Food’s Role In Autoimmunity | El Paso, TX.

Food:�Genes that determine illness are triggered by what we put into our bodies, literally what we eat. Our cells are literally created out of the foods we put into our bodies. Like most people do, we are likely eating nutrient-poor foods that create damaged dysfunctional cells. When we learn to eat foods that nourish the body, our cells repair themselves, and the new cells created will be optimal functioning cells.

Unhealthy foods create chronic inflammation, which is destructive to the body. Inflammation is normally the body�s healthy response to injury or infection. However, when inflammation becomes chronic, from constant assault on the gut by consuming the wrong foods, inflammation becomes the cause of destructive diseases, i.e. Lupus, Rheumatoid Arthritis, Colitis and other inflammatory diseases.

Disclosure

Terry Wahls, MD disclosed no relevant financial relationships with any commercial interest.

Environmental Factors In Autoimmune Diseases & MS

Environmental factors in autoimmune diseases and their role in multiple sclerosis. Cell Mol Life Sci. 2016; 73(24): 4611�4622.

Diet Papers

Autoimmune

• 1999 � 36
• 2002 -57
• 2008 � 78
• 2013 � 125
• 2016 � 150

Multiple Sclerosis

• 1999 � 9 papers (supplement)
• 2002 � 2 papers (supplement)
• 2008 � 26 papers
• 2013 – 48 papers
• 2016 -54 papers

Dietary Factors Associated With Autoimmunity

Nat Rev Rheumatol. 2017 Jun;13(6):348-358.

The two routes by which diet can influence our health:

(A) the metabolism of our cells and

(B) the population of our gut microbiota.

Paolo Riccio, and Rocco Rossano ASN Neuro
2015;7:1759091414568185
Copyright � by SAGE Publications Inc, or the American Society for Neurochemistry, unless otherwise noted.
Manuscript content on this site is licensed under Creative Commons Licenses.

The MS in America study, 2013
multiplesclerosis.net/ms-in-america-2013/use-of-remedies-in-ms/

The Swank Diet

• N=144 followed 50 years
• < 15 grams saturated fat vs. > 20 grams
• Greatest benefit earlier in the disease course
• More likely to remain ambulatory

1. Review of MS patient survival on a Swank low saturated fat diet. Nutrition. 2003 Feb;19(2):161-2. Review.
2. Effect of low saturated fat diet in early and late cases of multiple sclerosis. Lancet. 1990 Jul 7;336(8706):37-9.
3. Multiple sclerosis: twenty years on low fat diet. Arch Neurol. 1970 Nov;23(5):460-74

Low-Fat, Plant-Based Diet In Multiple Sclerosis: A Randomized
Controlled Trial

• This was a randomized-controlled, assessor- blinded, one-year long study
• N=61
• No change in EDSS, MRI
• Modestly reduced fatigue (MFIS)
• Trend reduced fatigue (FFS)

Low-fat, plant-based diet in multiple sclerosis: A randomized controlled trial Mult Scler Relat Disord. 2016 Sep;9:80-90.

Elemental Diet

• Predigested formula instead of food
• Reduced intestinal permeability
• Equivalent to steroids in the setting of
• Crohn�s disease
• Rheumatoid arthritis

1. Voitk AJ, Echave V, Feller JH, et, al: Experience with elemental diet in the treatment of inflammatory bowel disease. Is this primary therapy? Arch Surg, 1973;107: 329-333.
2. Tim LO, Odes HS, Duys PJ, et al. The use of an elemental diet in gastrointestinal diseases. S Afr Med J,1976;50: 1752-1756
3. Zoli G, Care? M, Parazza M et al, A randomized controlled study comparing elemental diet and steroid treatment in Crohn’s disease. Aliment
Pharmacol Ther. 1997 Aug;11(4):735-40.
4. Zachos M, Tondeur M, Griffiths AM. Enteral nutritional therapy for induction of remission in Crohn�s disease. Cochrane Database Syst Rev, 2007
January 24;(1)
5. Podas T, Nightingale JM, Oldham R, et al, Is rheumatoid arthritis a disease that starts in the intestine? A pilot study comparing an elemental diet with
oral prednisolone. Postgrad Med J. 2007 Feb;83(976):128-31
6. Podas T, Nightingale JM, Oldham R, et al, Is rheumatoid arthritis a disease that starts in the intestine? A pilot study comparing an elemental diet with
oral prednisolone. Postgrad Med J. 2007 Feb;83(976):128-31

