Gut Microbiota

3/29/2021

GUT MICROBIOTA

©Jeff Lavell, DC

Normal anatomy of lower GI

Aspects of the microbiome

Fiber/pre‐biotics Course Pro‐biotics Breakdown: Abnormal Gut Pathology • Gut dysbiosis • IBS/IBD •Leaky gut •SIBO Gut Protocols

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Prevalence of Digestive Issues

• Rarely mentioned as a health problem, more of an inconvenience! • 38 million Americans are victims of digestive disorders, including Crohn’s disease, ulcerative colitis, diverticulitis, celiac disease, IBS, constipation, diarrhea, GERD, candida and food allergies. • Economic impact of digestive disorders is $142 billion per year (1), compared to $124.5 billion for cancer, $58 billion for neurological disorders, and $88 billion for circulatory problems. • “Sufferers from IBS (the most common gastrointestinal disorder) incur an estimated $10 billion more in direct medical charges per year than a similar control group of people the same age and gender.” • From Weston A Price Foundation • (1) Peery AF, Dellon ES, Lund J, et al. Burden of Gastrointestinal Disease in the United States: 2012 Update. Gastroenterology. 2012;143(5):1179‐1187. ©Jeff Lavell, DC

Common Complaints • Poor taste • Slow bowels • Gas • Loose bowels • Bloating • Sticky bowels • Nausea • Irregular bowels • Burning/heartburn

What The Patient Thinks Is Right/Normal

• Tums • Loose stools • OTC Prilosec • Constipation • Pepto Bismol/Malox • “It’s just the way I • Rx: Omeprazole am” ©Jeff Lavell, DC

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What we should think

• That most patients have conditions that can be helped and basic physiologic principals apply regardless of patient or condition. • We will approach this as a “system” and utilize basic physiologic and nutritional principals to address key areas to create the clinical outcome we desire!

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Large Intestine Anatomy

• Colon (large intestine) • Ileocecal valve • Ascending colon • Transverse colon • Descending colon • Sigmoid colon • Rectum

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Large Intestine

• the mucosa of the large intestine does contain a large number of goblet cells. Goblet cells are specialized epithelial cells that secrete mucus. • The mucus produced by the goblet cells act as a lubricant to ease the passage of feces

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Absorb water (although the majority is Absorb absorbed in small intestine)

Feed bacteria Colon Feed Functions • Produces Vitamins

Promote defecation Promote • Should take 18‐24 hours from mouth to excretion.

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Role of Water in Bowel Function

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Action of colon with water

• Water reabsorption is a main function of the large intestine. It can absorb 300 ml, or about a cup and a half, of water a day. • This water removal dries out the feces. If food moves through the large intestine too quickly, it will not have sufficient time to absorb water, which will result in the passage of watery stool, or diarrhea. By contrast, when food residue remains in the large intestine for an extended period of time, too much water can be absorbed. This can result in constipation, which is defined as a hard stool or difficulty passing stool. Constipation may be due to a lack of fiber in the diet. • Any remaining nutrients from food are absorbed here before sending the indigestible matter to the rectum. • The colon absorbs vitamins that are created by the colonic bacteria, such as vitamin K (especially important as the daily ingestion of vitamin K is not normally enough to maintain adequate blood coagulation), vitamin B12, thiamine and riboflavin. • Source: Guyton and Hall Textbook of Medical Physiology

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Everybody Poops

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Bristol Stool Chart

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“All Disease Hippocrates Begins In The Gut.”

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Gut Health & Microbiota

• Gut health is multifaceted. • Nutrition, environmental toxins, and ability to eliminate waste all have huge factors in gut health. • Recent research has shown gut health even has a key impact on brain health! (more on that later)

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What We Know About The Gut Flora So Far…

1 2 3 4 5 6

10x the number Contains 150x Is 2 to 5 pounds Half your stool is Your gut is as Diversity is the of bacteria in the more genes as in of your weight. microbial mass. individual as your key, as close to gut as there are our genome. fingerprint. 1000 different cells in the body! bacterial types are possible.

Source: Dinan, Tmothy G, Caterhine Stan "Psychobiotics: A Novel Class of Psychotropic" by Timothy G. Dinan, Catherine Stanton, and John F. Cryan. Biological Psychiatry, Volume 74, Issue 10 (November 15, 2013), published by Elsevier Source: Noah Fierer. Forensic identification using skin bacterial communities. PNAS April 6, 2010 vol. 107 no. 14 6477‐6481

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Microbes are part of the whole body health influence of the GI tract Gastrointestinal Microbiota

http://journal.frontiersin.org/article/10.3389/fnint.2013.00070/full

http://www.nature.com/nrmicro/journal/v11/n4/fig_tab/nrmicro297©Jeff Lavell, DC 4_F1.html

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• Gut flora helps you to maintain weight or even lose weight! • Palmas V, Pisanu S, Madau V, et al. Gut microbiota markers associated with obesity and overweight in Italian adults. Sci Rep. 2021;11(1):5532. • Stanislawski MA, Dabelea D, Wagner BD, et al. Gut Microbiota in the First 2 Years of Life and the Gut Health For Association with Body Mass Index at Age 12 in a Norwegian Birth Cohort. mBio. 2018;9(5):e01751‐ Weight Loss? 18. • Turnbaugh PJ, Hamady M, Yatsunenko T, Cantarel BL, Duncan A, Ley RE, Sogin ML, Jones WJ, Roe BA, Affourtit JP, Egholm M, Henrissat B, Heath AC, Knight R, Gordon JI. A core gut microbiome in obese and lean twins. Nature. 2009 Jan 22;457(7228):480‐ 4. doi: 10.1038/nature07540. Epub 2008 Nov 30.

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E. Coli is a major bacteria in the gut

• Somewhere between 300 and 1000 different species live in the gut, with most estimates at about 500. However, it is probable that 99% of the bacteria come from about 30 or 40 species.

• Source: Beaugerie L, Petit JC (April 200Microbial-gut interactions in health and disease. Antibiotic-associated diarrhoea". Best Pract Res Clin Gastroenterol 18 (2): 337–52

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Potential Harmful and Beneficial Functions

• Generalized scheme of predominant groups of colonic bacteria, indicating how the genera may exhibit potentially harmful and beneficial functions. Guarner F. Digestion 2006; 73(Suppl 1): 5-12

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What Does The Gut Microbiota Do?

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Digestion Synthesize nutrients Immune system Neurotransmitters (1)

(1) Source: O’Mahony, S.M. et al. “Serotonin, tryptophan metabolism and the brain gut microbiome axis.” Behavioural Brain Research 277 (2015): 32‐48 ©Jeff Lavell, DC

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Gut Microbiota And Nutrition

• Several bacterial genera that are common in the distal intestine (e.g., Bacteroides, Bifidobacterium, and Enterococcus) are known to synthesize vitamins. Thiamine, folate, biotin, riboflavin, and panthothenic acid are water‐soluble vitamins that are plentiful in the diet, but that are also synthesized by gut bacteria. Likewise, it has been estimated that up to half of the daily Vitamin K requirement is provided by gut bacteria [1].

(1) Source: Eur J Cancer Prev. 1997 Mar;6 Suppl 1:S43‐5. Intestinal flora and endogenous vitamin synthesis. Hill MJ.

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Gut Flora & The Neurotransmitters They Contribute

Gamma‐ Dopamine Serotonin aminobutyric Acid (GABA)

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An Example: serotonin • “Peripheral serotonin is produced in the digestive tract by enterochromaffin (EC) cells and also by particular types of immune cells and neurons. Hsiao and her colleagues first wanted to know if gut microbes have any effect on serotonin production in the gut and, if so, in which types of cells. They began by measuring peripheral serotonin levels in mice with normal populations of gut bacteria and also in germ‐free mice that lack these resident microbes.” • “The researchers found that the EC cells from germ‐free mice produced approximately 60 percent less serotonin than did their peers with conventional bacterial colonies. When these germ‐free mice were recolonized with normal gut microbes, the serotonin levels went back up—showing that the deficit in serotonin can be reversed.” • ‐ See more at: http://www.caltech.edu/news/microbes‐help‐produce‐ serotonin‐gut‐46495#sthash.Q76q5fdw.dpuf

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• Recent research supporting a role for the Gut microbiota in maintaining normal brain function offers the intriguing possibility that Health the therapeutic targeting of the gut And The microbiome might be a viable strategy in in supporting CNS health (Forsythe et al., 2010). Brain

Source: Grenham S, Clarke G, Cryan JF, Dinan TG. Brain– Gut–Microbe Communication in Health and Disease. Frontiers in Physiology. 2011;2:94. doi:10.3389/fphys.2011.00094.

