Dirty Cells & Leaking Membranes – A Mother of Disease

Stig Bengmark MD PhD UCL - University College

London University, UK www.bengmark.com

stig@bengmark.se

"We are living in a world today where lemonade is made from

artificial flavors and

furniture polish is made from real lemons.“

Alfred E. Newman, Mad Magazine

DISCREET PERSISTANT INFLAMMATION - A MOTHER OF DISEASE

Bengmark S. J Clin Nutr 2004;23:1256-1266

MALFUNCTIONING MICROBIOTA DYSBIOSIS – A MOTHER OF DISEASE

The microbiota, its composition and diversity is depending on a stable, intestinal nutrient environment. WHEN STABLE, it:

• provides the host with energy-rich metabolites – nutrients, antioxidants and vitamins

• reduces general inflammation

• maintains immune homeostasis

• reduces protein wasting, increases urea breakdown

• protects against infections and various chronic diseases & premature aging

SYSTEMIC INFLAMMATION Finch CE, Crimmins EM Science 2004; 305:1736–1739

Individuals with higher levels of inflammatory markers/s: C-reactive protein, fibrinogen, factor VIII activity, interleukin-6 and TNF-α etc.

but yet no obvious signs of disease,

are candidates to develop

CHRONIC DISEASES and

COMPLICATIONS TO DISEASE & TREATMENTS

SIGNS OF CHRONIC INFLAMMATION Unexplained fatigue, sleep problems, frequent headache, hair loss, gray hair, dandruff, acne, skin rashes, dry eyes, frail nails, dry mouth or increased salivation, reduced sex functions, irregular menstruations, obstipation or diarrhea, osteoporosis, overweight, frequent infections, mental depression, easy breathless, sweaty feet, sweaty hand palms etc.

DNA – Not Your Destiny! Anand P et al Pharm Res 2008;25:2097-2116

Stressors like a calorie-rich diet:

• turn genes on and off

• activate epigenetic markers

• modify histones

• add methyl groups to DNA strands,

• & seem to affect what gets passed down to the offspring

CANCER & GENES Anand P et al Pharm Res 2008;25:2097-2116

“ GOOD FOR MICROBIOTA – GOOD FOR HEALTH

Avoid toxic substances:

Alcohol, tobacco, pesticides, drugs, AGE & ALEs, casein, gluten, zein, refined sugars, flour etc

Avoid processed foods Eat fresh greens

PHARMA & MICROBIOTA – INCOMPATIBLE! Antibiotics destroys about 90 % of microbiota functions: bile acid metabolism, eicosanoid and steroid hormone synthesis etc Caetano L et al. Antimicrob Agents Chemother. 2011;55:1494-1503

Chemotherapeutics reduces microbiota 100-fold;

decrease anaerobic bacteria up to 10,000-fold &

increase in PPMs 100-fold Van Vliet MJ et al. Clin Infect Dis 2009;49:262-270

Proton pump inhibitors during pregnancy increase the risk of offspring getting asthma Andersen AB et al. Aliment Pharmacol Ther 2012;35:1190-1198

Anti-hypertensives induce gastrointestinal dysbiosis & reduce mucosa protection, espec mucus production Nonzee V et al J Med Assoc Thai 2012;95:96-104.

PER BRANDTZAEG 1936 -

Brandtzaeg P et al Gastroenterology 1989;97:1562-84

The generation of secretory antibodies depends on a striking local preponderance (70%- 90%) of IgA immunocytes (plasma cells and plasma blasts) ……..

the gut is the major contributor to this unique defense system

THE GUT & Ig-PRODUCING IMMUNOCYTES Brandtzaeg P et al Gastroenterology 1989;97:1562-84

MICROBIOTA, IMMUNITY, DISEASE Maynard CL et al Nature 2012;489, Sept 13:431-441

EUBIOSIS DYSBIOSIS

PROCESSED FOODS INDUCE:

DYSBIOSIS, LEAKY MEMBRANES & MALFUNCTIONING IMMUNE FUNCTIONS

PROCESSED FOODS – DELETARIOUS FOR MICROFLORA

• About 80 percent of our food is processed: contains mainly sugars, leavening agents & completely synthetic ingredients – absorbed in small intestine and will not reach colonic microbiota.

• Meats and oil are not good foods for microbiota &

• Many meats tested contain UNACCEPTABLY high levels of antibiotic-resistant bacteria on:

- 81 percent of ground turkey

- 69 percent of pork chops - 55 percent of ground beef - 39 percent of chicken breasts, wings and thighs

PROCESSED FOODS INDUCE DYSBIOSIS

• Certain foods induce systemic inflammation: - animal products, espec diary, rich in IGF-1 - refined carbohydrates promotes IGF-1 synthesis (liver)

• Increase expression of inflammatory messengers

• Induce dysbiosis

• Increase membrane leakages &

• Destabilize the immune system

Contributory are: Mental & physical stress, lack of physical activity,, vitamin D deficiency, lack of anti-inflammatory minerals; Mg, Zn, Se, lack of omega-3 FFAs etc.

DYSBIOSIS facilitates

OBESITY & DISEASE

OBESITY - THE GLOBAL TZUNAMI - strongly associated to modern

agriculture & mass-produced cheap processed foods

LITTLE PROCESSED FOODS – LITTLE OBESITY

Jon Brower Minnoch, USA 1941 -1983, 635 kg – the world´s ever heaviest person

Joe, 22 weeks premature, 7 kg ”the heaviest baby in 8 years in the UK”

DIFFERENT MICROBIOTA IN OBESE vs LEAN Angelakis E et al Future Microbiol. 2012;7: 91–109

METABOLIC SYNDROME – DYSBIOSIS Tremellen K, Pearce K Med Hypotheses 2012;79:104-112

Lipopolysacharides = LPS ≈ENDOTOXIN

ENDOTOXIN & PROSPECT OF LIFE

Pussinen PJ et al. Diabetes Care 2011; 34:392–397

ENDOTOXIN - THE VILLAIN & ASSOCIATED 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 diesases Nolan JP Hepatology 2010;52:1829-1835.