Exclusion Diets

• Eliminated specific protein sources � RA Sx ?
• Raw vegan, vegan and gluten free vegan
• Systematic review of 14 RCTs
• Dietary benefits uncertain
• Small studies with risk of bias

1. Kjeldsen-Kragh J, Haugen M, Borchgrevink CF, Laerum E, Eek M, Mowinkel P, Hovi K, F�rre O. Controlled trial of fasting and one-year vegetarian diet in rheumatoid arthritis. Lancet. 1991 Oct 12;338(8772):899-902.
2. Kjeldsen-Kragh J, Haugen M, Borchgrevink CF, F�rre Vegetarian diet for patients with rheumatoid arthritis–status: two years after introduction of the diet. Clin Rheumatol. 1994 Sep;13(3):475-82
3. McDougall J, Bruce B, Spiller G, et al, Effects of a very low-fat, vegan diet in subjects with rheumatoid arthritis. J Altern Complement Med. 2002 Feb;8(1):71-5
4. Hafstro?m I, Ringertz B, Spa?ngberg A, et. al, A vegan diet free of gluten improves the signs and symptoms of rheumatoid arthritis: the effects on arthritis correlate with a reduction in antibodies to food antigens. Rheumatology (Oxford). 2001 Oct;40(10):1175-9.
5. Hagen KB, Byfuglien MG, Falzon L, et, al. Dietary interventions for rheumatoid arthritis. Cochrane Database Syst Rev. 2009 Jan 21;(1):
6. Smedslund G, Byfuglien MG, Olsen SU, et. al, Effectiveness and safety of dietary interventions for rheumatoid arthritis: a systematic review of
randomized controlled trials. J Am Diet Assoc. 2010 May;110(5):727-35

Exclusion Diets

• Atopic dermatitis improved n=20
• UC � fewer symptoms n=18
• Crohn�s food sensitivities identified in half n=42

1. J Tanaka T, Kouda K, Kotani M, et. al, Vegetarian diet ameliorates symptoms of atopic dermatitis through reduction of the number of peripheral eosinophils and of PGE2 synthesis by monocytes. J Physiol Anthropol Appl Human Sci. 2001 Nov;20(6):353-61.
2. Candy S et. al.. The value of an elimination diet in the management of patients with ulcerative colitis. S Afr Med J. 1995 Nov;85(11):1176-9
3. Pearson M Food intolerance and Crohn’s disease., Gut. 1993 Jun;34(6):783-7.

Milk May Be a Problem

• Antibody cross-reactivity between myelin oligodendrocyte glycoprotein and the milk protein butyrophilin in MS – Inducing antibodies reacting with myelin oligodendrocyte glycoprotein (MOG) and Cerebellar peptides
• Liquid cow milk (not cheese) and MS prevalence was highly correlated (rho = 0.836) across 27 countries and 29 populations.

1. Antibody cross-reactivity between myelin oligodendrocyte glycoprotein and the milk protein butyrophilin in multiple sclerosis J Immunol. 2004 Jan 1;172(1):661-8.
2. Correlation between milk and dairy product consumption and multiple sclerosis prevalence: a worldwide study. Neuroepidemiology. 1992;11(4-6):304-12.

Lectins

• �By eliminating lectins, which adversely influence both enterocyte and lymphocyte structure and function, it is proposed that the peripheral antigenic stimulus (both pathogenic and dietary) will be reduced and thereby result in a diminution of disease symptoms in certain patients with RA.�

Cordain L, Toohey L, Smith MJ, Hickey MS. Modulation of immune function by dietary lectins in rheumatoid arthritis. British Journal of Nutrition. 2000;83(03):207-217.

Lectins

• Lead to barrier damage and leaky gut increasing risk of autoimmunity.
• Are high in grains (esp. wheat), dairy, legumes, and nightshade vegetables (eggplant, tomatoes, peppers, white potatoes).
• Soaking, fermenting, cooking, high pressure cooking will decrease lectin content.

1. de Punder K, Pruimboom L. The dietary intake of wheat and other cereal grains and their role in inflammation. Nutrients. 2013 Mar 12;5(3):771-87.
2. Cordain L, Toohey L, Smith MJ, Hickey MS. Modulation of immune function by dietary lectins in rheumatoid arthritis. British Journal of Nutrition. 2000;83(03):207-217.