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Bacteria In Your Gut And Mood

• Originally studied in mice in 1990 (in Mankato!) researchers first noticed that stressed mice were more likely to get sick, and theorized that the bugs caused the infections. • So they decided to test if the microorganisms that relate to disease are affected by stress. When they added norepinephrine to a petri dish of bacteria there was a huge increase in growth of the bacteria, the non norepinephrine dishes did not show that at all. • Then, to see if bacteria could induce stress, mice were fed a liquid solution of Campylobacter jejuni, a bacterium that can cause food poisoning in humans but generally doesn’t prompt an immune response in mice. • When he ran them through a plexiglass maze raised several feet above the lab floor, the bacteria‐fed mice were less likely to venture out on the high, unprotected ledges of the maze. In human terms, they seemed anxious. Without the bacteria, they walked the narrow, elevated planks. • Therefore, introducing a pathological bacterium into the gut will cause a change in behavior.’ • This has begun to show in human studies as well.

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Gut Health & Inflammation

• Studies have shown elevations of TNF-α, IL-1β, IL-6 with poor gut health. • Source: Grenham S, Clarke G, Cryan JF, Dinan TG. Brain–Gut–Microbe Communication in Health and Disease. Frontiers in Physiology. 2011;2:94. doi:10.3389/fphys.2011.00094

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Vagus nerve innervates the digestive tract.

Poor vagal activity = decreased pancreatic enzyme secretion, poor gallbladder function, and poor gut function overall. It also suppresses the intestinal immune system and decreases intestinal blood flow.

This leads to increased growth in pathogenic yeast and bacteria, that cause Nerve Impact intestinal permeability or leaky gut, leaky gut causes a state of chronic low With Gut grade inflammation. Inflammatory cytokines produced in the gut travel through the blood and Health they cross the blood‐brain barrier.

Inflammatory cytokines once they get into the brain activate the microglial cells.

Microglial cells are the immune cells of the brain and once they’re activated by these inflammatory cytokines this is basically inflammation of the brain.

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Nerve Impact With Gut Health

80% of total So the gut Enteric nervous serotonin in the communicates system body is located in with the brain via The enteric It is considered generates the cytokines and gut nervous system to be separate intestinal motility enterochromaffin opiates and gut has been from the and enzyme cells in the gut peptides like referred to as the autonomic release and then and this is used neurotensin and second brain. nervous system. it provides primarily to substance-P. incoming input to regulate •Source: Wikipedia the vagus nerve. peristalsis and motility.

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Fiber Supporting A Healthy Gut

“In populations in which fiber constitutes a major portion of the diet conditions such as diarrhea, hemorrhoids, gallstones, hiatal hernia, varicose veins, appendicitis and heart disease are unknown”

Denis Parsons Burkitt (28 February 1911 – 23 March 1993)

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Fiber

•Benefits • Decreases GI transit time • Increases water retention without osmotic imbalance • Provides a substrate for symbiotic colonic bacteria • Reduces glycemic load of foods ingested • Improves transit time in the gut • Reduces haustra formation in diverticulitis • Improves tone of GI smooth muscle • Note: the vast majority of diverticulitis cases are caused by insufficient dietary fiber

• Any downside??? ©Jeff Lavell, DC

Gas!

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Fiber

•Two basic types: • Soluble • Insoluble

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Soluble Fiber

• These include mucilages, pectins, and gums. • These substances form a gel which mixed with liquid and increase bulk.

Found abundantly in:

• Avacados (10.5 grams • Peas(split peas 16 per cup) grams per cup) • Artichokes (10 grams • Lentils (15 grams per per cup) cup) • Prunes •Barley • Flaxseed • Carrots •Oats • Potatoes (particularly • Legumes (varies by the skins) type, but most around • Apples 13-15 grams per cup) • Psyllium • Berries

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Insoluble Fiber

•This fiber does not gel. •Found in: • Wheat • Brown rice and other unrefined grains • Unprocessed vegetables •Fruits • Green leafy veggies • Edible seeds (sunflower, pumpkin, & sesame)

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Mop vs. Broom

•Soluble and insoluble fibers ought to be eaten mostly raw. • Eating Raw is like a broom. • Cooking breaks down fiber and instead of getting a broom you end up with a mop.

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How Much Fiber?

•12-17 grams is adequate •20-35 grams is ideal

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How Much Water When Increasing Fiber?

•A few people will report bloating or an increase in constipation when taking fiber. • This is due to two factors: • Too much fiber, too soon • Too little water with the increase in fiber • Different fibers will absorb anywhere from 3 to 5 times their weight in water

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Non digestible starches that selectively stimulate the growth of symbiotic bacteria in the colon. • FOS: fructooligosaccharides • Arabinogalactans - from larch tree • Galacto-oligosaccharides Prebiotics • Inulin

• Lactobacilli and bifidobacteria use these as a substrate to grow upon

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Brain Maker

“It’s important to get back to foods that are rich in prebiotic fiber—which is a unique type of fiber. Foods like jicama, Mexican yam, asparagus, dandelion greens, garlic and onions are foods that contain high levels of a particular type of prebiotic fiber that’s called inulin. Inulin is really helpful in terms of nurturing good gut bacteria. Our healthy gut populations use prebiotic fiber such as inulin to multiply and to increase their metabolism, and facilitate the creation of amino acids, the provision of vitamins, the reduction of gut permeability, and therefore inflammation. They even facilitate the creation of serotonin and dopamine!”

Source: Brain Maker: The Power of Gut Microbes to Heal and Protect Your Brain–for Life. David Perlmutter Little, Brown, Apr 28, 2015

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Prebiotic: 2’‐ FUCOSYLLACTOSE (2’FL) Supports a Healthy Microbiome

Chemically equivalent to the most abundant Human Milk Oligosaccharide. Not normally consumed by adults. • Selectively supports the growth of beneficial bacteria • Supports a healthy microbiome • Elison, E., et al., Oral supplementation of healthy adults with 2'-O- fucosyllactose and lacto-N-neotetraose Baseline 2’FL intervention is well tolerated and shifts the Microbial Phylum Microbial Phylum intestinal microbiota. Br J Nutr, 2016. Diversity Diversity 116(8): p. 1356-1368.

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• Deficiencies in butyrate producing bacteria and decreased colonic expression of the butyrate transporter monocarboylate transporter-1 have been observed in IBD patients.1,2 • Clinical trials have indicated resistant starch supplementation significantly increased butyrate concentrations.3,4,5 • Butyrate regulates neutrophil function, increase tight junction protein expression, and reduces cytokine and chemokine release.6 • Butyrate has also been shown to promote fluid and electrolyte absorption in the gut.6 • Green Bananas are a low FODMAP food, therefore green banana resistant starch would be a low FODMAP ingredient.

1Thibault R et al. 2010. Inflamm Bowel Dis. 2Machiels K et al. 2014. Gut. 3Alfa MJ et al. 2018. Clinical Nutr. Resistant Starch 4Venkataraman A et al. 2016. Microbiome. 5Baxter NT et al. 2019. MBio. 6Shin A et al. 2018. Clin Gastroentero Hep

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Fermentate: Also known as: Whole food fermentate, dried fermentate, yeast fermentate or dried yeast fermentate

• Nutritious whole food product made using a unique, specialized fermentation process. • Made using specific yeast strain Saccharomyces cerevisiae (bakers yeast) • Fed proprietary nutrients • Specialized anaerobic fermentation process • Immune-related benefits • Prebiotic-like properties • May modulate the composition of the gut microbiome1 • 1Pinheiro I et al. 2017. BMC Complement Altern Med.

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Fiber and prebiotics

It’s been estimated the average American consumes about 5g a day of prebiotic fiber in comparison to our Paleolithic ancestors, who may have consumed as much as 135g in a single day. Source: Brain Maker: The Power of Gut Microbes to Heal and Protect Your Brain–For Life David Perlmutter , MD, FACN, ABIHM is a Board-Certified Neurologist and Fellow of the American College of Nutrition

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Probiotics

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Probiotics function through a variety of mechanisms

O’Toole, P.W. and Cooney, J.C. Interdisciplinary Perspectives on Infectious ©Jeff Lavell, DC Diseases, 2008:175285.