•ADHD, allergy, ALS, autism, autoimmune diseases, bipolar disease, cataracts, chronic fatigue syndrome, COPD, fibromyalgia, glaucoma, gulf war syndrome, HIV, iritis, macular degeneration, minimal encephalopathy, multiple sclerosis, nephropathies, obesity, osteoporosis, paradontosis, Parkinson, polycystic ovary syndrome, rheumatoid disease, stress, schizophrenia, stroke, uveitis

MEAT STORAGE – INFLAMMATION INDUCTION Erridge C J Food Sci 2011;76:72-79

VEGETABLE STORAGE – INFLAMMATION INDUCTION Erridge C Food Chem Toxicol 2011;49:1464–1467

DYSBIOSIS-INDUCED METABOLIC DISORDERS Cani PD et al Diabetes 2008;57:1470-1481

LPS concentration 10 to 50 X higher than those obtained during septic shock Mitaka C. Clin Chim Acta 2005; 351:17-29

Bifidobacterim spp.

HIGH FAT DIET & MICROBIAL TRANSLOCATION Amar J et al EMBO Mol Med 2011;13:559-572

Live intestinal bacteria found present in large numbers in adipose tissue (MAT), mesenteric lymph nodes (MLN) and blood AFTER ONLY ONE WEEK ON HIGH FAT DIET (HFD)

GUT MICROBIOTA & DERANGED METABOLISM Vrieze A et al Diabetologia 2010;53:606-613

• ↓ FFA oxidation

• ↑ endotoxin/s

• ↑SCFA production

• ↓incretin secretion

• ↓ butyrate production

• ↑FFA oxidation

• ↓ endotoxin/s

• ↓ SCFA production

• ↑Incretin secretion

• ↑butyrate production

THE MARCH from AGRICULTURE AQVA- & HORTICULTURE-based diet

Friday Aug 18.2011

President Bill Clinton – now a vegan

radically changed diet, lost 20 lbs. in weight

& improved his health, Clinton tells CNN.

After experiencing periodic heart problems leading up to the 2004 surgery, the former junk food lover now calls himself a vegan,

shunning meat, eggs, dairy and almost all oil

saying: "I like the vegetables, the fruits, the beans, the stuff I eat now,“

"I feel good, and I also have … more energy."

FOOD INTAKE & INFLAMMATION • 1. Low intake of fresh plant foods;

GREENS, vegetables, fruits, SPICES • 2. Higher intake of proteotoxins in certain

foods: casein, gluten, zein (corn) etc. • 3. Higher intake of heat- and storage-induced

proteotoxins: glycated (AGEs), lipoxidated molecules (ALEs),processed carbohydrates induces: - Dysbiosis: reduced numbers & diversity - Various body membranes leak like a sieve; leaky gut, leaky airways, leaky skin, leaky vagina, leaky eye cavity , leaky nose, leaky placenta, leaky blood-brain barrier etc.

VEGAN DIET & HEALTH Katcher HI et al Ann Nutr Metab 2010;56:245–252

Employees ( insurance company) with overweight and/or diabetes received either a low-fat vegan diet or regular food for 22 weeks. The vegan group reported improvements in: ● general health (p = 0.002) ● physical functioning (p = 0.001) ● mental health (p = 0.03) ● general vitality (p = 0.004) ● overall diet satisfaction (p = 0.001) ● reduced food costs (p = 0.003), but ● increased difficulty finding foods when eating out

INFLAMMATION REDUCTION – ECOBIOLOGICALS

plants, pro- and synbiotics

isothiocyanates in cruciferous vegetables, anthocyanins and hydroxycinnamic acids in cherries, blueberries, epigallocatechin-3-gallate (EGCG) in green tee, chlorogenic acid and caffeic acid in fresh coffee beans & fresh tobacco leaves,capsaicin in hot chili peppers, chalcones in apples, euginol in cloves, gallic acid in rhubarb, hisperitin in citrus fruits, naringenin in citrus fruits, kaempferol in white cabbage, blueberries myricetin in berries,rutin and quercetin in apples and onions, resveratrol and other procyanidin dimers in red wine. virgin peanuts, blueberries various curcumenoids, the main yellow pigments in turmeric curry foods, and daidzein and genistein from soybean

ANTI-ANGIOGENIC FOODS • Artichokes

• Berries: blackberries, blueberries, raspberries, strawberries

• Fermented, microb-enriched vegetables

• Garlic

• Green tea

• Kale

• Maitake mushroom

• Nutmeg

• Parsley

• PRE-, PRO- & SYNBIOTICS

• Red grapes

• Tomato, espec when heated to 60 C/140 F for 3-4 hrs (to release lycopen)

• Turmeric

TURMERIC with CURCUMINOIDS An Antioxidant, NFκB, COX-2, LOX & iNOS inhibitor:

A Shield Against Acute and Chronic Diseases

Bengmark S JPEN J Parenter Enteral Nutr. 2006;30:45-51

STABILISING CELL MEMBRANES Barry J et al, J Am Chem Soc 2009,131,4490-4498

CURCUMINOIDS REDUCES DISEASE Curcumin attenuates endotoxin-induced coagulopathy & prevents disseminated intravascular coagulation Chen HW et al J Endotoxin Res 2007;13:15-23 Curcumin pretreatment for 3 d before CLP - Prevents cellular alterations in macrophages - Decreases expression of TNF-α, - Down-regulates PPAR-γ in organs (liver) & - Reduces tissue injury and mortality Siddiqui AM et al Crit Care Med 2006 34:1874-1882

INDUSTRIAL & AGRICULTURAL REVOLUTION 100 % increase in per person intake of saturated fats 5000 % increase in consumption of dairy-derived foods 10000 % increase in refined sugar intake (1 lb => 100 lb)

Homo erectus 2 milj – 100 000 years bC

”diet consisted in GREEN LEAVES, WILD GRASSES, flowers, berries, nuts, honey, less in tubers, roots, occasional in red meat, shellfish and bird's eggs.”

PALEOLITHIC DIET “Much support that our genes, adapted during million of years to the lifestyle of our prehistoric ancestors badly tolerate the dramatic changes, especially in food habits, which have occurred”.

