SERUM-DERIVED BOVINE IMMUNOGLOBULINS:

Transcription

1 SERUM-DERIVED BOVINE IMMUNOGLOBULINS: A Major Breakthrough in Autoimmunity Jill C. Carnahan, M.D. ABFM, ABIHM, IFMCP Flatiron Functional Medicine, Louisville, CO

2 2 Website: Facebook:

3 THE LPS STORY Lipopolysaccharides are endotoxins

4 Lipopolysaccharide Lipopolysaccharides (LPS) are large molecules found in gramnegative bacteria. They are endotoxins which if absorbed elicit a strong immune response. The detection of antibodies against LPS reveals macromolecule-sized endotoxin infiltration through the intestinal barrier into the systemic circulation. Intestinal permeability can cause systemic inflammation through translocation of LPS

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6 In humans, the presence of LPS triggers an innate immune response, activating the immune system and producing cytokines. Inflammation is a reaction to those cytokines.

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8 Inflammatory Bowel Disease NSAID therapy Small Intestinal Bacterial Overgrowth (SIBO) Celiac disease Protozoal infections Fungal Infections Toxic Exposure Food Allergies/Mast cell disorders Chronic Alcoholism Diarrhea Strenuous exercise Increasing age Nutritional Depletions

9 Poor Dietary Choices Stress & Emotions Food Allergy Infection Lectins Systemic Disease Low Stomach Acid Toxic Exposure Altered Intestinal Permeability Malnutrition Dysbiosis Toxic Overload Elevated Total Toxic & Antigenic Burden Systemic Disease

10 Examples of gram negative bacteria E. coli Campylobacter Salmonella Pseudomonas Enterobacteriaceae Helicobacter Neisseria gonorrhoeae Chlamydia Others, such as Borrelia may also trigger immune reaction

11 Affects one third of the western population. Increased serum LPS during the first five hours of the post-prandial period following consumption of a meal. Meals that are high in fat and dense in calories cause greater increase Followed by elevated inflammation marked by measurable increases in interleukin-6, interleukin-1-alpha, interferon-gamma, triglycerides and postprandial insulin. Chronic metabolic endotoxemia has significant correlation to increases in the risk of developing many chronic diseases. Correlation with cardiovascular disease, diabetes, obesity, hypogonadism, autoimmunity and even mood disorders such as anxiety and depression.

12 AKA lipopolysaccharide (LPS) Inflammatory immunogens Component of gram-negative bacterial outer cell wall Adhesin for colonization of host Diversity of antigenic strains Circulates at low-grade levels in healthy individuals Toxicity mainly mediated by the lipid-a component Erridge, et al. Am J Clin Nutr. 2007;86:

13 Immune activation by LPS starts with pattern-recognition receptor called TLR4 TLR4 is important signaling protein in innate immune system found on the surfaces of innate immune defense cells like Macrophages and dendritic cells. These cells contain CD14, which binds to TLR4 to facilitate the recognition of patterns on gram negative and gram positive bacteria. Circulating LPS gets bound by a phospholipid transfer protein called LBP, which carriers LPS to the CD14-TLR complex for examination. Once LPS-LPB has bound to the CD14-TLR complex, it initiates an immune cascade that leads to the activation of NFKβ Activation of NFKβ leads to the increased expression of pro-inflammatory mediators TNFα, IL-1beta, IL-6 and MCP-1. Innate immune cells that become activated by LPS and subsequently cause the chronic release of pro-inflammatory cytokines, in all parts of the body, including the blood-brain barrier.

14 Metabolic Endotoxemia LPS is common trigger to of insulin resistance, obesity, and diabetes Endotoxemia increased during the fed and decreased during fasted state LPS serum concentration 2-3X threshold defines metabolic endotoxemia. High-fat diet increased the proportion of an LPS-containing microbiota in the gut.

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16 Metabolic Endotoxemia Metabolic endotoxemia was induced for 4 weeks in mice by continuous infusion of LPS Increased weight gain Increased markers of inflammation Increased Triglyceride production by liver Increase insulin resistance Metabolic endotoxemia dysregulates inflammatory tone and triggers weight gain and diabetes. Lowering plasma LPS concentration could be a potent strategy for the control of metabolic diseases.

17 TYPES OF DIETARY FATS AND ENDOTOXEMIA Endotoxin permeability and changes in serum endotoxin levels in the hours subsequent to the ingestion of a test meal containing either 50ml coconut (CO), vegetable (VO) and fish oil (FO) in otherwise healthy pigs (Mani. 2013).