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• Note: all the lactobacilli require sugar to grow • Unprocessed fermented foods are rich in these bacteria Probiotics • Bacteriocin production is also generally regarded as aprobiotictrait

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Lactobaccillus acidophilus

Bifidobacterium bididum

Probiotics L. bulgaricus • Note: all the lactobacilli require milk sugar (lactose) to grow • Unprocessed fermented foods are rich in these bacteria ©Jeff Lavell, DC

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Lactobacillus acidophilus (including LA‐5®)—The LA‐5 strain has been evaluated for its ability to interfere with the communication between other types of bacteria, thus promoting a healthy balance of microbes. The LA‐5 strain was also among several other lactobacilli that improved Clinically outcomes in subjects with occasional constipation, as well as those with lactose tolerance challenges.* Documented Lactobacillus paracaseissp. paracasei (L.casei 431®)—To support the Strains That natural gut environment, this strain of lactic acidproducing bacteria adheres to the intestinal tract and tolerates bile. This strain has been Work studied in humans and mice for its ability to support the gut during challenges and for its ability to help maintain the body's natural immune Synergistically system response.* With Prebiotic Bifidobacterium lactis (BB‐12®)—Bifidobacteria are very tolerant of both Fibers. acidic conditions and environments that contain bile. Bifidobacteria use a range of carbohydrates for energy (including GOS). Bifidobacteria are an important factor in all native microflora and their numbers vary depending on lifestyle, diet, exercise and age. Oral bifidobacteria have been shown to temporarily colonize the gut, competing with other bacteria to effectively support the natural bacterial balance.*

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Saccharomyces cerevisiae (brewers yeast) var. boulardii— Historically, this microbe was used to support normal stool Clinically consistency. In the gut, this yeast supports the growth of some bacteria and inhibits others through competition and Documented environmental modification of the gut.* Strains That Inulin—Inulin is a complex carbohydrate that can be Work digested by certain microorganisms, providing them with energy. Inulin supports the absorption of calcium and Synergistically magnesium.* With Prebiotic Fibers. Galactooligosaccharide (GOS)—Research suggests that GOS is a preferred substrate for BB‐12. In mice, GOS supplementation supported the active proteins and cells in the gut mucosa, and increased the amount of short‐chain fatty acid and lactate in the gut.*

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“Research shows that friendly bacteria survive transit through the acid environs of the stomach to the lower GI when ingested with naturally fermented foods”

Source: P. Marteau. Survival of Lactic Acid Bacteria in a Dynamic Model of the Stomach and Small Intestine: Validation and the Effects of Bile. Volume 80, Issue 6, Pages 1031‐1037 (June 1997)

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Eat Bacteria Rich Food

• Kimchee • Kombucha • Cultured yogurt • Raw milk/Kefir • Sauerkraut • Fermented meats • Fermented vegetable

• Source: Brain Maker: The Power of Gut Microbes to Heal and Protect By Gandydancer (original file) via Wikimedia Your Brain–for Life. David Perlmutter Little, Brown, Apr 28, 2015

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Acidify GI tract (alkalizing)

• A number of ways to do it. • Apple Cider Vinegar (a number of recipes are available) • Recipe I like is tablespoon Bragg's Raw Apple Cider Vinegar 1 tablespoon raw local honey or maple syrup 6 ounces of filtered water…drink 3x per day. • Supplement with products that acidify the GI tract. • Best one is of course Lactic Acid producing products help.

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Gut Dysbiosis

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Aberrant Intestinal Microbiota

• The intestinal microbiome is established at birth • Diets high in refined carbohydrate and low in fiber will alter the biome and favor unfriendly bacteria. • A history of antibiotic use will alter bacterial gut composition

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Antibiotics & Gut Dysbiosis

• “The primary cause of dysbiosis is the use of antibiotics, which kill >99% of the good bacteria. Other factors that can cause or contribute to the development of dysbiosis include stress, birth control pills, and junk foods.” • Source: Ross Pelton, RPh, PhD, CCN. Antibiotics, Probiotics, and Microflora. Published Online: July 1, 2005. http://www.pharmacytimes.com/issue/phar macy/2005/2005-07/2005-07-9743

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4 years of disturbance? Abstract • Antibiotic administration is the standard treatment for the bacterium Helicobacter pylori, the main causative agent of peptic ulcer disease and gastric cancer. However, the long-term consequences of this treatment on the human indigenous microbiota are relatively unexplored. Here we studied short- and long-term effects of clarithromycin and metronidazole treatment, a commonly used therapy regimen against H. pylori, on the indigenous microbiota in the throat and in the lower intestine. The bacterial compositions in samples collected over a four-year period were monitored by analyzing the 16S rRNA gene using 454- based pyrosequencing and terminal-restriction fragment length polymorphism (T-RFLP). While the microbial communities of untreated control subjects were relatively stable over time, dramatic shifts were observed one week after antibiotic treatment with reduced bacterial diversity in all treated subjects in both locations. While the microbiota of the different subjects responded uniquely to the antibiotic treatment some general trends could be observed; such as a dramatic decline in Actinobacteria in both throat and feces immediately after treatment. Although the diversity of the microbiota subsequently recovered to resemble the pre treatment states, the microbiota remained perturbed in some cases for up to four years post treatment. In addition, four years after treatment high levels of the macrolide resistance gene erm(B) were found, indicating that antibiotic resistance, once selected for, can persist for longer periods of time than previously recognized. This highlights the importance of a restrictive antibiotic usage in order to prevent subsequent treatment failure and potential spread of antibiotic resistance. • Source: Jakobsson HE, Jernberg C, Andersson AF, Sjölund-Karlsson M, Jansson JK, Engstrand L. Short-Term Antibiotic Treatment Has Differing Long-Term Impacts on the Human Throat and Gut Microbiome. Ratner AJ, ed. PLoS ONE. 2010;5(3) ©Jeff Lavell, DC

Antibiotics, Children & Food Allergies

Abstract • Background: To assess the relationship between any systemic antibiotic prescription within the first year of life and the presence of an ICD‐9‐CM diagnosis code for food allergy (FA). Methods: This was a matched case–control study conducted using South Carolina Medicaid administrative data. FA cases born between 2007 and 2009 were matched to controls without FA on birth month/year, sex, race/ethnicity. Conditional logistic regression was used to model the adjusted odds ratio (aOR) of FA diagnosis. All models were adjusted for presence of asthma, wheeze, or atopic dermatitis. Results: A total of 1504 cases and 5995 controls were identified. Receipt of an antibiotic prescription within the initial 12 months of life was associated with FA diagnosis in unadjusted and adjusted models (aOR 1.21; 95 % CI 1.06–1.39). Compared to children with no antibiotic prescriptions, a linear increase in the aOR was seen with increasing antibiotic prescriptions. Children receiving five or more (aOR 1.64; 95 % CI 1.31–2.05) antibiotic prescriptions were significantly associated with FA diagnosis. The strongest association was noted among recipients of cephalosporin and sulfonamide antibiotics in both unadjusted and adjusted models. • Conclusions: Receipt of antibiotic prescription in the first year of life is associated with FA diagnosis code in young children after controlling for common covariates. Multiple antibiotic prescriptions are more strongly associated with increases in the odds of FA diagnosis • Source: Love BL, Mann JR, Hardin JW, Lu ZK, Cox C, Amrol DJ. Antibiotic prescription and food allergy in young children. Allergy, Asthma, and Clinical Immunology : Official Journal of the Canadian Society of Allergy and Clinical Immunology. 2016;12:41. ©Jeff Lavell, DC

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Gut Dysbiosis

• Imbalance of the good to bad bacteria in the gut. • Heavily involved in other gut conditions, like leaky gut, IBS, and IBD!

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Gut Disbiosis Symptoms

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How to Determine is Dysbiosis Exists?

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Gut Dysbiosis: IBD & IBS

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• A syndrome has no definitive diagnostic criteria. Irritable bowel • More of a collection of symptoms syndrome (IBS) that matches…disease of elimination rather than confirmation. Lower GI pathophysiology • Highly related to the gut flora Inflammatory balance in the gut (gut dysbiosis) Bowel • Chief diagnostic criteria are: Disease/Ulcerative Colitis (IBD) • Bleeding mucosa • Frank blood in stools

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•Symptoms may occur alone or in combination with other Signs & Symptoms symptoms such as: • Bloating • Abdominal discomfort • Increased frequency of bowel movements • Painful bowel movements •Gas • Diarrhea • Constipation • Increased mucus production

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•IBS is the most frequent GI disorder and accounts for 30-50% of all referrals to gastroenterologists. • Poorly understood • It is believed to affect approximately one- Incidence fifth of the population, though it is estimated that 60-75% of symptomatic people do not seek medical attention • Source: Madden JAJ, Hunter JO. Br J Nutr 2002; 88(Suppl 1): S67- S72

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IBS Classification Systems

IBS‐D IBS‐C IBS‐A

Diarrhea Constipation predominates and predominates and Alternating often relieves bowel movement constipation & symptoms, increased often relieves diarrhea mucus symptoms

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Magnesium and IBS‐C

• What Does the Research Say? • Magnesium does have a well-established reputation for its laxative qualities. However, there does not appear to be any direct research support for the use of magnesium as a treatment for IBS-C. • Of interest is a study that looked at the relationship between constipation and water, fiber, and magnesium intake. The study was conducted in Japan with 3,835 subjects who were between the ages of 18 and 20. Constipation was not found to be associated with low fiber intake or low intake of water from fluids. Constipation was, however, associated with low intake of magnesium and low intake of water from foods. • The laxative effect of magnesium appears to come through two different mechanisms. Magnesium relaxes the muscles in the intestines, which helps to establish a smoother rhythm. Magnesium also attracts water. • The increased amount of water in the colon serves to soften the stool, helping to make stools easier to pass. ©Jeff Lavell, DC

Psychological Symptoms

•Anxiety and/or depression frequently accompany IBS symptoms to varying degrees. •If you have good patient rapport: • Ask about psychological stress • Make an appropriate referral • Make nutritional recommendations consistent with stress alleviation

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IBD

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Dysbiosis Defined

• Round JL, Mazmanian SK. The gut microbia shapes intestinal immune responses during health and disease. Nat Rev Immunol. 2009 May, 9(5):313‐23

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IBS vs IBD

IBD IBS Symptoms Eye inflammation Abdominal pain Extreme fatigue Cramps Intestinal scarring Constipation Joint pain Diarrhea Malnutrition Bowel urgency Rectal bleeding Weight loss Bowel urgency

Testing Extensive lab work Normal labs Abnormal tissue biopsy Normal tissue biopsy Other Autoimmune component No autoimmune component

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Deviations in human gut microbiota: a novel diagnostic test for determining dysbiosis in patients with IBS or IBD.