Eaton BS, Konner M. Paleotlithic nutrition: a consideration of its nature and

current implications. N Engl J Med 1985;312:283-289

Contained more of: (X = times more) Minerals 2 X Fibers/greens 4 to 10 X Antioxidants 10 X Omega-3 FA 50 X Lactic acid bacteria >1010 X

Contained less of: (X = times less) Protein 2 X Saturated FA 4 X Sodium 10 X

PALEOLITHIC FOODS Carrera-Bastos P et al Res Rep Clin Cardiol 2011;2:15-35

VITAMIN D DEFICIENCY COMMON IN PATIENTS

Burkina Faso:

115 nmol/L

(> 70 nmol/L)

Luxwolda MF et al. Brit J Nutr

2012; E-pub

• 95% of Afro-Americans undergoing renal transplantation Tripathy SS et al Transplantation 2008;85: 767–770

• 85 % of patients undergoing hip or knee replacement

• Breijawi N et al Eur Surg Res 2009;42:1–10

• 77 % of chronic pancreatitis patients Dujsikova H et al Pancreatology 2008;8:583–586

• 67 % of renal transplantation patients Ducloux D et al Transplantation 2008;85: 1755–1759

• 57 % obesity surgery patients (79 % in black and Hispanic) Gemmel K et al Surg Obes Rel Dis 2009,5, 54–59

Vitamin D deficiencies (< 30 nmol/L)

In Westerners undergoing surgery:

VITAMIN D DEFICIENCY & DISEASE • Aging

• Allergy

• Alzheimer’s disease

• Asthma

• Athletic performance

• Autism

• Cancer

• Cavities

• Colds

• Crohn´s disease

• Cystic fibrosis

• Depression

• Diabetes 1 and 2

• Eczema

• Heart disease

• Hearing loss

• Hypertension

• Infertility

• Influenza

• Insomnia

• Liver diseases

• Macular degeneration

• Migraines

• Multiple Sclerosis

• Muscle pain

• Obesity • Periodontal disease

• Pre-eclampsia

• Psoriasis

• Rheumatoid diseases Schizophrenia

• Seizures

• Septicemia

• Tuberculosis

MICROBIOTA - AFRICAN & EUROPEAN De Filippo C et al Proc Natl Acad Sci USA 2010; 107:14691–14696

Maccaferri S et al Dig Dis 2011;29:525–530

LEAKY BARRIERS

• Gastrointestinal tract

• Airways

• Skin

• Oral cavity

• Vagina

• Nose

• Eye cavity

• Placenta

• Blood brain barriers

DAVID JP BARKER 1838 – The thrifty epigenotype hypothesis -

Barker, D.J.P. Maternal Nutrition, Fetal Nutrition, and Disease in Later Life". Nutrition, 1992;13: 807-813

Curr Opin Nephrol Hypertens 1997; 6:106-110

We know that “disorders of adult life, including coronary heart disease, stroke and diabetes, arise through interaction between influences in our adult lifestyle and genetically determined susceptibility.” “Recent research, however, suggest that growth in

utero may also play an important role”

“Even brief periods of … may permanently change or `programme´ the body…and lead to persistent changes in blood pressure, cholesterol metabolism, insulin response to glucose, and in a range of other metabolic, endocrine and immune parameters.”

INFLAMMATION IN OBESE PREGNANT WOMEN Basu S et al Obesity 2011;19:476-482

MCP1 IL-8 IL-6 TNFα Leptin CD14 TLR4 TRAM2

LEAKY PLACENTA A shocking 9/20 (43 %) of umbilical cord blood, cultivated from healthy neonates, born by cesarean section, demonstrate positive growth: Enterococcus faecium, Propionibacterium acnes, Staphylococcus epidermidis & Streptococcus sanguinis Jiménez E et al. Curr Microbiol 2005;51:270–274.

ATHEROSCLEROSIS & BACTERIAL DEBRIS Nicolaou G et al J Atheroscler Thromb 2012;19:137-1498

Bacteria & bacterial debris in human atheroma, in the past considered harmless,

seems to contribute to disease progression via TLR- dependent lipid body formation in macrophages

Dennis Burkitt 1911 - 1993 Suggested that many Western diseases, rare in Africa are primarily the result of diet and lifestyle.

Reported an association between low fibre in diet higher risk of colorectal cancer as well as other diseases such as CHV and diabetes

GI PERISTALSIS – UK vs UGANDA Appr GI transit time: UK: 100 hrs vs Uganda: 20 hours Appr stool weight: UK 60 g/day vs Uganda 600 g/day Burkitt DP et al Lancet 1972;300 (7792):1408-11

British geriatric patients:

GI transit time: >14 days in > half of the patients Brocklehurst JC, Khan MY. Gerontol Clin 1969;11:293-300

FOOD PATTERN UGANDIAN CHIMPANZEES Potts KB et al Int J Primatol 2011;32:669-690

ripe fruits = RF (black), unripe fruits = UF (white) , young leaves = YL (grey), seeds, flowers

Boutenko V. Green for Life. North Atlantic Books Calif, USA, 2010

NOT FOOD FOR MICROBIOTA:

Cooked carbohydrates 60 %

Animal meat and fat 25 %

Refined Oils ??? 10 %

Total 85 %

Foods rich in animal fat induce release of bile acids – detrimental to microbiota & inducing dysbiosis

MAGNESIUM – A KEY MOLECULE IN CELL REPLICATION Mg involved in > 300 biochemical processes

Mg deficiency associated with: • Body aches

• Chronic bowel problems

• Diabetes type 2

• Fatigue

• Headaches, migraine

• Heart disease

• Hypertension

• Insulin resistance

• Leg cramps

• Low energi

• Muscle twitches

• Obesity • Osteoporosis

• Premenstrual tensionl

• Restless legs

• Stroke

MAGNESIUM & SEPSIS PROTECTION

•Magnesium replacement provides significant protection against endotoxin Salem M et al Crit Care Med 1995;23:108-118

• Administration of Mg to animals with sepsis improves organ function and survival time Harkema JM et al Crit Care Med 1992;20:263-275

HYPOMAGNESEMIA IN CRITICALLY ILL Limaye CS et al J Assoc Physicians India 2011;59:19-22

52% of patients show Mg-deficiency on admission to MICU & suffer increased:

• Mortality rate (57.7% vs 31.7%)

• Need for ventilatory support (73% vs 53%)

