide benefit.  
    2. Probiotic foods such as yogurt, kefir, tempeh, kimchi, tempeh.  
    3. You can also get them as supplements.  Lactobacillus and Bifidobacteria are the most common. Different genus, species and strains available. 
    4. Different probiotics can confer different health benefits. 
    5. Largely unregulated so it is important to research which strains and brands of probiotics are proven effective.  Some studies have shown probiotic-related deaths.  
    6.  Check out this resource to see which probiotics 
    7. Check out this article on a summary of probiotics 
    8. Check out this article for potential side effects.  
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