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Institutionen för klinisk vetenskap, intervention och teknik Huddinge 2018-04-27. www.synbiotics.se www.bengmark.com stig@bengmark.se. GUT-DERIVED PROTEIN-BOUND UREMIC TOXINS – NEW PERSPECTIVES ?? Stig Bengmark MD PhD , London University, UK.

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synbiotics.se bengmark stig@bengmark.se

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  1. Institutionen för klinisk vetenskap, intervention och teknik Huddinge 2018-04-27 www.synbiotics.se www.bengmark.com stig@bengmark.se • GUT-DERIVED PROTEIN-BOUND UREMIC TOXINS – NEW PERSPECTIVES ?? • Stig Bengmark MD PhD, London University, UK

  2. DIFFERENT LIFESTYLE – DIFFERENT DISEASE PATTERNClayton P, Rowbotham J Int. J. Environ. Res. Public Health 2009;6:1235-1253

  3. THIRD MILLENIADISEASES increases in incidencein recent 27 years(1990 – 2017)USALear R. The Root Cause in the dramatic rise of Chronic Disease https://app.box.com/s/iyjuzrxtkx3gpblu4vmt0wjrgsxykuzc Chronic fatigue syndrome 11027 percent Bipolar disease in youth 10833 percent Fibromyalgia 7727 percent AUTISM 2094 percent Celiac Disease 1111 percent ADHD 819 percent Lupus 787 percent Hypothyroidism 702 percent Osteoarthritis 449 percent Sleep Apnea 430 percent Diabetes 305 percent Alzheimer’s disease 299 percent Mental Depression 280 percent Asthma 142 percent

  4. APR & CPR – NUTRITIONAL CONTROLBengmark S Nutrition 2001;17:489-495

  5. ”WARNING SIGNALS” - CHRONIC INFLAMMATION Unexplainedfatigue, sleep problems, frequentheadache, hair loss, gray hair, dandruff, acne, skin rashes, dryeyes, frailnails, drymouth or increased salivation, reduced sex functions, irregular menstruations, obstipation or diarrhea, osteoporosis, overweight, frequentinfections, mental depression, easybreathless, sweatyfeet, sweaty hand palms etc. www.bengmark.com

  6.  POOR EATING – POOR IMMUNITY  PRESENT PALEO THE FRONT DOOR – SHORTCUT 1 Sugar and Suger-like substancesenters the body in upperjejunum via the portal vein – adding to app 60 % POSTPRANDIAL INFLAMMATION 15 % THE BACK DOOR – THE DANGEROUS ROUTE app 30 % animal fats & vegetableoilenters via the lymphatic system and remains in circulation for hours – INDUCING POSTPRANDIAL INFLAMMATION > 10 % THE MAIN DOOR < 20 % raw greens, vegetables, fruitsare FOODS FOR MICROBIOTA and reaches the largeintestineafter 2-3 hours, enhancing immune system & preventing inflammation app 80 %

  7. FOOD INTAKE & INFLAMMATION  Low intake of fresh plant foods; GREENS, vegetables, fruits, SPICES  Higher intake of proteotoxins in certain foods: casein, gluten, zein (corn) etc.  Higherintake of heat- and storage-inducedproteotoxins: glycated (AGEs), lipoxidatedmolecules (ALEs),processedcarbohydratesinduces: - Dysbiosis: reduced numbers & diversity - Variousbodymembranesleak like a sieve; leaky gut, leaky airways, leaky skin, leaky vagina, leaky eye cavity , leaky nose, leaky placenta, leaky blood-brain barrier etc. www.bengmark.com

  8.  PROCESSED FOODS – THE VILLAIN  Excess of refined foods; fats, sugars, bioactive peptides, hormones, chemicals (pharmaceuticals) • Destabilizes the immune system • Increases proxidant actions • Creates dysbiosis - Reduced microbiota • Stimulates overexpression of NF-κB, COX-2, LOX, iNOS & • Reduces resistance to disease

  9. PLANT FOOD PREVENTS CHRONIC DISEASESAune D. et al Int J Epidemiol2017;46:1029-1056RECOMMENDATION for optimal health 1 – 1 ½kg/person/day Eating 800 g fruit and vegetables a day – or 10 portions – is associated with:28 % reduced risk of cardiovascular disease  24 % reduced risk of heart disease  33 % reduced risk of stroke 13 per cent reduced risk of total cancer 31 % reduction in premature death

  10. TRANSITION FROM AGRICULTURE AQVA- & HORTICULTURE-BASED DIET After experiencing long-term health problems, including quadruple bypass surgery 2004, the former President & “junk food lover” was advised by his doctors to become a vegan. He radically changed diet  shunning meat, eggs, dairy and almost all oils &  lost 20 lbs. in weight & improved his health.  saying:"I like the vegetables, the fruits, the beans, the stuff I eat now“ "I feel good, and I also have … more energy."