• Duration of mechanical ventilation (4.27 vs 2.15 days),

• Rate of sepsis (38% vs 19%)

• Hypocalcemia (69% vs 50%)

• Hypoalbuminemia (80.76% vs 70.8%)

Magnesium-rich foods – Foods for microbiota mg/100 gr

• Pumpkin &Squash seeds 540

• Cacao 20-22 % 520

• Sesami seeds 350

• Almonds 280

• Soya beans 265

• Cashew nuts 260

• Rosehip, dry 240

• Oat bran 235

• Peanuts 190

• Peas 150

• Lentils 80

• Spinach 79

• Prunes 52

• Avocado 41

• Banana 35

• CHEESE 35

• Broccoli 23

• FRENCH FRIES 35

• BREAD, whole 24

• HAMBURGERS 20

• KETCHUP 18

• MILK 15

• CREAM 14 BUTTER 3

FLORA IN WESTERNERS • Lb plantarum, a dominating LAB, obsaerved

in only 25 % of omnivorous Americans & in 65 % of vegetarian Americans

Finegold SM et al. Human intestinal microflora in health and disease Academic Press, London, UK, 1983. pp 3-31

• Benefial common colonic LAB species present only in about 50 % or less of healthy Scandinavians: Lb plantarum 52 %, Lb rhamnosus 26 %, Lb paracasei ssp paracasei 17 % Ahrné S et al. J Appl Microbiol 1998;85:88-94

MICROBIOTA & OBESITY Million M et al. Int J Obesity 2012;36:817-825

Obese (n=68) Controls (n=44) P-value

L. plantarum 0 (0%) 8 (18.2%) 0.0004

L. paracasei 10 (14.7%) 17 (38.6%) 0.004

L. reuteri 6 (8.8%) 1 (2.3%) 0.16

L. rhamnosus 3 (4.4%) 4 (9.1%) 0.27

L. ruminis 3 (4.4%) 4 (9.1%) 0.27

L. salivarius 5 (7.4%) 2 (4.5%) 0.43

ENDOTOXIN & OBESITY Fei N, Zhao L. ISME J. 2012 E-pub

A person weighing 174.8 kg lost 51.4 kg after 23 weeks on traditional Chinese medicinal foods, whole grains, & prebiotic fibres recovered totally from hyperglycemia and hypertension.

The endotoxin-producing Enterobacter cloacae B29 - found to constitute 35% of the gut bacteria - decreased to non-detectable. The Enterobacter cloacae inoculated in germfree mice induces obesity and insulin resistance.

DIET & LONGEVITY Robbins J: Health at 100. USA 2007

80/10/10 DIET

80 % raw greens 10 % vegetable fats

10 % vegetable proteins

AVOCADO – THE No 1 MIRACLE FRUIT? • possess antioxidant and radical scavenging activities of unique

proportions.

• rich in monosaturated fats, vitamins E, C, carotenoids and sterols – including lutein, alpha-carotene, beta-carotene, neoxanthin, violaxanthin, zeaxanthin, antheraxanthin, chlorophylls, and pheophytins.

Avocado oil shown to reduce inflammation and protect tissues from destruction, especially the musculoskeletal system. Boileau, C Arthritis Res Ther 2009;11:R41

Supply of avocado/avocado oil shown to increase the uptake of carotenoids several-fold; lutein by 5 times, alpha-carotene 7 times, and beta-carotene 15 times. Unlu NZ et al J Nutr 2005;135:431–436

RED PALM OIL & COCONUT OIL • The richest natural source of dietary pro-vitamin A

carotenes, said to contain 15 X more pro-vitamin A carotenes than carrots and 300 X more than tomatoes.

• The most abundant source of vitamin E, α-tocotrienol, and α-iocotrienol, lycopenes, squalene, Co-enzyme Q10, and saturated and unsaturated fatty acids (near 1:1 ratio) (known to maximize absorption of carotenoid anti-oxidants). MCFAs are absorbed directly into the portal vein, and rapidly transported to the liver for beta-oxidation, while LCFAs, are transported via the thoracic duct and directly into the systemic circulation, here systemic inflammation.

FOOD INTAKE & INFLAMMATION • 1. Low intake of fresh plant foods; greens,

vegetables, fruits, spices

• 2. High intake of proteotoxins: casein, gluten, zein (corn) etc

• 3. High intake of heat- and storage-induced proteotoxins: glycated (AGEs), lipoxidated molecules (ALEs),processed carbohydrates & animal fats induces: - Dysbiosis: reduced numbers & diversity

• - Body membranes leaking like a sieve; leaky gut, leaky airways, leaky skin, leaky vagina, leaky eye cavity , leaky nose, leaky placenta, leaky blood-brain barrier etc.

Dubos RJ, Schaedler RW J Exp Med 1962;115:1161-1172

CASEIN & GLUTEN IMPAIRS LACTOBACILLUS GROWTH

Without casein and gluten with casein and gluten

NON-CELIACS & DYSFUNCTIONAL FLORA Tiellström B et al Scand J Gastroenterol. 2007;42:1204-1208

• Children with celiac disease (CD) known to have an aberrant gut microflora.

• Non-CD relatives have impaired intestinal microbial metabolism:

• - significantly lower level of acetic acid and total SCFAs – significantly increased level of i-butyric acid and free tryptic activity (FTA) than healthy controls.

GLUTEN & SURFACE MOLECULE EXPRESSIONS Class II, CD86, CD40, CD54 Nikulina M et al J Immunol 2004;173:1925-1933

100 µg/ml gluten matches the effects of 10 ng/ml LPS (ENDOTOXIN)

GLUTEN SENSITIVITY & CHRONIC DISEASES Ruuskanen A et al. Scand J Gastroenterol. 2010;45:1197-1202 Glutenoids affects genetic markers: HLA-B8, HLA DQ2, HLA DQ8,

increase systemic inflammation & are associated with diseases such as:

• ADHD

• arthritis

• Addison´s disease allergy

• Autoimmune disorders

• Autism

• Bipolar disease

• Dermatitis herpetiformis

• Diabetes mellitus

• Epilepsia

• Graves´disease, infections

• Inflammatory bowel diseases – IBD

• Irritable bowel syndrome – IBS

• Lupus erythematosus

• Mental depression

• Myasthenia gravis

• Obesity • Osteoporosis

• Pernicious anemia

• Polymyalgia rheumatica

• Psoriasis

• Schizophrenia

• Scleroderma

• Sepsis

• Sjögren’s syndrome

• Thyreotoxicosis

• Vitiligo

A NEW ENTITY - GLUTEN SENSITIVITY (GS) Sapone A et al. BMC Medicine 2011, 9:23

Often seen in diffuse often ignored distresses; lack of energy, mental depression, encephalopathy/‘foggy mind’, diffuse abdominal pain, bloating, diarrhea, eczema and/or rash, various headaches, numbness in the legs, arms or fingers, joint pain, fatigue etc.