Paleo Diet Studies & Improved Biomarkers

• Improved glycemic control, insulin sensitivity, a1c, BP, and superior satiety
• More weight loss
• Better lipids �
• � Lower TC, Trigs & ApoB,
• � Higher HDL
• Decreased liver fat

Efficacy Of The Autoimmune Protocol Diet For Inflammatory Bowel Disease

• N=15
• 6 week elimination of grain, legumes, nightshades, dairy, eggs, coffee, etoh, nuts, sugars, oils, food additives followed by 5 weeks of maintenance
• Endoscopy before and after � erosions or elevated calprotectin

Konijeti GG1 Efficacy of the Autoimmune Protocol Diet for Inflammatory Bowel Disease
Inflamm Bowel Dis. 2017 Aug 29.

Diet & Psoriasis N = 1206 Survey Responses

Specific diets with the most patients reporting a favorable skin response were:

• Pagano (72.2%),
• Vegan (70%),
• Paleolithic (68.9%).
• Additionally, 41.8% of psoriasis respondents reported that a motivation for attempting dietary changes was to improve overall health.

Pagano Diet Organic Foods

• 80% alkaline foods vegetables & fruit
• 20% acidic – meat and whole grain
• Avoid night shades, sugar, red meat, white flour

Dietary Removals N = 1037 Survey Responses

• Junk foods: 66.7%
• Sodium/salt: 34.5%
• White flour : 55.7%
• Nightshades: 28.8%
• High fat foods: 50.4%
• Caffeine: 27%
• Red meat: 49.5%
• Alcohol: 45%
• Pork: 26.8%
• Shellfish: 18%
• Gluten: 44.6%
• Dairy: 41.3%
• Tobacco: 36.1%
• Other: 9.2%

Dietary Additions N = 988 Responses

• Vegetables: 58.8%
• Fish oil/omega – 3: 56.8%
• Oral vitamin D: 55.6%
• Fruits: 54.7%
• Probiotics: 44.4%
• Organic foods: 39.6%

Dietary Behaviors in Psoriasis: Patient-Reported Outcomes from a U.S. National Survey. Dermatol Ther (Heidelb). 2017 Jun;7(2):227-242.