RESULTS: • Validation confirms microbiota dysbiosis was detected in 73% of IBS patients, 70% of treatment‐naïve IBD patients and 80% of IBD patients in remission, vs. 16% of healthy individuals.

• Source: Aliment Pharmacol Ther. 2015 Jul;42(1):71‐83. Deviations in human gut microbiota: a novel diagnostic test for determining dysbiosis in patients with IBS or IBD. Casén C et. al.

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•The long‐standing assumption that ulcerative colitis (UC) is an autoimmune disease has been revised to incorporate evidence suggesting that commensal microflora and their products are auto‐antigens, and that UC is caused by loss of tolerance towards otherwise harmless IBD Autoimmune and components of the normal intestinal flora. microflora • Source: Farrell RJ, Peppercorn MA. Lancet 2002; 359(9303): 331‐340

• Slide courtesy of Kerry Bone

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Further evidence of dysbiosis

•UC and Dysbiosis • Compared to healthy people, UC patients have increased levels of IgG directed against the normal flora1 • There may be an increased number of bowel bacteria in UC, but reduced counts of protective bacteria such as Lactobacilli and Bifidobacteria1 • Lactobacilli numbers were found to be lower in UC patients during the active phase • Sources: • Cummings JH, Macfarlane GT, Macfarlane S. Curr Issues Intest Microbiol 2003; 4(1): 9‐20 • Bullock NR, Booth JC, Gibson GR. Curr Issues Intest Microbiol 2004; 5(2): 59‐64

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• Gut dysbiosis • These same factors may also play a major role in the development of Type I diabetes. • Researchers found that by simply providing probiotics to animals with altered gut flora they could reduce the incidence of the disease.

• Source: The “Perfect Storm” for Type 1 Diabetes The Complex Interplay Between Intestinal Microbiota, Gut Permeability, and Mucosal Immunity. Outi Vaarala, Mark A. Atkinson, Josef Neu. Diabetes October 2008 vol. 57 no. 10 2555‐2562

Clinical Note

©Jeff Lavell, DC

• There is suggestion that the misfolding of proteins in the brain may be an etiologic explanation for some neurologic disorders. Brain inflammation, which may originate from the gut, is one notable hypothesis behind protein Misfolding of misfolding. • Source: De Theije CG, Wu J, da Silva SL, et Proteins Linked al. Pathways underlying the gut‐to‐brain connection in autism spectrum disorders to Gut? as future targets for disease management. Eur J Pharmacol. 2011;668 Suppl 1:S70‐S80. • Source: Soto C. Unfolding the role of protein misfolding in neurodegenerative diseases. Nat Rev Neurosci. 2003;4:49‐60.

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Gut Health & Neurodegeneration

It appears that age-related changes in the gut microbiota might be Brain-derived neurotrophic factor, a bidirectionally linked to age-related neurotrophin that protects and neurodegeneration.[4] encourages survival of healthy brain • Connor B, Young D, Yan Q, Faull RL, Synek B, cells and whose production may be Dragunow M. Brain-derived neurotrophic factor is influenced by gut bacteria, is shown to reduced in Alzheimer's disease. Brain Res Mol be decreased in people with Alzheimer Brain Res. 1997;49:71-81. Abstract [3] • Friedland RP. Mechanisms of molecular mimicry disease. involving the microbiota in neurodegeneration. J Alzheimers Dis. 2015 Jan 13. [Epub ahead of print]

©Jeff Lavell, DC

Sulfide bacteria

•UC and SRB (sulfide reducing bacteria) • In patients with active UC, there is an over‐production of hydrogen sulfide which is toxic to the intestinal mucosa by competing with short‐chain fatty acids (SCFA)1 • This appears to be due to an excess (or greater activity) of sulfate‐ reducing bacteria (SRB): such as Desulfibrio desulfuricans 1

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• Patients advised to avoid nuts, Dietary garlic, onions, red meat, and Recommendations‐ cruciferous vegetables. Low sulfur diet • Source: Roediger WE. Lancet 1998; 351(9115): 1555

©Jeff Lavell, DC

IBD Differential Diagnosis: Crohn’s vs. ulcerative colitis

Crohn's Disease Ulcerative Colitis

Patchy areas of inflammation Continuous inflammation Linear and serpiginous (snake‐like) ulcers Continuous ulceration

Depth of inflammation varies: may be transmural & deep into tissues Depth of inflammation is shallow & mucosal in UC Fistulae (abnormal passageways between organs) commonly seen in Fistulae seldom seen in UC Crohn’s

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Diet may contributes to these poor functional response and status

©Jeff Lavell, DC Sartor and Mazmanian. Am J Gastroenterol Suppl (2012) 1:15–21

North and South Relationship

Abstract OBJECTIVE: Bile acids are derived from cholesterol and are potent physiological laxatives. The aim of this study was to investigate whether bile acid synthesis is altered in constipation. MATERIAL AND METHODS: Female patients with constipation (23 IBS‐C, 4 functional constipation (FC)) were studied and compared with non‐constipated subjects (16 IBS‐D, 20 healthy women). Body mass index (BMI), blood lipids, lanosterol, sitosterol, colonic transit (oro‐anal transit time (OATT), reference < or =4.3 days) and stool frequency were measured. C4 (7‐alpha‐hydroxy‐4‐cholesten‐3‐one) levels reflecting bile acid synthesis were measured at 0800 h and 1300 h. RESULTS: When all the groups of constipated and non‐constipated subjects were compared, it was found that only stool frequency and OATT differed between groups (p <0.001). When constipated patients were categorized according to OATT, absence of the usual C4 increase at lunchtime was noted in 82% of patients with delayed OATT compared with 17% in subjects with normal OATT (p <0.001). Symptom severity did not differ between groups. A subset of the patients with severely delayed OATT had markedly elevated C4 levels. CONCLUSIONS: Patients with IBS‐C and FC have marked changes in bile acid synthesis in relation to colonic transit. The diurnal rhythm is altered in the slow transit colon when there is no C4 peak at lunchtime. Alterations in bile acid metabolism may be implicated in the pathophysiology of constipation.

Source: Scand J Gastroenterol. 2008;43(12):1483‐8.Altered bile acid metabolism in patients with constipation‐predominant irritable bowel syndrome and functional constipation.Abrahamsson H1, Ostlund‐Lindqvist AM, Nilsson R, Simrén M. ©Jeff Lavell, DC

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Quest Diagnostics: Available Tests for the Differential Diagnosis and Management of Inflammatory Bowel Disease

Test Code Test Name Specimen Type Clinical Use 70171 ANCA Screen with Reflex to ANCA Titer Serum Diagnose IBD; differentiate UC and CD Includes titer for C‐ANCA, P‐ANCA, and/or atypical P‐ANCA. 16796 Calprotectin, Stool Stool Diagnose intestinal inflammation; differentiate IBD from IBS; monitor patients with IBD 4420 C‐Reactive Protein (CRP) Serum Detect inflammatory disorders, including IBD; monitor patients with IBD 16503(X) Inflammatory Bowel Disease Differentiation Panel Serum Diagnose IBD; differentiate UC and CD; Includes ANCA screen with reflex to P‐ANCA,C‐ANCA, and atypical P‐ANCA titers; differentiate IBD from vasculitides myeloperoxidase antibody; proteinase 3 antibody; and Saccharomyces cerevisiae IgG and IgA antibodies. 17321(X) Lactoferrin, Quantitative, Stool Stool Diagnose intestinal inflammation; differentiate IBD from IBS; monitor patients with IBD 8796 Myeloperoxidase Antibody (MPO) Serum Differentiate IBD from vasculitides 34151 Proteinase‐3 Antibody Serum Differentiate IBD from vasculitides 10295 Saccharomyces cerevisiae Antibodies (ASCA) (IgA) Serum Differentiate UC and CD 17609 Saccharomyces cerevisiae Antibodies (ASCA) (IgA, IgG) Serum Differentiate UC and CD 10294 Saccharomyces cerevisiae Antibodies (ASCA) (IgG) Serum Differentiate UC and CD 809 Sed Rate by Modified Westergren Whole blood Detect inflammatory disorders, including IBD

*UC: Ulcerative Colitis, CD: Crohn’s Disease©Jeff Lavell, DC

Abstract • AIM: To investigate patient‐reported outcomes from, and adherence to, a low FODMAP diet among patients suffering from irritable bowel FODMAP syndrome and inflammatory bowel disease. • CONCLUSION: These data suggest that a diet low Diet For IBS in FODMAPs is an efficacious treatment solution in the management of functional bowel and IBD? symptoms for IBS and IBD patients.