Gluten-free diet increases energy, enthusiasm, well-being & frequently also improve clinical signs.

And improved chronic diseases.

Freedom of symptoms reported in chronic diseases & a few cases of therapy-resistant epilepsy & Non- Alzheimer dementia

PROLAMINS & TRYPTOPHAN/CORTEX Choi S et al Physiol Behov 2009;98:156-162

An up to 8-fold decrease in cortex tryptophan & similar decrease in serotonin observed after feeding: • Marked reductions; Zein (corn)

• Significant reductions: Casein (dairy) & Gluten (wheat, rye, barley)

• Small reductions: Lactalbumin (dairy)

• Small increases: Vegetable protein (soy

GLUTEN-FREE DIET & TYPE 1 DIABETES Matteo-Rocco P et al. J Clin Endocrinol Metab 2003;88: 162–165

Gluten-free diet tried in 15 patients with diabetes but no gluten intolerance

Insulin sensitivity increased significantly in 12/14 subjects after six months on gluten-free diet (P 0.04) & decreased again in 10/13 subjects after 6 months on “normal” diet (P=0.07)

GLUTEN-FREE DIET in IRRITABLE BOWEL SYNDROME Biesiekierski Jr et al. Am J Gastroenterol 2011;106: 508-514

EXCLUSION (GLUTEN-RESTRICTED) DIET IN ADHD Pelsser LMJ et al Lancet 2011;377:494-503

Crossover study 100 children, aged 4-8 yrs, 9 weeks + 4weeks A. Total, B. Inattention, C. Hyperactivity D. Abbreviated Connor Scale scores (ACS)

ANCIENT GRAINS

• Amaranth – Aztec culture, high protein & mineral content • Quinoa – Inca culture, high protein & mineral content • Sorghum (durra, jowari, milo) -

5th in world, versatile, low energy, most cost-effective • Millet – 6th highest in world, versatile, mild flavor • Teff – staple in Ethiopia, tiny seed, high mineral content •

SORGHUM (durra, jowari, milo) – A SUPER GRAIN! Dykes L, Rooney LW Cereal Foods World 2007;52:105-111

Many thousend top athletes agree, among them the two best

tennis players of the world – Novak Djokovic & Andy Murray, who abstain from gluten, lactose

and processed carbohydrates, insisting that this gives them

much greater energy.

FOOD INTAKE & INFLAMMATION

• 1. Low intake of fresh plant foods; greens, vegetables, fruits, spices

• 2. High intake of proteotoxins: casein, gluten, zein (corn) etc

• 3. High intake of heat- and storage-induced proteotoxins: glycated (AGEs), lipoxidated molecules (ALEs),processed carbohydrates & animal fats induces: - Dysbiosis: reduced numbers & diversity - Body membranes leaking like a sieve; leaky gut, leaky airways, leaky skin, leaky vagina, leaky eye cavity , leaky nose, leaky placenta, leaky blood-brain barrier etc.

HEAT-INDUCED DYSFUNCTIONING

PROTEINS – ”smoking with the

stomach” Bengmark S JPEN 2007;31:430-440

Louis Camille Maillard 1878 – 1936 Undertook studies of the reaction between amino acids and sugars, and suggested association to development of chronic disease, especially renal disease.

This work was considered a major contribution, and the reaction was named after him – Maillard reaction & he was awarded several prices, including the French Academy of

Medicine award in 1914.

AGEs & INFLAMMATION-INDUCTION Bohlender JM Am J Physiol Renal Physiol 2005;289:F645-659

AGES/ALES IN TISSUES Dys-functioning, glycated proteins induce about 50 times more free radicals than non-glycated proteins (AGEs and ALEs), which:

-accumulate in tissues (amyloid) &

- make the body auto-fluorescing

- impair DNA repair mechanisms - induce tissue accumulation of toxins - reduce antioxidant defense

induce inflammation & infection weaken immune system & accelerate development of various diseases Thorpe SR, Baynes JW Amino Acids 2003;25:275-281

HEAT & ACRYLAMIDE PRODUCTION Tareke C et al J. Agric. Food Chem. 2002;50:4998-5006

Toasted bread contains several-fold more of acrylamide than untoasted Wheat: 11–161 vs < 5 mg/kg . Rye: 27–205 vs 7–23 mg/kg Granby K et al Food Additiv Contamin 2008; 25:921–929

AGEs/ALEs IN FOODS HEATED MEAT (espec. bacon, sausages), POULTRY, FISH:

AGE content increases with exposure to temperature: boiling (1000 kU/serving) frying (9000 kU/serving) Goldberg T et al. J Am Diet Assoc 2004;104:1287-1291

HEATED DAIRY: powdered milk (rich in ice cream, baby & clinical nutrition formulas) & cheese, espec. hard cheeses

HEATED GRAIN PRODUCTS: Toasted bread, bread crusts & crisp breads

HEATED VEGETABLE OILS: heated olive oil ca 8000 kU OTHERS: Egg yolk powder, lecithin powder, coffee, espec

dark roasted, hard-cured teas, roasted and salted peanuts, dark and sugar-rich alcoholic beverages, broth, Chinese soy, balsamic vinegar, Cola drinks etc

DISEASES WITH ELEVATED AGEs/ALEs • ADHD

• Aging

• Allergy

• Autoimmune diseases

• Alzheimer´s disease

• Amyotrophic lateral sclerosis

• Atherosclerosis

• Cardiovacular diseases

• Cataract • Chronic liver diseases • Chronic pulmonary disorders

• Creutsfeldt-Jakob disease

• Diabetes

• Familial amyloidotic polyneuropathy

• Fibromyalgia • Glaucoma • Hormone deficiencies • Macula degeneration • Nephropathies

• Obesity • Osteoporosis • Paradontosis • Parkinson´s disease • Polycystic Ovary Syndrome • Rheumatoid diseases • Ruptured Achilles tendon • Sepsis • Stroke

37 698 men and 83 644 women (2.96 million person- years) followed for > 28 years.