1. Lindeberg, S., Jo?nsson, T., Granfeldt, Y. et al. Diabetologia (2007) 50: 1795. doi:10.1007/s00125-007-0716-y
2. O?sterdahl M, Kocturk T, Koochek A, Wa?ndell PE. Effects of a short-term intervention with a paleolithic diet in healthy volunteers. European Journal of
Clinical Nutrition. 2007;62(5):682�685. doi:10.1038/sj.ejcn.1602790.
3. Jo?nsson T, Granfeldt Y, Ahre?n B, et al. Beneficial effects of a Paleolithic diet on cardiovascular risk factors in type 2 diabetes: a randomized cross-over pilot study. Cardiovascular Diabetology. 2009;8:35. doi:10.1186/1475-2840-8-35.
4. Frassetto LA, Schloetter M, Mietus-Synder M, Morris RC, Sebastian A. Metabolic and physiologic improvements from consuming a paleolithic, hunter- gatherer type diet. European Journal of Clinical Nutrition. 2009;63(8):947�955. doi:10.1038/ejcn.2009.4.
5. Halberg N, Henriksen M, So?derhamn N, et. al, Effect of intermittent fasting and refeeding on insulin action in healthy men. J Appl Physiol (1985). 2005 Dec;99(6):2128-36.
6. Ryberg M, Sandberg S, Mellberg C, et al. A Palaeolithic-type diet causes strong tissue-specific effects on ectopic fat deposition in obese postmenopausal women. Journal of Internal Medicine. 2013;274(1):67�76. doi:10.1111/joim.12048.
7. Ruiz-Nu?n?ez B, Dijck-Brouwer DAJ, Muskiet FAJ. The relation of saturated fatty acids with low-grade inflammation and cardiovascular disease. The Journal of Nutritional Biochemistry. January 2016. doi:10.1016/j.jnutbio.2015.12.007.
8. Otten J, Stomby A, Waling M, et al. Benefits of a Paleolithic diet with and without supervised exercise on fat mass, insulin sensitivity, and glycemic control: A randomized controlled trial in individuals with type 2 diabetes. Diabetes/Metabolism Research and Reviews. January 2016. doi:10.1002/dmrr.2828.
9. Konijeti GG1, Kim N, Lewis JD, Groven S, Chandrasekaran A. Efficacy of the Autoimmune Protocol Diet for Inflammatory Bowel Disease. Inflamm Bowel Dis. 2017 Aug 29. doi: 10.1097/MIB.0000000000001221.
10. Spreadbury I. Comparison with ancestral diets suggests dense acellular carbohydrates promote an inflammatory microbiota, and may be the primary dietary cause of leptin resistance and obesity. Diabetes Metab Syndr Obes. 2012;5:175-89.
11. Eaton SB, Konner MJ, Cordain L. Diet-dependent acid load, Paleolithic nutrition, and evolutionary health promotion. Am J Clin Nutr. 2010;91:295-7. Andersson A, et al. Whole?grain foods do not affect insulin sensitivity or markers of lipid peroxidation and inflammation in healthy, moderately overweight subjects. J Nutr.2007 Jun;137(6):1401?7.
12. Tighe P, et al. Effect of increased consumption of whole ? grain foods on blood pressure and other cardiovascular risk markers in healthy middle?aged persons: a randomized controlled trial. Am J Clin Nutr. 2010 Oct;92(4):733?40.
13. Brownlee IA, et al. Markers of cardiovascular risk are not changed by increased whole?grain intake: the WHOLEheart study, a randomised, controlled dietary intervention. Br J Nutr. 2010 Jul;104(1):125?34.
14. Masters RC, et al. Whole and refined grain intakes are related to inflammatory protein concentrations in human plasma. J Nutr. 2010 Mar;140(3):587?94.
15. Katcher HI, et al. The effects of a whole grain-enriched hypocaloric diet on cardiovascular disease risk factors in men and women with metabolic syndrome. Am J Clin Nutr. 2008 Jan;87(1):79?90.

Nutrient Triage

Low micronutrient intake may accelerate the degenerative diseases of aging through allocation of scarce micronutrients by triage.

• � Zn, Mg, Biotin, Vitamin K, D, A
• � Lipoic Acid, Acetyl carnitine

Low micronutrient intake may accelerate the degenerative diseases of aging through allocation of scarce micronutrients by triage.
Proc Natl Acad Sci U S A. 2006 Nov 21;103(47):17589-94.

What To Eat?

• Fruit and vegetable consumption and mortality from all causes, cardiovascular disease, and cancer: systematic review and dose response meta-analysis of prospective cohort studies.
• 16 studies – 833,234 participants

Risk Of All Cause Mortality Associated With Servings/Day Of Fruit & Vegetables

Fruit and vegetable consumption and mortality from all causes, cardiovascular disease, and cancer: systematic review and dose-response meta-analysis of prospective cohort studies. BMJ. 2014; 349: g4490

Dose-Response Relation Between Fruit & Vegetable Consumption & Risk Of All Cause Mortality

BMJ. 2014; 349: g4490.