  11. LOW AGE DIET, EXERCISE & HEALTHMarcias-Cervantes et al Nutrition 2015;31:446-451 Improvment on Low AGE diet + exercise

  12.  HEATING OF FOODS – NEGATIVE EFFECTSBenlloch-Tinoco M et al. Food Chem 2015;187:254–262 FreshMicrovawedConventionallyheated LUTEIN: Spinach Kale Carrots Broccoli Peppers Sweetcorn Tomatoes PHa: pheophytin A BETACAROTENE: Peppers Lettuce Kale Carrots Spinach Mustard Greens Turnip Greens ChineseCabbage Phb: Pheophytin B CHLOROFYLL: Microg/cup Parsley 380 Spinach 240 Cress, garden 160 Green beans 80 Arugula 80 Leeks 80 Endive 50 Sugar peas 50 Chinesecabbage 40

  13.  PREVENTING DYSBIOSIS IS KEY TO DISEASE & INFECTION CONTROL Brandtzaeg P et al Gastroenterology 1989;97:1562-84 Per Brandzaeg 1936 - 2016 • A strikinglocalpreponderence (70-90 %) of IgAimmunocytes in the gut: plasma cells, plasma blasts • The gut content is constantlytested by recognition cells such as dentritic cells (DC) & • Programming/tuning the immune system  Each DC commandsabout 1200 T-cells  If derangedmicrobiota - DYSBIOSIS & LEAKY GUT willinduce INFLAMMATION & facilitate INFECTION & DISEASE

  14. DENDRITIC CELL & IMMUNE REGULATIONVan Baarlen P et al PNAS 2009;106:2371–2376

  15. THE DENDRITIC CELL IN ACTION Kraehenbuhl JP, Corbett M. Science 2004;303:1624-1625

  16. HIGH FAT DIET & MICROBIAL TRANSLOCATIONAmar J et al EMBO Mol Med 2011;13:559-572 ADIPOSE TISSUE BLOOD LYMPH NODES Live intestinal bacteria found in large numbers in blood, adipose tissue (MAT) & mesenteric lymph nodes (MLN) AFTER ONLY ONE WEEK ON HIGH FAT DIET (HFD)

  17. ENDOTOXIN - ASSOCIATED CHRONIC DISEASES: Alzheimer Jaeger LB et al. Brain Behav Immun. 2009; 23: 507–17 Cognitive impairment Lee JW et al. J Neuroinflammation 2008; 5: 37 Arterio-/Coronary Diseases Heo SK et al Immunol Lett 2008;120:57-64 Diabetes type 1 Nymark M et al Diabetes Care 2009 32(9): 1689–1693 Diabetes type 2 Andreasen AS Intensive Care Med. 2010;36:1548-1555 Cancer Hsu RY et al Cancer Res. 2011;71(5):1989-1998 Chronic Liver diesasesNolan JP Hepatology 2010;52:1829-1835. ADHD, allergy, ALS, autism, autoimmune diseases, bipolardisease, cardiorenaldiseasecataracts, chronicfatiguesyndrome, COPD, fibromyalgia, glaucoma, gulf warsyndrome, HIV, iritis, hypertension,macular degeneration, minimal encephalopathy, multiplesclerosis, nephropathies, obesity, osteoporosis, paradontosis, Parkinson, polycysticovarysyndrome, rheumatoiddisease, stress, schizophrenia, stroke, uveitis, etc

  18. UNDERSTANDING:INFLAMMATION - Perinatal - Postprandial & INNATE IMMUNITY= UNDERSTANDING DISEASEInflammation – the mother of Disease! http://bengmark.com/stig-intervjuas-av-daniel-sword/