- Premature deaths increased with 13 % by eating red meat

- 20 % by eating processed meat: cured, bacon, sausages

Pan A et al Arch Intern Med 2012;172:555-563

448,568 men and women, age 35-69 studied during 13 years:

- A daily piece of steak about the size of a cassette tape – associated with a 13% greater chance of dying during the course of the study.

- An extra daily serving of processed red meat was linked to a 20% higher risk of death during the study.

- 72 percent increased risk of dying in heart disease &

- 11 per cent increased risk of dying in cancer Rohrmann S et al BMC Medicine 2013;11:63

DAIRY-INDUCED INFLAMMATION

Dietary proteins of cow´s milk induce inflammation: • release inflammatory mediators

• increase intestinal permeability

• induce leakage of large molecules; albumin, hyaluronan etc Jalonen T J Allerg Clin Immunol 1991;88:737, Isolauri E Gastroenterology 1993;105:1643, Bengtsson U et al. J Clin Exp Allerg 1996;26:197, Allerg Clin Immunol 1997;100:216

AGEs IN VARIOUS MILK PRODUCTS Baptista J, Carvalho R Food Res Int 2004;37:739-747

ENTERAL NUTRITION INDUCES DYSBIOSIS Haskel Y et al. Crit Care Med 1994;22:108-113

Enteral nutrition induces:

• loss of mucosal protein content

• intestinal microbial overgrowth

• leaky gut:

- Vivonex (Nestle) 53%

- Criticare (Mead-Johnson) 67%

- Ensure (Ross Lab) 60%

FUTURE NUTRITION OF CRITICALLY ILL ? Hospital-made nutrition solutions?

Fresh fruit and vegetable juices? Green Smoothies? Gaspacho?

BOVINE MILK & CHRONIC DISEASES • Allergy Rautava S, Isolauri EJ

Pediatr Gastroenterol Nutr. 2004 Nov;39:529-535

• Breast cancer Outwater JL et al Med Hypotheses 1997;48:453-461, Hjartåker A et al Int J Cancer 2001;93:888-893

• Colorectal cancer Manousos O et al Int J Cancer 1999;83:15-17, Ma et al J Nat Cancer Inst;2001:93:1330-1336

• Coronary heart disease Briggs RD et al. Circulation 1960;21:538-542, Marshall T BMJ 2000;320:301-305

• Chronic constipation Iacono G et al N Engl J Med 1998;339:1100-1104

• Diabetes type 1 Gimeno SGA, De Souza JMP Diabetes Care 1997;20:1256-1260, Virtanen SM et al Diabet Med 1998;15:730-738

• Malabsorption O´Keefe SJD et al Am J Clin Nutr 1991;54:130-135

• Ovarian cancer Larsson SC et al Am J Clin Nutr. 2004;80:1353-1357, Ganmaa D, Sato A Med Hypotheses.

2005;65:1028-1837

• Parkinson disease Park M et al. Neurology 2005;64:1047-1051

• Testicular and prostate cancer Ganmaa D et al. Med Hypotheses 2003;60:724-730, Qin LQ et al Nutrition and Cancer 2004;48:22-27

ESTROGENS IN MILK Malekinejad H et al J Agric Food Chem 2006;54: 9785-9791

Background: The dramatic increase in testicular, breast, prostate, ovarian, and corpus uteri, and large bowel cancers.

60-80% of the intake of oestrogens originates in the Western world from milk and other dairy foods. The daily intake of oestrogens through milk is 372 ng, “dramatically more than currently recognized.” The content is twice as high in 3.5 % fat milk than in non-fat milk & extremely high in butter!

DAIRY CONSUMPTIONS & IGF-1 The Endogenous Hormones and Breast Cancer Collaborative Group

Lancet Oncol 2010; 11: 530–42

• a positive association between intake of dairy products or milk and IGF-I conc. reported in several cross-sectional studies

• increase in IGF-I in response to a higher intake of milk and dairy products observed in both younger and older participants

• IGF-I conc. found significantly lower in vegans compared with lactoovo-vegetarians and omnivores in the EPIC-Oxford cohort

FREE ESTROGENS IN DAIRY PG/G E1 E2 - 17Β E3

Whole milk 3.7 6.4 9.0 Skimmed milk 20.2 3.4 8.2 Whey 3.6 1.5 3.0 Cottage cheese 34.9 10.8 6.1 Butter 539.4 82.3 86.8

Wolford ST, Argoudelis CJ J Dairy Science 1979;62:1458-1463

DIET AND BREAST CANCER Carroll KK Cancer Res 1975;35:3374-3383

THE GREAT P

•Plantarum

•Paracasei

•Pediococcus pentosaceus

Lb PLANTARUM & IMMUNE EFFECTS Van Baarlen P et al PNAS 2009;106:2371–2376

Lb paracasei – the master? • the strongest inducer of Th1 & repressor of Th2 cytokines when more than 100 strains are compared Fujiwara D et al. Int Arch Allergy Immunol 2004;135:205–215

CONTROL OF PATHOGENS The ability of 50 different LAB to control 23

different pathogenic Clostridium difficile tested:

27 were totally ineffective 18 antagonistic to some

5 effective against all:

2 strains - Lb paracasei s. paracasei

3 strains - Lb plantarum

Naaber P et al. Med Microbiol 2004;53:551-554

FERMENTATION ABILITY • The ability of 712 different LAB to ferment

oligofructans (inulin, phleins) studied:

• 16/712 able to ferment the phleins &

• 8/712 able to ferment the inulin type fibre.