18 Why does the type of fat matter? Saturated fat (SFA) and n-3 PUFAs have opposite effects on LPS receptor, TLR4, and lipid rafts Lipid-A component of LPS is composed of SFA Endotoxin toxicity is reduced when SFA in lipid-a is substituted for n-3 PUFAs Lee, et al. J Biol Chem. 2004;279: How does endotoxin enter the blood? Paracellular pathways Via tight junctions Transcellular pathways Via lipid rafts (endocytosis) Rigid portion of membrane Composed of cholesterol, SFA Important in cell signaling Triantafilou, et al. J Cell Sci. 2002;115: ;

19 CONDITION Leptin Resistance Chronic Constipation Mood and Appetite Disorders Depression Cognitive Decline Loss of Memory and Recall Depression Anorexia Anxiety Chronic Pain Parkinson s Hypogonadism (low testosterone) Autoimmunity MECHANISM LPS ELEVATED enters and LPS causes AND inflammation DISEASEin the enteric nervous system leading to a disruption in the gut-brain axis of communication. LPS enters the enteric nervous system and causes disruption in signals for gastric emptying and bowel motility. LPS disrupts ghrelin function which has a direct impact on appetite and mood, LPS can migrate to the blood-brain barrier and cause inflammation along with inhibition of dopamine receptors. Inflammation in the blood brain barrier leads to cognitive decline LPS can get into the amygdala and hippocampus which disrupts memory function LPS can increase the turnover of serotonin in the synapse and CNS reducing the concentration in those regions The reduction of serotonin in the synapse and CNS is proposed as a possible mechanism for anorexia. LPS disrupts key communication between the hypothalamic-adrenal-pituitary axis thereby increasing the expression of corticosteroid releasing hormone Elevated LPS in sensory neurons in the dorsal root stimulate nociceptors. Intra-cranially LPS causes microglial activation and neuronal loss Increased circulating LPS and the subsequent chronic immune activation has feedback inhibition of testosterone production. GELDING theory. Chronic activation of the innate immune system in various tissues leads to the bystander effect where self-tissues inadvertently become targeted by the immune system.

20 GUT PERMEABILITY CHRONIC INFLAMMATION Stress induces endotoxemia and increasing barrier permeability Karin de Punder* and Leo Pruimboom Frontiers in Immunology published: 15 May 2015 Chronic non-communicable diseases (NCDs) are the leading causes of work absence, disability, and mortality worldwide. Most of these diseases are associated with low-grade inflammation. In combination with modern life-style factors, the increase in bacteria/bacterial toxin translocation arising from a more permeable intestinal wall causes a lowgrade inflammatory state. We support this hypothesis with numerous studies finding associations with NCDs and markers of endotoxemia, suggesting that this process plays a pivotal and perhaps even a causal role in the development of lowgrade inflammation and its related diseases.

21 HOW DOES A HEALTHY MICROBIOME PROTECT AGINST METABOLIC ENDOTOXEMIA? Neutralize LPS -increase siga -increase PAMP Increase Mucin2 production Increase tight junction protein expression Increase regeneration of expelled IEC Tissue Barriers. 2015; 3(1-2): e Published online 2015 Jan 15. doi: /

22 SBI (SERUM-DERIVED BOVINE IMMUNOGLOBULINS)

23 SBI Stats GRAS since 12/ human studies 6 randomized, placebo-controlled trials 3 open-label 34 are retrospective case studies and series 57 studies total Over 450 peer-reviewed studies done on plasma and its sub-fractions (SBI is part of sub-fractions) 530 subjects have been exposed to SBI in documented clinical research for 1 day-24 months at doses ranging from 5-20g per day Since 2013, 4.7 million doses prescribed Dairy-free, sugar-free, non-gmo

24 Immunoglobulin history Ehrlich rejected the idea of inherited immunity so used mice and switched offspring for nursing. The mice nursed by treated females were protected showing antibody transfer through milk. While engineering a vaccine for cholera in the late 80s, Fasano discovered a toxin that could open tight junctions and that started the search for zonulin. Zonulin discovered in 2000.

25 SBI Protect Mechanism of action Passive immunity Dysbiosis Abnormal microbiota Infections Intestinal Permeability Lifestyle-induced Endotoxemia results Dendritic cells present antigens to T-cells who have B-cells start antibody production Immune system activation Inflammation ensues

26 Why Treating Leaky Gut makes sense Once we were able to see a direct correlation between the genes that regulate zonulin and the genes associated with autoimmunity, the connection between intestinal permeability and autoimmunity was made. Three Conditions must be present for autoimmunity to develop 1. Genetics, 2. Environmental Trigger 3. LEAKY GUT Two major stimuli that increases zonulin in everyone: 1. Gluten 2. Translocated colon bacteria in the small intestines (SIBO)

27 PRRs: I see you, PAMPS (pathogen-associated molecular patterns)

28 When one or more PRRs recognize a pathogenic or dangerous molecular pattern, a cascade of intracellular signals is triggered. Consistent among these signals is an upregulation of inflammatory cytokines. Tom Guilliams Ph.D. in Supporting Immune Function Roadmap (p. 25) Inflammatory Cytokines: IL-1 IL-12 IL-18 TNF α

29 SBI and PAMPs When Ig bind antigens, it removes PAMPS from interacting with PRRs. This prevents immune activation. Lack of immune activation means lack of excessive inflammation. Decreased inflammation means less tissue damage. Less tissue damage allows enterocytes and their junctions to be restored without assault. Dampens molecular mimicry.