1. Neuroprotective Effect of Brassica oleracea Sprouts Crude Juice in a Cellular Model of Alzheimer’s Disease. Med Cell Longev.2015;2015:781938
2. Learning and memory promoting effects of crude garlic extract. Indian J Exp Biol.2013 Dec;51(12):1094-100.
3. Enhancement of the neuroprotective activity of Hericium erinaceus mycelium co-cultivated with Allium sativum extract. Arch Physiol Biochem.2015 Feb;121(1):19-25.
4. Mori K, Obara Y, Hirota M, Azumi Y, Kinugasa S, Inatomi S, Nakahata N. Nerve growth factor-inducing activity of Hericium erinaceus in 1321N1 human astrocytoma cells. Biol Pharm Bull. 2008 Sep;31(9):1727-32.
5. Lee DH, Kim HW. Innate immunity induced by fungal ?-glucans via dectin-1 signaling pathway. Int J Med Mushrooms. 2014;16(1):1-16.
6. Akramiene D, Kondrotas A, Didziapetriene J, Kevelaitis E Effects of beta-glucans on the immune system. Medicina (Kaunas).2007;43(8):597-606.
7. Lai PL, Naidu M,Sabaratnam V,Wong K, DaviP, Kuppusamy UR, Abdullah N, Malek SN. Neurotrophic properties of the Lion’s mane medicinal mushroom, Hericium erinaceus (Higher Basidiomycetes) from Malaysia Int J Med Mushrooms.2013;15(6):539-54.
8. Phan CW, David P, Naidu M, Wong KH, Sabaratnam V. Therapeutic potential of culinary-medicinal mushrooms for the management of neurodegenerative diseases: diversity, metabolite, and mechanism. Crit Rev Biotechnol.2015;35(3):355-68.
9. Scientifica (Cairo).2016;2016:3109254.
10. Berry antioxidants: small fruits providing large benefits. J Sci Food Agric.2014 Mar 30;94(5):825-33
11. Dietary and plant polyphenols exert neuroprotective effects and improve cognitive function in cerebral ischemia. Recent Pat Food Nutr Ag. 2013 Aug;5(2):128-43.
12. The impact of fruit flavonoids on memory and cognition. Br J Nutr.2010 Oct;104 Suppl 3:S40-7. d
13. Grape juice, berries, and walnuts affect brain aging and behavior. J Nutr. 2009 Sep;139(9):1813S-7S.
14. Fruit polyphenolics and brain aging: nutritional interventions targeting age-related neuronal and behavioral deficits. Ann N Y Acad Sci.2002 Apr;959:128-32.
15. Reversing the deleterious effects of aging on neuronal communication and behavior: beneficial properties of fruit polyphenolic compounds. Am J Clin Nutr.2005 Jan;81(1 Suppl):313S-316S.
16. Krikorian R, Shidler MD, Nash TA, Kalt W, Vinqvist-Tymchuk MR, Shukitt-Hale B, Joseph JA. Blueberry supplementation improves memory in older adults. J Agric Food Chem.2010 Apr 14;58(7):3996-4000.
17. Funding for the studies was provided by the US Highbush Blueberry Council, the National Institute on Aging, and Wild Blueberries of North America. Dr. Krikorian has disclosed no relevant financial relationships.
18. Lobo GP Amengual J, Baus D, Shivdasani RA Genetics and diet regulate vitamin A production via the homeobox transcription factor ISX. J Biol Chem.2013 Mar 29;288(13):9017-27

?-carotene Is Not Retinol (Vitamin A)

• ?-Carotene is converted to vitamin A in the intestine by the enzyme ?-carotene-15,15′- monoxygenase (BCMO1) to support vision, reproduction, immune function, and cell differentiation.
• Considerable variability in BCMO1 exists and can effect individual vitamin A status

Lobo GP Amengual J, Baus D, Shivdasani RA Genetics and diet regulate vitamin A production via the homeobox transcription factor ISX. J Biol Chem.2013 Mar 29;288(13):9017-27.

Leung WC, Hessel S, Me?plan C, Flint J, Oberhauser V, Tourniaire F, Hesketh JE, von Lintig J, Lietz G. Two common single nucleotide polymorphisms in the gene encoding beta-carotene 15,15′-monoxygenase alter beta-carotene metabolism in female volunteers. FASEB J. 2009 Apr;23(4):1041-53. doi: 10.1096/fj.08-121962. Epub 2008 Dec 22.

Feasibility & Safety Study N=20

Study Diet

Nutritional Adequacy (%RDA) US Diet Vs. Study Diet

Multimodal Intervention Improves Quality Of Life

Mood & Cognition

In the setting of progressive MS Improved thinking ability and reduced anxiety and reduced depression

Average daily servings of the study diet recommended (vegetables/fruits) and excluded (gluten/dairy/eggs) foods p < 0.01 difference from baseline to 12 months

Average Scores On The Mood Measures At Each Study Visit

Average Scores On The DKEFS & WAIS Sub-Scales At Each Study Visit.