• World J Gastroenterol. 2016 Apr 21;22(15): Follow‐up of patients with functional bowel symptoms treated with a low FODMAP diet. Maagaard L1, Ankersen DV1, Végh Z1, Burisch J1, Jensen L1, Pedersen N1, Munkholm P1.

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Further Evidence

• Int J Mol Med. 2012 May;29(5):723‐31. doi: 10.3892/ijmm.2012.926. Epub 2012 Feb 24. • The role of diet in the pathogenesis and management of irritable bowel syndrome (Review). • El‐Salhy M1, Ostgaard H, Gundersen D, Hatlebakk JG, Hausken T. Abstract • Most patients with irritable bowel syndrome (IBS) believe that diet plays a significant role in inducing IBS symptoms and desire to know what foods to avoid. It has been found that the intake of calories, carbohydrates, proteins and fat by IBS patients does not differ from that of the background population. IBS patients were found to avoid certain food items that are rich in fermentable oligo‐, di‐ and monosacharides and polyols (FODMAPs), but they did have a high consumption of many other FODMAP‐rich food items. The diet of IBS patients was found to consist of a low calcium, magnesium, phosphorus, vitamin B2 and vitamin A content. There is no consistent evidence that IBS patients suffer from food allergy, nor is there documented evidence that food intolerance plays a role in IBS symptoms. Abnormalities in gut hormones have been reported in IBS patients. As gut hormones control and regulate gastrointestinal motility and sensation, this may explain the abnormal gastrointestinal motility and visceral hypersensitivity reported in these patients. Guidance concerning food management which includes individually based restrictions of FODMAP‐rich food items and individual evaluation of the effects of protein‐, fat‐ and carbohydrate‐rich/poor diets may reduce IBS symptoms. ©Jeff Lavell, DC

Nutritional Considerations

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•Apples and pears contain pectins • Pectins are a family of complex Demulcent polysaccharides Foods •Okra is a mucilage fiber • Mucilaginous plants have the characteristic "goo" or slime

©Jeff Lavell, DC

•Related to colon (large intestine) function • Diffuse lumbar pain – may radiate into the groin or lower abdomen • Constipation and/or diarrhea • Toxic bowel Clinical • Flatulence – gas forming organisms will only thrive in an alkaline GI medium Correlations • Headaches • TFL painful on palpation • Palpation tenderness over the colon • Transverse process of L4 nodular and tender • L4 joint dysfunction

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•Herbs such as: Boswellia, Celery Seed, Ginger, and Turmeric are supportive of any chronic inflammatory disease such as I.B.S., Crohn’s disease, Ulcerative colitis, and arthritis. Boswellia • Celery seeds facilitate the clearing out of acidic waste products in the joints.

©Jeff Lavell, DC

Gut Dysbiosis Functional Nutrition Treatment

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©Jeff Lavell, DC

Coconut Oil & Gut Health

• The saturated fats in coconut oil have anti‐microbial effects • Contains lauric, capric and caprylic acids which are known to be anti‐viral. • It also has been shown to be anti‐fungal, affecting both Candida and Malassezia. 1 • By helping to destroy the pathogenic bacteria and fungus it is documented by research to improve overall gut health.

• Rial SA, Karelis AD, Bergeron K‐F, Mounier C. Gut Microbiota and Metabolic Health: The Potential Beneficial Effects of a Medium Chain Triglyceride Diet in Obese Individuals. Nutrients. 2016;8(5):281.

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Dietary medium chain triglycerides (MCT), which have been found to promote lipid catabolism, energy expenditure and weight loss also have an ability to improve both intestinal microbiome and permeability. Coconut Oil “MCT‐enriched diets could therefore be used and Obesity to manage metabolic diseases through modification of gut microbiota.”

• Source:Rial SA, Karelis AD, Bergeron K‐F, Mounier C. Gut Microbiota and Metabolic Health: The Potential Beneficial Effects of a Medium Chain Triglyceride Diet in Obese Individuals. Nutrients. 2016;8(5):281.

©Jeff Lavell, DC

A number of studies have shown promise when it comes to coconut oil.

Lipids. 2009 Jul;44(7):593‐601.Effects of dietary coconut oil on the biochemical and anthropometric Coconut Oil profiles of women presenting abdominal obesity. • This study showed 40 women were given either 30 grams (2 tablespoons) of either coconut oil or soybean oil for 28 days.They and Weight were instructed to eat fewer calories and walk every day. These were the results: Loss • Both groups lost weight (about 2 pounds). • Only the coconut oil group had decreased waist circumference (belly fat) while the soybean oil actually had a mild increase in belly fat. Coconut oil did not cause overall weight loss compared to soybean oil, but it did lead to a significant reduction in belly fat. • The coconut oil group had increased HDL (good) cholesterol levels, while the soybean oil had reduced HDL and increased LDL.

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ISRN Pharmacol. 2011;2011:949686. Epub 2011 Mar 15.An open‐label pilot study to assess the efficacy and safety of virgin coconut oil in reducing visceral adiposity. Liau KM1, Lee YY, Chen CK, Rasool AH. Coconut Oil and In this second study this time involving Weightloss obese men:

• 30 grams of coconut oil (2 tablespoons) for 4 weeks reduced waist circumference by 2.86 cm, or 1.1 inches

©Jeff Lavell, DC

Whereas the primary fuel source for the energy‐hungry brain is glucose, when insulin resistance and suboptimal metabolism (hypometabolism) develops in the brain, both the brain's structure and function are compromised. Ketone bodies provide a much needed alternative fuel source to glucose that can recharge metabolic processes within the brain, resulting in an almost immediate improvement in cognitive function. (1)

They are preferentially oxidized by the liver, and when provided in Coconut Oil large enough quantities, they give rise to ketone bodies. Due to their smaller size they do not form micelles and are not stored in adipose tissue. (2)

• Source: Effects of beta‐hydroxybutyrate on cognition in memory‐impaired adults. Neurobiol Aging. 2004 Mar;25(3):311‐4. Mark A Reger, Samuel T Henderson, Cathy Hale, Brenna Cholerton, Laura D Baker, G S Watson, Karen Hyde, Darla Chapman, Suzanne Craft. • Source: Hypometabolism as a therapeutic target in Alzheimer's disease. BMC Neurosci. 2008 ;9 Suppl 2:S16. Epub 2008 Dec 3. Lauren C Costantini, Linda J Barr, Janet L Vogel, Samuel T Henderson.

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Avoid Gut Wrecking Foods

• The types of food choices that threaten the bacteria are foods: 1. Low in fiber 2. High in simple sugars 3. Foods that contain artificial sweeteners.

• Source: Brain Maker: The Power of Gut Microbes to Heal and Protect Your Brain–for Life. David Perlmutter Little, Brown, Apr 28, 2015

©Jeff Lavell, DC

Bowel & Immunity

• The gut is constantly exposed to a high antigenic load coming from the diet and commensal bacteria. • The Gut-Associated Lymphoid Tissue (GALT) constitutes the most extensive and complex part of the immune system and is capable of efficiently distinguishing invasive pathogens from innocuous antigens. • Source: Ramiro-Puig E, Pérez-Cano FJ, Castellote C, Franch A, Castell M. [The bowel: a key component of the immune system]. [Article in Spanish]. Rev Esp Enferm Dig. 2008 Jan;100(1):29-34.

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Gut Chemicals

• Imbalances of gut bacteria can lead to the breakdown of the lining of the gut so that chemicals, like Lipopolysaccharides (LPS), that should stay in the gut get into the systemic circulation and amplify inflammation.

• Bacterial-derived lipopolysaccharides (LPS) play an essential role in the inflammatory process of inflammatory bowel disease. A defective intestinal tight junction (TJ) barrier is an important pathogenic factor of inflammatory bowel disease and other inflammatory conditions of the gut.

• Source: Lipopolysaccharide Causes an Increase in Intestinal Tight Junction Permeabilityin Vitro and in Vivo by Inducing Enterocyte Membrane Expression and Localization of TLR-4 and CD14. Am J Pathol. 2013 Feb; 182(2): 375–387. Shuhong Guo,∗† Rana Al-Sadi,∗† Hamid M. Said,‡ and Thomas Y. Ma

©Jeff Lavell, DC

• Gut Barrier Components: • Lumen • Commensal Bacteria • Tight Junctions • Intestinal epithelial cells • Occludin family of peptides (see figure previous Altered Intestinal slide) Immune •GALT Responsiveness • Mucosal barrier cells • M-cells • Goblet cells • Paneth cells • Intraepithelial lymphocytes

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GALT & Leaky Gut

• Too much intestinal permeability (Leaky Gut) causes GALT to generate more Immunoglobulins (secretory IgA in particular) in response to foreign proteins.