  19. INFLAMMATION INVOLVES ABOUT 1200 GENESaffectsa wide range of effector molecules; pro-inflammatory cytokines, chemokines, MMPs and metabolic proteins BIOLOGICALS aimed to targetsingle genes; anti- TNF-α, anti- IL-1β, anti-HER2, IL-12/IL-23, IFN-γ, IL-17A, IL-2 and IL-6, and inhibitor of NF-КB etc. Uni-targetting Immediatepowerfuleffects Limited by toxicity Negative to microbiota Sometimes short-lasting effects Substancialadverseeffects Indicated - aggressive diseases ECO-BIOLOGICALS; utilizes the antiinflammatory effects of microbes and plants; greens, vegetables, fruits & spices to support microbiota Multi-targetting Slower and weakereffects GRAS – e.g. no toxicity Support microbiota Long-lasting effects No adverseeffects Indicated - prevention and earlydisease

  20. THE BATTLE FIELDPOSTPRANDIAL INFLAMMATIONGENERAL INFLAMMATIONCHRONIC DISEASESMyles IA Nutrition Journal 2014;13:61

  21.  DAILY BLOOD GLUCOSE VARIATIONS Freckmann G et al J Diabetes SciTechnol. 2007; 1: 695–703 Normal: 72-108 mg/dL = 4-6 mmmol/l  fasting, max 157 = 8.7 aftermeal.

  22. POSTPRANDIAL HYPERLIPIDEMIA IN METABOLIC SYNDROMEAlcala-Diaz JF et al. PlosOne 2014;9:e96297

  23.  POSTPRANDIAL LIPIDEMIA & INFLAMMATION Khor A et al Nutr Res. 2014;34:391-400 • Postprandial inflammatory activity is a strong risk factors for atherosclerosis Ebenbichler CF CurrOpinLipidol 1995;6:286–290 (& other chronic diseases) • increases content of endotoxin in blood (eqv to smoking 3 cigarettes) Erridge C et al Am J ClinNutr 2007;86:1286 –1292 • leads to cascades of inflammatory and oxidative stress Ceriello A et al. Diabetes 2004;53:701–710 • release of tumor necrosis factor-α, a key proinflammatorycytokineErridge C et al Am J ClinNutr 2007;86:1286 –1292 • increases numbers of & activates leukocytes Alipour A et al ArteriosclerThrombVascBiol 2008;28:792–797 • Inflammatory reaction potentiated by simultaneous intake of sugar Ceriello A et al. Diabetes 2004;53:701–710

  24.  POSTPRANDIAL INFLAMMATION & ENDOTOXEMIA Erridge C et al Am J ClinNutr 2007;86:1286 –1292 

  25.  POSTPRANDIAL METABOLISM – IMPACT OF VINEGAR  Mitrou P et al Eur J ClinNutr 2015;69:734-739 Vinegar Vinegar

  26. INDUCERS OF POSTPRANDIAL INFLAMMATIONLópez-Moreno J et al.J Agric2017;65:7756-7763 Rich in: Saturated Fat Monosaturated Fat + Omega-3 Fats (animal fat) (sunfloweroil 85 % oliveoil 75 %, canolaoil 58 %) (tallow 50 %, lard 40 %) LFHCC = COMPLEX CARBOHYDRATES

  27. FATTY ACIDS – CHAIN LENGTH & METABOLISMWein S. Diabetes Metab Res Rev 2009;25:185-194 Dietary long-chain fatty acids – LCFAs - impair insulin sensitivity & lipid metabolism – LCFA TOP SOURCES: C14, C16, C18 – mainly dairy and meat: C14, C16, C18 – mainly from dairy and meat Medium chain fatty acids – MCFAs - protect from lipotoxicity and subsequent insulin resistance MCFA TOP SOURCES: Coconut oil and palm kernel oil

  28. SATURATED FATTY ACID METABOLISMMCFA: CoconutOil 85,2, Palm kerneloil 81,5, Palm Oil 45,3, Olive Oil 14.5 (70 % monosaturated) LCFA: Animal fats

  29. FAT UTILIZATION  72 HRSSoeters P et al Am J PhysiolEndocrinalMetab 2012;303:E1397-1407

  30.    DERANGED MICROBIOTA – CHD   Sabatino A et al. Nephrol Dial Transplant, 2015;30:924–933 • Reduced intake of Dietary fibres - Prescribed restriction of potassium intake leads to reduced intake of fruits and vegetables • Prolonged intestinal transit time - Often comorbidities; inactivity malnutrition, diabetes, cerebrovascular, heart disease, constipation • Increased amount of proteins available for proteolysis - Increased production of protein-bound uremic toxins • Increased intestinal permeability - Leaky gut Uremia, intestinal ischemia, aggressive ultrafiltration affects the barrier function • Dysbiosis - Antibiotics, phosphate binders etc affects microbiota