Relapsing Remitting MS

Reduce Fatigue

?Mental & Physical QoL 16% (> 5 points)

Improved Motor Function

A Simplified Model Of FMD?Mediated Effects On Glucocorticoid, Immune Suppression & Oligodendrocyte Regeneration & Differentiation In MS

N=60 6 Month Human Clinical Trial

• FMD 100 ml broth, 1 T flax oil tid, 200 � 350 Kcal, Plus enema as needed 7 days Mediterranean diet
• Ketogenic(KD) 160gmfatm<100gPro,<50g CHO
• Usual diet

Change at 3 month of (k) overall quality of life, (l) change in health, (m) physical health composite, and (n) mental health composite. The dotted line represents a threshold that is thought to be clinically important

A Diet Mimicking Fasting Promotes Regeneration and Reduces Autoimmunity and Multiple Sclerosis Symptoms. Cell Rep. 2016 Jun 7; 15(10): 2136�2146

Mechanisms

• Nutrient triage
• Nutritional adequacy
• � Metabolism and repair
• Phytonutrients
• � Improving biotransformation (detox)
• � Changing gene expression � e.g. NfkappaB, Nrf2
• Shifting gut microbiome

The Two Routes By Which Diet Can Influence Our Health:

(A) the metabolism of our cells and

(B) the population of our gut microbiota.

Paolo Riccio, and Rocco Rossano ASN Neuro
2015;7:1759091414568185
Copyright � by SAGE Publications Inc, or the American Society for Neurochemistry, unless otherwise
noted. Manuscript content on this site is licensed under Creative Commons Licenses.

Gut Brain Immune Axis

• Gut microbiota influence the brain and immune system balance
• Diet influences the microbiome strongly
• Exercise, sleep, stress level also important
• Changes in the colon mucosa every early in the disease process

Does the Gut Microbiota Influence Immunity and Inflammation in Multiple Sclerosis Pathophysiology? J Immunol Res. 2017;2017:790482 The multiple sclerosis microbiome? Ann Transl Med. 2017 Feb;5(3):53.
Microbiota-gut-brain axis and the central nervous system. Exp Mol Med. 2017 May 26;49(5):e339
Microbiota-gut-brain axis and the central nervous system. Oncotarget. 2017 May 10
Microbiota in T-cell homeostasis and inflammatory diseases Exp Mol Med. 2017 May; 49(5): e340.
Mucosal biopsy shows immunologic changes of the colon in patients with early MS Neurol Neuroimmunol Neuroinflamm. 2017 Jun 14;4(4):e362.

The composition of gut microbiota is influenced by multiple factors, such as diet and host genotype. Within the gut, ecological processes such as selection and evolution take place. The use of antibiotics reduces the numbers and diversity of gut microbiota.

8 Studies 250 Patient Fecal Samples

van den Hoogen WJ1, Laman JD2, ‘t Hart BA2,3.Modulation of Multiple Sclerosis and Its Animal Model Experimental Autoimmune Encephalomyelitis by Food and Gut Microbiota Front Immunol. 2017; 8: 1081.

Vegetables & Microbiota In RRMS

• N=20 high vegetable/low protein vs. SAD
• 1year
• Change in microbiota
• Change in inflammatory cytokines, microbiota
• Relapses 9/10 in Western diet vs. 3/10 in high vegetable diet

Immunological and Clinical Effect of Diet Modulation of the Gut Microbiome in Multiple Sclerosis Patients: A Pilot Study. Front Immunol. 2017 Oct 25;8:1391.

• 2014 Paleo the most frequent diet related google search
• 2017 US News and World Report Paleo diet ranked 38 of 38 diets reviewed due to lack of RCTs
• Peer reviewed diet papers since 1985 � Paleo 180
  � Vegan 525
  � Atkins 1478
  � Vegetarian 3020
  � Mediterranean 4834

Diet & Food

• Low saturated fat
• Elemental diets / exclusion diets
• Raw vegan
• Low fat vegan
• Autoimmune paleo
• Modified Paleo (Wahls)
• Fasting Mimicking Diet
• Ketogenic Diets
• Higher quality diet (food), stress reduction, movement � are relatively safe with large favorable benefits for all cause mortality
• 3 month trial of a grain free, dairy free, sugar free vegetable rich (or gluten free vegetarian) diet is relatively safe with potential for many favorable benefits

Dr. Terry Wahls

University of Iowa Departments of Internal Medicine/ Neurology Dr. Terry Wahls LLC

The Wahls Institute P.L.C.

Dietary Approaches to Treating MS Related Fatigue RRMS & Fatigue Study funded by NMSS MSDietStudy@healthcare.uiowa.edu Live within 500 Miles of Iowa City, Iowa
info@wahlsinstitute.com