©Jeff Lavell, DC

• Pathogenic and commensal microbes in the gut can mimic the cell surface molecules of the host to pass through the tight junctions of the gut and gain access to the body Molecular Mimicry • Once inside this results in systemic changes that may be detrimental to ones health, just like the previous slide with celiac.

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• Cross-reactivity is the reaction between an antigen and an antibody which was generated against a different but similar antigen • Because of molecular mimicry, the immune system can mount Cross Reactivity an immune response against its own tissues. • Modulating an over zealous immune response is necessary • Reducing the flow of antigens across the gut is imperative!

©Jeff Lavell, DC

Identify and remove Most Common gut allergens:

01 02 03 04 Corn Wheat/gluten Soy Milk/Dairy

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Gut Allergens Masquerade as GI Disease

• Before making any specific supplemental suggestions it is best to: • Eliminate allergens that can mimic GI disease and cause confounding results. • Use an elimination diet for 2-3 weeks to rule out the Main Four Allergens as the source of digestive problems.

©Jeff Lavell, DC

Leaky Gut

©Jeff Lavell, DC

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“A ballooned colon will certainly let poisons pass into the ‐Royal Lee 1959 circulating blood that an intact colon will stop”

©Jeff Lavell, DC

Lower GI pathophysiology

•Pathophysiology related to Gut Permeability – i.e. permeability of tight junctions (aka “leaky gut”). • The gut regulates the absorption of many nutrients based on the permeability of the tight junctions (spaces between cells). • Most gut conditions have some involvement of a leaky gut.

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©Jeff Lavell, DC

Etiology

Three factors play a role in the development of Leaky Gut: 1. Aberrant intestinal microbiota 2. Loss of mucosal integrity 3. Altered intestinal immune responsiveness

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Clinical Note

These same factors may also play a major role in the development of Type I diabetes. • Researchers found that by simply providing probiotics to animals with altered gut flora they could reduce the incidence of the disease.

Signs/Symptoms

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Leaky Gut Syndrome has been linked with many conditions: Leaky Gut & • Celiac Disease Other • Multiple Sclerosis • Fibromyalgia Conditions • Autism • Chronic Fatigue Syndrome • Irritable Bowel Syndrome • Eczema • Dermatitis • Ulcerative Colitis

©Jeff Lavell, DC

Medical Treatment Model

• Leaky Gut is not a recognized diagnosis in the medical profession • Often misdiagnosed as an intestinal infection or an inflamed gut • Often mismanaged with medications that actually worsen the condition by causing more dysbiosis. For example: • Antibiotics • Steroids • Anti‐inflammatory drugs • Colectomy

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• Gut Barrier Components Affected by Intestinal Permeability: • Lumen Altered • Commensal Bacteria Intestinal • Tight Junctions • Intestinal epithelial cells Immune • Occludin family of peptides (see figure previous Responsiveness slide) • GALT • Mucosal barrier cells • M‐cells • Goblet cells • Paneth cells • Intraepithelial lymphocytes

©Jeff Lavell, DC

Leaky Gut NSAIDs & Leaky Gut Chemical Consumption and Food of NSAIDs Sensitivites

Intensity of pan and complications increase with each repetition of the cycle Histamine Worse Pain Release

©Jeff Lavell, DC

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Leaky Gut Testing

• LOW secretory IgA is associated with leaky gut. Look for this in the labs!

©Jeff Lavell, DC

IGG/IGA testing: Cyrex Labs

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ELISA/EIA (Enzyme Immunoassays) panels

• IgG testing is based on the findings that certain subclasses of IgG have been associated with the in vitro degranulation of basophils and mast cells, the activation of the complement cascade, (both of which are important mechanisms in allergy and anaphylaxis) and the observation that high circulating serum concentrations of some IgG subtypes have been measured in certain atopic individuals. • Source: • Berry, J.B., and Brighton, W.D. Familial human short term sensitizing (IgG S‐TS) antibody. Clin Allergy 1977; 7:401‐406. • Parish, W.E., Short term anaphylactic IgG antibodies in human sera. Lancet 1970; ii:591‐2. • Stanworth, D.R., Immunochemical aspects of human IgG4. Clin. Rev. Allergy 1983; 1:183‐95. • Brighton, W.D., Frequency of occurrence of IgG (S‐TS). Clin. Allergy 1980; 10:97‐100. • Wintroub, B.U., and Soter, N.A., Biology of the mast cell and its role in cutaneous inflammation. Springer Semin. Immunopathol. 1981; 4:55.

©Jeff Lavell, DC

•TheIntestinal Permeability Assessment gastrointestinal test directly measures the ability of two non-metabolized sugar molecules to permeate the intestinal mucosa. The patient drinks a Genovea: Gut premeasured amount of lactulose and mannitol. The degree of intestinal permeability or malabsorption is Permability reflected in the levels of the two sugars recovered in a urine sample collected over the next 6 hours. • Used for leaky gut (urine test) • Great test as it is done at home by the patient!

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Lab Tests

•CDSA – Genova Diagnostics • The Comprehensive Digestive Stool Analysis provides diagnostic tools for analysis of digestion, colonic environment and absorption.

©Jeff Lavell, DC

Leaky Gut Trick

• 1500 mg pure GABA if they get tired/sleepy within 30 minutes that is an indicator of leaky gut due to poor gut membrane junctions.

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Therapeutic Goals: A. Reduce systemic allergic reactions Functional B. Improve immune competence & regulation Treatment C. Normalize bowel function Strategy • Chiropractic • Allergen identification & elimination diet D. Balance gut flora

©Jeff Lavell, DC

A. Reduce Systemic Allergic Reactions

Avoid the allergen Avoid • IgG [ELISA/EIA (Enzyme Immunoassays) panels] testing can be helpful, but the tests are very expensive

Improve Improve hepatic clearance of antigenic material

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Hepatic Antigen Clearance

• Antigen-antibody clearance is related to a mild or extreme reaction to an allergen • Evaluate Liver For Toxin Clearance • Toxicity Questionnaire • Scores above 40 indicate a clinical need to address the liver and kidney’s ability to detoxify

©Jeff Lavell, DC

Support Healthy • Related Nutritional support Histamine • Natural Antihistamine with Liver Response • Liver Support Products • Immune Support

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• Arginine product which increases blood circulation via nitric oxide pathway has been shown to help liver health and liver damage. • Ozsoy Y, Coskun T, Yavuz K, Ozbilgin K, Var A, Ozyurt B. The effects of L-arginine on liver damage in experimental acute cholestasis an immunohistochemical study [published correction appears in HPB Surg. 2013;2013:492846. Ozsoy, Mustafa [removed]; Namlı, Kemal [corrected to Ozbilgin, Kemal]]. HPB Surg. 2011;2011:306069. • Some evidence that Arginine combined with Citriulline Natural will give a better clinical outcome. • Crenn P, Cynober L. Effect of intestinal resections on Antihistamine arginine metabolism: practical implications for nutrition support. Curr Opin Clin Nutr Metab Care. 2010 Jan;13(1):65-9. • Yakritron: Has histamine effect • Action: • Improves hepatic portal circulation • Filters antigen/antibody complexes and has an “anti-histamine effect”

Liver Support Product: Milk Thistle aka Silymarin

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Increases glutathione synthesis

Prevents depletion of glutathione

Protects the liver from damage

Acts as an antioxidant

Silymarin has been shown to decrease fasting plasma glucose levels in patients with insulin- dependent diabetes associated with cirrhosis

Velussi, M., Cernigoi, A. M., De Monte, A., Dapas, F., Caffau, C., and Zilli, M. Long‐term (12 months) treatment with an anti‐oxidant drug (silymarin) is effective on hyperinsulinemia, exogenous insulin need and malondialdehyde levels in cirrhotic diabetic patients. J Milk Thistle: Silymarin Hepatol. 1997;26(4):871 Milk Thistle. Natural Standard. Available at http://www.naturalstandard.com.buproxy.bastyr.edu:20 48/databases/herbssupplements/milkthistle.asp?. Accessed on 5 April 2018

Normalize Gut Biota

• Make use of products that can help to balance the gut ecosystem, both through dietary avoidance and implementation. • • Can make use of supplementation strategies to help as well. A weed, seed and feed approach.

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Weed Seed & Feed

Monday‐Friday Feed & Seed the gut flora with: • Pro‐biotics • Pre‐biotics Repeat for 6 weeks and then reassess

Weed the gut flora Saturday & Sunday with: • Wormwood • Garlic • Andrographis • Anise

L. plantarum: Intestinal Barrier

Critical function to prevent noxious contents of the intestinal lumen from accessing internal sites and entering the circulation. • Linked with inflammation • Barrier defects are reliably associated with human disease •IBD • Celiac disease • Systemic diseases involving other organ systems (Type 1 diabetes, MS) • Intestinal epithelium is single cell layer thick • Two highly dynamic permeability pathways: Pore & Leak ©Jeff Lavell, DC

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C. Chiropractic

• Avoid foods that cause “sensitivities” for 4-6 months (under supervision of a qualified practitioner.)-SEE NEXT SLIDE • Avoid products containing gluten. • Avoid caffeine • Contain additives and artificial sweeteners C. Dietary (kills gut flora) • Avoid sugar, alcohol, vinegar, too much fruit, Recommendations bread and refined carbohydrate foods that allow Candida Albicans to proliferate. • Eliminate packaged, processed, and convenience foods • Contain: Additives, Flavor Enhancers, high levels of Sugar and Salt, Hydrogenated Fats, Artificial Sweeteners, and other harmful ingredients.