  31. DYSBIOSIS – CHRONIC KIDNEY DISEASEVaziri ND et al Kidney International, 2013;83:308–315 FEW GOOD BACTERIA FEW BAD BACTERIA

  32.  MAJOR COLON-DERIVED TOXINS  Meyer TW, Hosstetter TH Kidney Int 2012;81:949-954 INDOLE COMPOUNDS Indoxylsulfate indoxyleglucoronide 5-Hydroxylindole Indole-3propionic acid PHENYL COMPOUNDS D-Cresolsulfate p-Cresolglucoronide Phenylsulfate phenylglucoronide Alpha-N-phenylacetyl-l-glutamine Phenylpropionylglycine Cinnamoylglycine 4-Ethylphenyl sulfate Hippuricacid

  33.  CLEARANCE PROTEIN-BOUND UREMIC TOXINS Atherton JG et al Am J Physiol - RenalPhysiol 2018 – E-pub March 14 • Hemodialysis & Peritoneolysisdo not contribute significant clearance of protein-bound uremic toxins (PBUTs). • The exceptional PBUTs that are removed return to high before the next dialysis session. • PBUTS, especially p-cresylsulfate (pCS), increase the oxidative burst of human leukocytes, & cause immune dysfunction • High levels of BPUTs are linked with increased general mortality, especially with cardiovascular morbidity: cardiac death, myocardial infarction, peripheral vascular disease, ischemic stroke, vascular calcifications and decline in renal function • The PBUTs faction is large but clearance slow - =>10 times lower (PCStotal 23 ± 5 ml/min) compared to urea (urea 292 ± 52 ml/min) • The PBUTS reduction (PCStotal 31 ± 13 %) is significantly smaller than for urea (urea 75 ± 5 %), and the utilization of different dialysis membrane types do not improve the reduction ratio

  34.  PROTEIN-BOUND UREMIC TOXINS – PBUTsSirich TL et al.  J Am SocNephol 2013;25: 615–622. • PBUTs such as indoxylsulfate (IS) and p- cresylsulfate (pCS), are 116-fold resp 41-fold higher, than in healthy controls. • BUT: pre-dialysis concentrations of toxins with comparable molecular weight, such as urea and creatinine, are only 5- and 13-fold higher.

  35. ELIMINATION DIALYSIS – UREA VS. PBUTsEloot S et al. PLOS ONE | DOI:10.1371/journal.pone.0147159 UREA PBUT

  36. PROTEIN-BOUND UREMIC TOXINS – CLEARANCEEloot S et al. PLOS ONE | DOI:10.1371/journal.pone.0147159 :Pcresylglucuronide

  37.  END STAGE RENAL DISEASE  characterised by Poorappetite, reducedcaloricintake and increased malabsorptionIncreasedproduction of potentiallytoxiccompounds Siminoff ML et al Lancet 1976;ii:818-821 Frequentmicrobialovergrowth, especiallywhen serum creatininereachesabove 6 ml/dl, and glomular filtration falls below 20 ml/min Siminoff ML et al Nephron 1978;22:63-68

  38.  TREATMENT WITH PRO- & SYNBIOTICS documented to to: • Reduce serum levels of proinflmmatorycytokines; TNFα, Il-1, Il-6 etc • Reduce PAI-1, fibrinogen/s • Promotefibrinolysis • Reducecholesterol/s, FFA/s, ALT/s, bilirubin/s • Increase albumin/s, prothrombinactivity & • Reduceclinicalsigns of inflammation

  39.  LAB IN CRD – EARLY EXPERIENCES Hida M et al Nephron 1976;74:349-355 Oral administration of antibiotic-resistant lactic acid bacteria • Increaseappetite, caloricintake, bodyweight, mid-arm circumference • Reduce levels of fecal putrefactive metabolites to levels comparable with those of healthy subjects. • Increase amino acid levels (tryptophan) & serum albumin levels • Eliminates dysbiosis and normalizes intestinal microflora • Reduce levels uremic toxins