30 Molecular Mimicry and Autoimmunity Many microbes produce structures that resemble or mimic the structures found in human tissues. Specific microbial proteins have amino acid homology with human proteins and/or homologous bacterial peptides and appear to stimulate (auto)immunity toward similar human peptides. Thus, when the immune system fights against the microbe, the antibodies and T-cells can crossreact with tissues of the human host. Ringrose JH. HLA-B27 associated spondyloarthropathy, an autoimmune disease based on crossreactivity between bacteria and HLA-B27? Ann Rheum Dis Oct;58(10): Wucherpfennig KW. Mechanisms for the induction of autoimmunity by infectious agents. J Clin Invest Oct; 108(8):

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32 Which patients does this affect? Lyme (co-infections) Autoimmunity (intestinal permeability, inflammation, molecular mimicry Crohn s, UC, RA, Hashimoto s, Lupus, MS Autism (Leaky Gut/Leaky Brain) Immunosuppressed Fibromyalgia (inflammation, infection) IBS/IBD Intestinal Permeability Hypersensitivities/MCAS Allergies, Eczema, Rashes, Chemical and Food Sensitivities

33 Pharma s Not Helping the Situation All of these medications are common in Autoimmune patients and have a negative side effect for the risk of the immune system activation unnecessarily

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35 LPS, Zonulin and Neuroinflammation 1. Zonulin release due to gliadin and bacteria 2. Immune Response and Inflammation 3. Zonulin, toxins, LPS, inflammatory cytokines enter circulation 4. BBB leaky due to zonulin and same products enter 5. Neuroinflammation noted in Alzheimer s, Autism, Mood disorders, Cognitive decline, Schizophrenia

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37 Binding capacity of SBI

38 Zonulin upregulated in certain conditions *SIBO Gluten intake Celiac Type 1 Diabetes MS Crohn s *Ovarian cancer *Pancreatic cancer *Gliomas Schizophrenia *Autism * indicates not ideal to give dairy. High index of suspicion for endotoxemia in ALL these patients

39 Contraindications Allergy to beef No drug interactions No restrictions on duration No adverse events

40 Don t over-complicate Mechanism Leaky gut Dysbiosis GI inflammation Need for dairy-free Need for lower endotoxins Reduce histamine levels Conditions Enteropathy (IBS, IBD) Autoimmunity Lyme Mold Autism *Chemotherapy HIV

41 Dosing is simple: 2.5g-5g twice daily

42 CLINICAL CASE STUDIES

43 Case 1 35 y/o female with ulcerative colitis PMHx UC diagnosed 2 years prior to office visit PSHx none Social married, 3 children, high stress sales job Medications mesalamine Diet SCD diet

44 Cyrex Array 2 - Results

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47 Assessment Assessment Ulcerative Colitis Plan L-glutamine butyrate enemas SBI 5g twice daily High dose Probiotic twice daily Anti-microbial herbal regimen x 8 weeks Vitamin D3 5000IU Omega 3 s 3g daily

48 Case 2 72 y/o women with rheumatoid arthritis and fibromyalgia PMHx Hypertension Hashimoto s thyroiditis Fibromyalgia Rheumatoid arthritis Fibromyalgia PSHx Bilateral knee replacement Partial Hysterectomy at 44y/o for fibroids in uterus Cholecystectomy Tonsillectomy

49 Case 2 FHx Mother s sister died of breast cancer; sister has fibromyalgia recent diagnosis; Father died auto-accident; Mother lived to be 94y/o; Mother s older sister had RA Social - lives with husband of 40+ years, provided home health care for clients Diet gluten-free Meds Methylcobalamin 2500mcg/0.4ML use 2500mcg 2-3X weekly Armour thyroid 60mg daily Venlafaxine ER 75mg daily Trazadone 50mg at bedtime Felodipine 5mg 1 PO daily Methotrexate 2.5mg daily

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52 Assessment Rheumatoid Arthritis Fibromyalgia Hashimoto s Presumed leaky gut and endotoxemia

53 Plan Multivitamin daily Vitamin D3 5000IU Omega 3s-3g daily High dose probiotics twice daily Digestive enzymes with meals Curcumin daily Glutamine 4g twice daily SBI 2.5-5g twice daily Magnesium at bedtime

54 Questions?