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• Elimination diet for 30 days • Main aggravating substances are: • Wheat/gluten •Soy Identify • Eggs • Sulphites - wine/dried fruit Allergens • Peanuts • Shellfish •Corn •Dairy • Food additives

Elimination Diet

Once foods are After leaky gut is identified through lab addressed: testing or elimination • Reintroduce offending diet they need to be foods in small quantities avoided one at a time • Avoidance keeps •This may take several inflammation out of the months and careful record gut keeping on gut responses

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D. Support Related Nutritional support: Digestive • HCL & Pancreatic enzymes • Okra & Vitamin E3 Function • Gallbladder support • Fiber containing products

E. Support Related Nutritional Support: Healthy • Probiotic Products Gut Flora • Inulin/Pre-biotics • Colostrum

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Colostrum

Colostrum is the first Provides antibodies for form of milk produced Occurs immediately the newborn for disease by the mammary glands following the birth of protection. (IgG, IgA, of mammals (including the newborn. and IgM) as well as humans) lymphocytes.

It also has a mild Has a mild yellow hue laxative effect which to its color. helps pass the • Source: Wikipedia meconium which clears excessive bilirubin.

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Colostrum from Wikimedia Commons Amada44 Source:

While amazing for babies it has shown benefits for the adult.

A number of published studies have shown great validity with using colostrum with Colostrum gastrointestinal conditions. Promise has been shown with using colostrum with allergies due to the IgG binding effect it has. • Ulfman LH, Leusen JHW, Savelkoul HFJ, Warner JO, van Neerven RJJ. Effects of Bovine Immunoglobulins on Immune Function, Allergy, and Infection. Front Nutr. 2018;5:52.

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Colostrum And Gut Health

• Intestinal membrane and barrier function can get compromised allowing bacteria and bacteria byproducts such as LPS, pathogens, and food allergens to cross through. When this occurs this creates inflammation and mucosal compromise. • Colostrum (bovine source) can inhibit the NF‐κB signaling pathway and induction of pro‐inflammatory cytokines in HT29 cells, suggesting colostrum has direct anti‐inflammatory effects on intestinal epithelium. • Bovine IgG as a second anti‐inflammatory mechanism by preventing translocation of bacterial components across the epithelial layer. • An MJ, Cheon JH, Kim SW, Park JJ, Moon CM, Han SY, et al. Bovine colostrum inhibits nuclear factor kappaB‐mediated proinflammatory cytokine expression in intestinal epithelial cells. Nutr Res.(2009) 29:275–80. ©Jeff Lavell, DC

NSAID Induced GI Damage & Colostrum

• NSAID‐induced increases in intestinal permeability were reduced in human volunteers receiving colostrum. • Co‐administration of the health food supplement, bovine colostrum, reduces the acute non‐steroidal anti‐inflammatory drug‐ induced increase in intestinal permeability.Playford RJ, MacDonald CE, Calnan DP, Floyd DN, Podas T, Johnson W, Wicks AC, Bashir O, Marchbank T Clin Sci (Lond). 2001 Jun; 100(6):627‐33.

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Colostrum…Probiotic?

• A baby’s microbiome is influenced by a variety of factors, one of the surprising sources is breast milk. • Colostrum and breast milk have shown to have a lot of beneficial bacteria, in fact more than 200 different species! • The human milk microbiota: origin and potential roles in health and disease.Fernández L, Langa S, Martín V, Maldonado A, Jiménez E, Martín R, Rodríguez JM Pharmacol Res. 2013 Mar; 69(1):1‐10. • Colostrum has been shown a wide variety of microorganisms including Staphylococcus, Streptococcus and Bacteroides genera, as well as probiotic bacteria such as Alloiococcus spp. They have been shown to reduce the incidence and severity of several gastrointestinal infections by both competitive exclusion mechanisms and production of antimicrobial compounds • Toscano M, De Grandi R, Peroni DG, et al. Impact of delivery mode on the colostrum microbiota composition. BMC Microbiol. 2017;17(1):205. Published 2017 Sep 25.

•Celiac Disease • An autoimmune disorder of the small intestine that occurs in genetically predisposed people of all ages from middle infancy on up. • Symptoms include chronic diarrhea, Differential failure to thrive (in children), and fatigue, but these may be absent, and symptoms Diagnosis in other organ systems have been described. • A growing portion of diagnoses are being made in asymptomatic persons as a result of increased screening.

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SIBO

Infection: • Small Intestinal Bacterial Overgrowth (SIBO) implicated in IBS.1 • Theory is controversial2 • Conventional therapies aimed at SIBO have shown success rates of 5 to 80% in IBS patients2 • Changes in the colonic flora, especially Etiology reduced levels of Bifidobacteria, have also been consistently found3 • Sources: • Lee RH, Pimentel M. Curr Gastroenterol Rep 2006; 8(4): 305‐311 • Van Citters GW, Lin HC. Curr Gastroenterol Rep 2005; 7(4): 317‐320 • Quigley EM. J Dig Dis 2007; 8(1): 2‐7

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Bile and small intestine bacteria

• The remarkable ability of bile acids to solubilize polar lipids during digestion has generally been considered the sole function of conjugated bile acids in the small intestine. Work during the past decade (see below) has suggested that luminal conjugated bile acids have a second function: to inhibit the growth of bacteria in the small intestine. This study verified that indeed bile acids offer protection against pathologic bacteria in the small intestine. • Hofmann AF, Eckmann L. How bile acids confer gut mucosal protection against bacteria. Proceedings of the National Academy of Sciences of the United States of America. 2006;103(12):4333‐4334.

Avoid foods that cause “sensitivities” for 4-6 months (under Avoid supervision of a qualified practitioner.)

Avoid sugar, alcohol, vinegar, too much fruit, bread and refined Avoid carbohydrate foods that allow Candida Albicans to proliferate. SIFO Dietary Eliminate packaged, processed, and convenience foods Eliminate •Contain: Additives, Flavor Enhancers, high levels of Sugar and Salt, Hydrogenated Recommend Fats, Artificial Sweeteners, and other harmful ingredients. ations Avoid Avoid dairy products which feed the yeast.

Avoid Avoid fermented products which feed the yeast.

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Other Lower GI Pathologies • Diverticulitis • Constipation • Diarrhea

•Diverticulitis • Diverticulitis is a common digestive disease particularly found in the large intestine. • Diverticulitis develops from diverticulosis, which involves the formation of pouches (diverticula) on Lower GI the outside of the colon. • Diverticulitis results if one of these diverticula pathophysiology becomes inflamed or infected. • Chief diagnostic criteria are diverticula visualized on CT or colonoscopy • Gut pain accompanies infection of enlarged haustra

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•Diverticulitis • Diverticulosis, otherwise known as "diverticular disease", is the condition of having diverticula in the colon which are outpocketings of the colonic mucosa and Diverticulitis submucosa through weaknesses of muscle layers in the colon wall. • Often asymptomatic until infection develops

Low Residue Diet

•A low residue diet is recommended to reduce flare‐ups of diverticula. • The low residue diet is designed to reduce the frequency and volume of stools while prolonging intestinal transit time. • It is similar to a low fiber diet, but typically includes restrictions on foods that increase bowel activity, such as milk and milk products and prune juice. • A low residue diet typically contains less than 10‐15 grams of fiber per day.

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Lower GI pathophysiology: Constipation

• Causes • Lack of bile • Too little water • Too little fiber • Denis Burkitt, former missionary surgeon in Uganda, originally proposed based on his work among indigenous peoples, that ‘indigestible roughage was a requisite component of a healthy diet. • Burkitt laid part of the blame of constipation on diets that were high in carbohydrates (refined) but lacking the fiber we’d evolved to eat.