  40.  LAB ELIMINATES UREMIC TOXINS & CARCINOGENS Simenhoff ML et al Miner Electrolyte Metab 1996;22:92-96 8 hemodialysis patients weretreatedwith a courseof oral Lactobacillusacidophilus(LBA) in an attempt to alter this SBBO. Serum dimethylamine (DMA) levelsdroppedsignificantly from 224 +/- 47 to 154 +/- 47 micrograms/dl at the end of lactobacillustreatment (p < 0.001). Nitrosodimethylamine, a carcinogen, levelsalsodecreasedsignificantly from 178 +/- 67 (untreated) to 83 +/- 49 ng/kg. Patients nutritional status, assessed as serum albumin, bodyweight, caloricintake, midarmmuscle area (MAMA) and appetiteimprovedmodestly, but not statisticallysignificant. 

  41.  PROBIOTICS IN CHRONIC KIDNEY DISEASE Natarajan R et al Biomed Res Int. 2014;2014:568571 22 CKD patients completed a study receiving either 30 billion CFU of S. thermophilus KB 19, L acidophilus KB 27, & B. longum KB 31—or placebo (a 1 : 1 blend of cream-of-wheat and psyllium husk)  Positive findings but not statistically significant observed:  decline in WBC count (𝑃 = 0.057)  reductions in levels of C-reactive protein (𝑃 = 0.071)  total indoxyl glucuronide (𝑃 = 0.058). &  in other uremic toxin levels  or measures of quality of life.

  42.  12 WEEKS PROBIOTICS – DIABETIC HEMODIALYSIS PATIENTS Soleimani A et al. KidneyInt 2017;91:435-442 60 diabetic hemodialysis patients received randomly for 12 weeks a capsule containing Lactobacillusacidophilus, Lactobacilluscasei and Bifidobacteriumbifidum or placebo (unknown). Clearly statistically significant improvement were observed :  decreases in fasting plasma glucose decreases in serum insulin • decreases in homeostasismodelassessingestimated insulin resistance • decreases in homeostasis model of assessing-estimated beta-cell function • improvements in insulin sensitivity check index  reductions in serum high-sensitivity C-reactive protein  reductions in plasma malondialdehyde(= reduced general inflammation)  increased total antioxidant capacity

  43.  PERITONEAL DIALYSIS REDUCES INFLAMMATION Wang I-K et al Beneficial Microbes, 2015; 6(4): 423-430 39 patients on peritonealdialysisreceivedduringsixmonthseither a capsulecontaining109 cfuBifobacteriumbifidumA218, 109 cfuBifidobacteriumcatenulatumA302, 109 cfuBifidobacteriumlongumA101, & 109 cfuLactobacillusplantarumA87 or a capsulewith the same amountofmaltodextrin.

  44. LbShirota – EFFECTS ON BLOOD UREAMiranda Alatriste PV et al NutrHosp2014;29:582-590

  45. HEATING POISONS (AGEs) IN RENAL DISEASEAgalou S et al. BiochemSoc Trans 2003;31:1394-96 Plasma conc of free AGEs: • Nε-carboxymethyl)lysine (CML) • Nε-(carboxyethyl)lysine (CEL) increased app. 8-fold & 22-fold resp. in hemodialysis patients.

  46. Available at http://bengmark.com/research-articles/

  47. Louis Camille Maillard 1878 – 1936 Demonstrated association between development of chronic disease, especially chronic renal disease and exposure to chemicals due to chemical between amino acids and sugars. This work was considered a major contribution, and the reaction was named after him – Maillard reaction & He was in 1914awarded several prices, including the Highest price of the French Academy of Medicine.

  48.  HEAT-INDUCED TOXINS (AGEs & ALEs) IN FOODS  “smoking with the stomach” Dys-functioning, glycated PROTEINS (AGEs) and lipoxidated fats/oils (ALEs) induceabout 50 timesmore inflammation in the bodycompared to non-heated proteins and fats/oils  accumulate in tissues (amyloid)  weakens immune system  impairs DNA repair mechanisms  reduce antioxidant defense induce inflammation & infection accelerate development of various diseases. Bengmark S. Modified Amino Acid-Based Molecules; Accumulation and Health Implications. In Amino Acids in Human Nutrition and Health. Ed Mello JFD, CABI Allingford, UK, 2011

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