• Only four species had the ability: Lactobacillus plantarum (several) Lactobacillus paracasei subsp. paracasei, Pediococcus pentosaceus &

Lactobacillus brevis Müller M, Lier D. J Appl Bact 1994;76:406-411

SYNBIOTIC 2000 Synbiotic AB, Sweden: www.synbiotics.se, synbiotics@gmail.com

400 billion Lactic acid bacteria:

1010 of Pediococcus pentosaceus 5-33:3

1010 of Leuconostoc mesenteroides 32-77:1

1010 of Lactobacillus paracasei sbsp. paracasei

1010 of Lactobacillus plantarum 2362

10 gram bioactive fibers:

2.5 g of betaglucan

2.5 g of inulin

2.5 g of pectin

2.5 g of resistant starch

NEUTROPHILS IN LUNG TISSUE Tok D et al J Trauma 2007;62:880-885

• Synbiotic 2000 9.00±0.44 • Only LAB 8.40±0.42 • Only the fibres 31.20±0.98 • Placebo 51.10±0.70 • p< 0.05

MYEOLOPEROXIDASE – MPO Tok D et al J Trauma 2007;62:880-885

U/g

• Synbiotic 2000 25.62±2,19

• Only LAB 26.75±2,61

• Only the fibres 56.59±1,73

• Placebo 145.53±7,53

p< 0.05

MALONALDEHYDE – MDA Tok D et al J Trauma 2007;62:880-885

nmol/mg

• Synbiotic 2000 0.22±1,31 •Only LAB 0.28±3,55 •Only the fibres 0.48±5,32 •Placebo 0.67±2,94

p< 0.05

NITRIC OXIDE micromol/g

• Synbiotic 2000 17.16±2,03

• Only LAB 8.91±2,24

• Only the fibres 47.71±3,20

• Placebo 66.22±5,92 p< 0.05

SYNBIOTIC 2000 IN LUNG INJURY Ilkgul O et al Br J Int Care. 2005;15:52-57

• Placebo Only fibres Synbiotic 2000

SYNBIOTIC 2000 IN LIVER TRANSPLANTATION

50 to 85 % of transplant patients develop nosocomial infections within 30 days.

Synbiotic 2000 or Only fibres daily from the day before surgery + during 14 postop days

30 day-infection rate: Synbiotic 2000 1/33 - 3 %

Only fibres 17/33 - 51 % Rayes N et al. Am J Transplant 2005;5:125-131

SYNBIOTIC 2000 IN LIVER TRANSPLANTATION

Isolated bacteria: Synbiotic 2000 Fibres only

Enterococcus faecalis 1 11

Escherichia coli 0 3

Enterobacter cloacae 0 2

Pseudomonas aeruginosa 0 2

Staphylococcus aureus 0 1

Total 1 18

Rayes N et al. Am J Transplant 2005;5:125-131

SYNBIOTIC 2000 IN PANCREATECTOMY INFECTIONS:

Control (Only fibers) 16/40 - 40 % Synbiotics 2000 5/40 - 13 % p< 0.05

Synbiotic 2000 Control Wound infections 4 6 Peritonitis 0 5 Pneumonia 0 4 Urinary 1 1 Sepsis 0 2 Cholangitis 0 1 Empyema 0 1 Total 5 20 Rayes N et al. Ann Surg 2007;246:36-41

SYNBIOTIC 2000 IN PANCREATECTOMY ISOLATED BACTERIA:

Synbiotic 2000 Fibres Enterobacter cloacae 2 8 Enterococcus faecalis/faecium 1 7 Escherichia coli 0 7 Klebsiella pneumoniae 2 2 Proteus mirabilis 1 1 Staphylococcus aureus 0 2 Total 6 27

Rayes N et al. Ann Surg 2007;246:36-41

SYNBIOTICS IN ACUTE PANCREATITIS Oláh A et al Hepato-gastroenterology 2007;54:36-41

Synbiotic 2000 Fibres Only Total number of infections 9/33 ( 27 %) 15/29 ( 52 %) Pancreatic abscesses 2 2 Infected necrosis 2 6 Chest infections 2 4 Urinary infections 3 3 SIRS 3 5 MOF 5 9 SIRS + MOF 8 14 p<0.05 Late (>48h) MOF 1 5 Complications 9/33 15/29 p<0.05 Surgical drainage 4/33 ( 12 %) 7/29 ( 24 %) Mean hospital stay 14.9 ±6.5 19.7±9.3 Dead 2/33 ( 6 %) 6/29 ( 18 %)

SYNBIOTICS IN ACUTE PANCREATITIS

Oláh A et al Hepato-gastroenterology 2007;54:36-41

Isolated Microorganisms: SYNBIOTIC 2000 Fibres Only Pseudomonas aeruginosa 1 4 Enterococcus faecalis 1 2 Enterobacter spp 1 1 Streptococcus spp 2 - Staphylococcus aureus 1 1 Enterococcus faecium 1 - Candida spp - 2 Staphylococcus haemolyticus - 1 Serratia spp - 2 Klebsiella spp - 1 Escherichia coli - 1 Stenotrophomonas maltophilia - 1 Citrobacter freundii - 1 Total 7 17

SYNBIOTIC 2000 IN MULTIPLE TRAUMA 102 patients supplied 15 days with either Synbiotic

2000 Forte or placebo

The treated patients demonstrated reduced: - Mortality - Rate of infection (P = 0.01) - Rate of SIRS & severe sepsis (P = 0.02) - Numbers of days on mechanical ventilation (P= 0.001) - ICU stay (P = 0.01) Kotzampassi K et al. World J Surgery 2006;30:1848-1855

SYNBIOTIC 2000 IN TRAUMA PATIENTS

Spindler-Vesel A et al. JPEN 2007;31:119-126

TOTAL NUMBER OF INFECTIONS:

Alitraq Abbott-Ross (glut+arg) 16/32 50 %

Nova Source Novartis (+guargum) 17/29 58 %

Nutricomp peptide Braun (+peptide) 13/26 50 %

Nutricomp standard (+Synbiotic 2000) 4/26 15 %

NUMBER OF CHEST INFECTIONS: Alitraq Abbott-Ross (glut +arg) 11/32 34 %

Nova Source Novartis (+guargum) 12/29 41 %

Nutricomp Braun (peptide) 11/26 42 %

Nutricomp standard (+Synbiotic 2000) 5/26 19 %

REDUCTIONS IN INFECTIONS/POSITIVE BLOOD CULTURES

Liver transplantation, 66 patients1

Patients with postop. infections 16 => 1 = 94 per cent

Patients with pos. blood cultures 11 => 1 = 91 per cent

Pancreatdoudenectomy for cancer, 80 patients2

Patients with postop. infections 16 => 5 = 69 per cent

Patients with pos. blood cultures 27=> 5 = 82 per cent

Severe pancreatitis – 62 patient3

Patients with infections 15 => 9 = 40 per cent

Patients with pos. blood cultures 17 => 7 = 59 per cent

Severe trauma, treated with Synbiotic 2000 Standard – 52 patients4 Patients with infections 23/30 (77 %) => 17/35 (49 %)