•Constipation continued • Burkitt believed he could draw a direct line of causation from the absence of fiber in refined carbohydrates to constipation, hemorrhoids, appendicitis, diverticulitis, polyps, and finally, Lower GI malignant colon and rectal cancer. • Burkitt’s theory involved a slowing of transit pathophysiology time of foods without fiber and a change in the bacterial flora of the stool. • Burkitt and Walker published their findings in the Lancet in 1972

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•The definition of constipation includes the following: • Infrequent bowel movements (3 or less/week) • Difficulty during defecation (straining during more than 25% of bowel movements or a subjective sensation of hard stools) • The sensation of incomplete bowel evacuation. Signs/Symptoms • Severe cases ("fecal impaction") may feature symptoms of bowel obstruction (vomiting, very tender abdomen) and "paradoxical diarrhea", where soft stool from the small intestine bypasses the impacted matter in the colon • Types 1 and 2 on the Bristol Stool Chart indicate constipation

•One out of eight report trouble with bowel movements •One third of people over the age of 60 • Elderly are most at risk - not necessarily due to aging •Increases with: Incidence 1.Drug use 2.Too little fiber and fresh foods 3.Sedentary lifestyle

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•Laxatives Medical • Stimulant type Treatment • Hyperosmolar type Model • Saline • Lubricant • Bulk forming

Clinical Pearl

•Except for bulk forming laxatives ‐ routine use should be discouraged • Pharmacologic laxatives and enemas or colonics can cause “lazy bowel” • Suppression of the defacatory reflex • Haustra or dilation of rectum or sigmoid colon may also result

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•Dihydrophenylisatin • the known laxative agent in prune juice among others unknown Prune juice • “SYNERGY”

• Causes: Lower GI • Infection in gut/gut dysbiosis Pathophysiology: • Stress (enteric brain effects) Diarrhea • Allergen • Poor gallbladder function

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Gut Support Protocols

Glutamine

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• L‐glutamine is the most abundant amino acid in the bloodstream and it makes up 30‐35 percent of the amino acid nitrogen Glutamine in your blood. and • The addition of glutamine to parenteral nutrition prevents deterioration Endothelial of gut permeability and preserves mucosal Tissue structure. 1 1. Lancet. 1993 May 29;341(8857):1363‐ 5.Glutamine and the preservation of gut integrity. Van der Hulst RR1, van Kreel BK, von Meyenfeldt MF, Brummer RJ, Arends JW, Deutz NE, Soeters PB.

• Glutamine • Supports glutathione levels, supports and protects healthy intestinal tissue especially where there is reduced glutaminase activity) • Glutathione, the main antioxidant of Glutamine and intestinal epithelial cells, is suggested to play an important role in gut barrier Glutathione function and prevention of inflammation‐ related oxidative damage. 1 1. Toxicol Appl Pharmacol. 2005 May 1;204(3):320‐8. Intestinal glutathione: determinant of mucosal peroxide transport, metabolism, and oxidative susceptibility.

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Protein and Glutathione Production

•“Glutathione is not an essential nutrient for humans, since it can be biosynthesized in the body from the amino acids L-cysteine, • L-glutamic acid (which makes glutamine), and glycine. The sulfhydryl group (SH) of cysteine serves as a proton donor and is responsible for its biological activity.”

From Wikipedia: Glutathione

Cysteine as it occurs in whey is very sensitive and if broken does not provide glutathione enhancement. It is broken by pasteurization at too high a temperature, excessive agitation and oxidation.

Cysteine and Glutathione Production

“Cysteine is a sulfur- containing amino acid that contributes to the sulfhydryl group in the glutathione The amount of cysteine in molecule. This makes your system is the limiting Whey protein contains cysteine the most crucial of the three building blocks for factor in how much cysteine. glutathione.” glutathione you can make. (http://www.immunehe althscience.com/cysteine.html )

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There are a number of things to consider with whey protein and one of them is the denatured vs. undenatured argument. Each has advantages and disadvantages.

Undenatured is whole proteins that are processed at low temperatures. Denatured protein while not bad at all from a protein standpoint does affect the amino acid profile. Whey Cold processing of concentrate allows some of the beneficial bacteria to remain active. This also significantly boosts levels of Protein the master antioxidant glutathione. As we all know oxidation causes cellular damage, regardless of the cell type. Increase glutathione levels you increase cellular health/protection.

Whey also contains glutamine which is essential in musculoskeletal recovery.

Whey Protein

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FOOD ADVICE FOR TISSUE HEALING

 Eat foods high in vitamin A, Vitamin C and bioflavinoids, such citrus fruits, berries, buckwheat, dark leafy greens (such as spinach and kale), and sea vegetables.  Avoid refined foods, such as white breads, pastas, and sugar.  Eat sources of protein on a regular basis and excellent add in is whey protein.  Kale  Contains a number of organosulfer compounds  Antiseptic for the gut, supports detoxification and provides Vitamin A precursor molecules

Key Ingredients: When you consume whole food vitamin C you get the advantage of bioflavonoids, J, K and P factors, and tyrosinase in addition to Whole Food ascorbic acid.

Vitamin C Action: Vitamin C is essential for Complex mucin production, necessary for collagen synthesis, blood formation, and plays a role in RBC oxygen delivery

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• Whole Food Vitamin A and immune function • Vitamin A is commonly known as the anti- infective vitamin, because it is required for normal functioning of the immune system • The skin and mucosal cells (cells that line the airways, digestive tract, and urinary tract) Whole Food function as a barrier and form the body's first line of defense against infection Vitamin A • Source: Semba RD. Impact of vitamin A on immunity and infection in developing countries. In: Bendich A, Decklebaum RJ, eds. Preventive Nutrition: The Comprehensive Guide for Health Professionals. 2nd ed. Totowa: Humana Press Inc; 2001:329-346.

Chlorophyll & Wound Healing

•Oxygen delivery improves wound healing. A rationale for the use of chlorophyll is that it has two important properties: – It is demulcent on contact with the wound due to the fat soluble factors in the chlorophyll as well as coating and soothing the mucus membrane – Detoxifier: neutralizes guanadine – Supports blood, tissue oxygenation and healing – Source of vitamins A, D, E & K – When ingested it provides heme molucule to support blood hemoglobin production – Source: Said HK. Et al. Transdermal sustained-delivery oxygen improves epithelial healing in a rabbit ear wound model. Arch Surg. 2005 Oct;140(10):998- 1004. – Source: SACK PW, BARNARD RD. Studies on the hemagglutinating and inflammatory properties of exudate from nonhealing wounds and their inhibition by chlorophyll derivatives. N Y State J Med. 1955 Oct 15;55(20):2952-6.

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Nutrition and • Anti‐microbial and Mucosal Support the Stomach • Golden Seal Liquids/tablets

• Proponents of the use of botanical dietary supplements often argue that their complexity leads to enhanced efficacy due to synergistic interactions among multiple constituents. Here we demonstrate that extracts from the aerial portions of Hydrastis canadensis contain both the known antimicrobial agent berberine and other compounds (hitherto unidentified) that synergistically increase the antimicrobial activity Golden Seal of berberine. • Ettefagh KA, Burns JT, Junio HA, Kaatz GW, Cech NB. Goldenseal (Hydrastis canadensis L.) extracts synergistically enhance the antibacterial activity of berberine via efflux pump inhibition. Planta medica. 2011;77(8):835‐840. doi:10.1055/s‐ 0030‐1250606.

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Golden Seal

• Key Ingredients: • Golden seal root. Active constituents are berberine and hydrastine. • Action: • Antibacterial, antifungal, antiprotozoal • Cytotoxic and acts directly on the bacteria

Golden Seal Root

Anti‐microbial & Other antimicrobial Trophorestorative Actions remedies, such as Garlic Astringent phytonutrients will help to resolve H. • Because of its bitterness, it is such as Grape Seed extract best given as a tablet. pylori presence is also antimicrobial • Many ulcer patients find raw Garlic difficult to take

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• Golden Seal is restorative to mucous membranes and also antibacterial. However, because of its bitterness it is best given as a tablet • Also other antimicrobial remedies such as Thyme herbal liquid and raw crushed Garlic will help to resolve H. pylori presence, although many ulcer Golden Seal patients find raw Garlic difficult to take. • Astringent herbs such as Grape Seed extract, Rhubarb and Green Tea are also antimicrobial. • Kerry Bone: Principals and Practice of Phytotherapy

Lower GI Treatment Considerations

• View it more of a pillar approach to treatment. • Think of the pathophysiology and regions involved. • This will vary by patient. • Be thorough in your investigation…use your tools! • Great history is key! • Lab testing • Food questionnaire

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Functional Tests Potential Gluten Laboratory/Diagnostic Tests Conventional Tests • Intestinal • 3-month gluten elimination trial (Gold standard) • Endoscopy – permeability • Anti-deaminated gliadin IgG and IgA biopsy • Indican, lactate • Anti-gliadin IgG and IgA • Capsule • Organic acids • IgA anti-endomysium antibody endoscopy • IgA and IgG anti-transglutaminase ELISA (tTG) • Breath test • Stool DNA • Total IgA (IgA deficiencies 10 times more common in CD) • Motility • Fecal calprotectin • HLA DQ2, DQ8 • Stool Culture • Fecal lactoferrin • Intestinal biopsy • Serologies • Stool SCFAs • Antibodies to • Lactulose-mannitol intestinal permeability parasites • Zonulin

Gastrointestinal Testing

• Gut flora…the most key! • Transit time/Elimination Pillars for • Think North vs. South lower GI • Liver, gallbladder, stomach all involved. • Inflammation treatment: • Vascular function • Immune • Epithelium

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Q & A

Protocols

Thank You!