Severe trauma, treated with Synbiotic 2000 Forte – 72 patients5

Patients with post-trauma infections 13 => 5 = 62 per cent Patients with pos. blood cultures 13 => 5 = 62 per cent

REDUCTIONS IN USE OF ANTIBIOTICS, ARTIFICAL RESPIRATION, TIME IN ICUs & IN HOSPITAL

Liver transplantation – 66 patients1 Days on Antibiotics 3.8 => 0.1 = 3.7 (97 %)

Days in ICUs 10.2 => 8.8 = 1.4 (14 %)

Days in Hospital 27.9 => 27.8 = 0.1(3 %) Pancreatdoudenectomy for cancer - 80 patients2 Days on Antibiotics 10 => 2 = 8 (80 %) Days in ICUs 6 => 2 = 4 (67 %)

Days in Hospital 22 => 17 = 5 (23 %)

Severe acute pancreatitis – 62 patients3

Days in Hospital 19.7 => 14.9 = 4.8 (24 %) Severe trama treated with Synbiotic 2000 Forte – 65 patients5

Days on Artificial Respiration 24 => 19 = 5 (21 %)

Days in ICUs 41.3 => 27.7 = 13.6 (33 %)

MULTI-STRAIN SYNBIOTICS IN

DISTAL COLITIS

Rectal application, 10 patients, studied before (D0), and after 7 (D7), 14 (D14) and 21 (D21) days of treatment:

D0 D7 D14 D21

Urgency 1.9 1.2 1.0 1.0

Episodes of diarrhoea 2.4 1.3 0.9 0.8

Nightly diarrhoea 0.5 0.1 0 0

Visible blood 2.2 1.2 0.8 0.8

Consistency of stool 1.1 0.9 0.7 0.8

Pathmakanthan S, et al, Gut 2002; 51(Supp lIII) A307

Emelie – a child with cystic fibrosis • 2000 – severe cystic fibrosis, repeat chest

infections, diarrhea, loosing weight, supplemented Synbiotic 2000

• 2 months later – gained 2.5 kg in weight, no diarrhea, no chest infections, no antibiotics

• 2007 – still on Synbiotics, undergone liver transplantation, no complications, (won 2 Gold and one Bronze medal at World Championship in Western horse-riding)

CALORIC RESTRICTION – KETOGENIC FOODS

Calorie restriction and restricted ketogenic diets - reduce glucose

- elevate ketone levels,

& are

-anti-inflammatory -anti-invasive -anti-angiogenic

-anti-tumorogenic

pH 9.0 - watermelon, asparagus, garlic, carrots

pH app 8,5 - dates, figs , apricots, mango, parsley, lemon, lime, grape fruits, various algi & sea grasses

Greens - especially when organic: spinach, arugula, broccoli, sprouts, nettles

Fruits - especially when organic: avocado, pears, apples, bananas, berries, grapes, peaches

pH app 8.0 - peas, pumpkin, parsnip

INTERMITTENT FASTING & WEIGHT Hatori M et al Cell Metabolism 2012;15: 848-860

NA=normal diet, free access, FA= free access to fat diet, NT & FT=time-restricted normal or fat diet

DAILY FASTING REDUCES OBESITY & IMPROVES HEALTH

Hatori M et al Cell Metabolism 2012;15: 848-860

CALORIE RESTRICTION EFFECTS IN INDIVIDUAL WITH MORBID OBESITY (174.8 kg) The volunteer lost 30.1 kg after 9 weeks & 51.4 kg after 23 weeks, on a diet composed of whole grains, traditional Chinese medicinal foods and prebiotics Abbreviations: AST = aspartate aminotransferase ALT = alanine aminotransferase BM = body mass index DBP = diastolic blood pressure GGT = gamma-glutamyl transferase HbA1c = glycated hemoglobin HDL = high-density lipoprotein cholesterol IL-6 = interleukin-6 LBP = lipopolysaccharide-binding protein LDL = low-density lipoprotein cholesterol SBP = systolic blood pressure

Fei N, Zhao L. ISME J. 2012 E-pub

HEALTH – TEN COMMANDMENTS 7 NOS (restrict) & 3 YES (increase)!

1. Restrict intake of insulinotrophic foods (refined carbohydrates)

2. Restrict intake of highly pro-inflammatory fructose

3. Restrict intake of dairy products

4. Restrict intake of foods heated above 100o

5. Restrict exposure to chemicals including pharmaceutical drugs

6. Restrict exposure to in microb-derived highly inflammatory endotoxin

7. Eliminate/Minimize intake of foods rich in proteotoxins such as casein, gluten and zein (corn)

8. Increase the intake of fresh and raw greens, fresh spices vegetables, INCLUDING FERMENTED VEGETABLES

9. Increase intake of ancient anti-oxidant-rich, high fiber, low-calorie containing grains, seeds, peas, beans, almonds & nuts

10. Supplement vitamin D and omega fatty acids in large doses

SUBSTITUTING VITAMIN D Gant WB et al Prog Biophys Mol Biol 2009;99:104-113

to all European to only 40 ng/mL (not 70)

will for example reduce the costs of care of

cardiovascular diseases by 13.5 %,

infections incl influenza 7 %, type 2 diabetes

7 %, cancer 6.4 %, osteoporosis 1.5 % &

multiple sclerosis 1 % &

reduce the total economic burden

of disease by no less than 17.7 % &

save EUR 187 000 000 000

Gut microbiota,

immune development and function

Bengmark S.

Pharmacological

Research

2013 March;69:87-113

www.bengmark.com stig@bengmark.se

”Make peace with your

microbiota!”

Thank you!