Mol Syst Biol. 2007;3:124. Epub 2007 Jul 10. Links Human disease classification in the postgenomic era: a complex systems approach to human pathobiology. Loscalzo J, Kohane I, Barabasi AL. Department of Medicine, Brigham and Women&apos;s Hospital, Boston, MA 02115, USA. firstname.lastname@example.org Contemporary classification of human disease derives from observational correlation between pathological analysis and clinical syndromes. Characterizing disease in this way established a nosology that has served clinicians well to the current time, and depends on observational skills and simple laboratory tools to define the syndromic phenotype. Yet, this time-honored diagnostic strategy has significant shortcomings that reflect both a lack of sensitivity in identifying preclinical disease, and a lack of specificity in defining disease unequivocally. In this paper, we focus on the latter limitation, viewing it as a reflection both of the different clinical presentations of many diseases (variable phenotypic expression), and of the excessive reliance on Cartesian reductionism in establishing diagnoses. The purpose of this perspective is to provide a logical basis for a new approach to classifying human disease that uses conventional reductionism and incorporates the non-reductionist approach of systems biomedicine.
Assomade - Relazione Dott. Ongaro
Dr. Filippo Ongaro, MD
Board Certified Anti-Aging & Regenerative Medicine (ABAARM)
Diplomate Functional Medicine (AFMCP)
Certified International School Gynecological Endocrinology (ISGE)
ISMERIAN-Institute for Regenerative and Anti-Aging Medicine
3 conditions, 3 specialities but 1
Rheumatoid arthritis rheumatology
Multiple sclerosis neurology
…the result is a focus on
treating each symptom complex
as a separate and distinct
“disease” with a separate and
It is apparent that – in its rush to diagnose –
conventional medicine is focused on the branches
and leaves of the tree…
Organ System Diagnosis
Signs and Symptoms
and not the trunk and roots.
Mind and Spirit
Experiences, Attitudes, Beliefs
Organ System Diagnosis
Signs and Symptoms
Fundamental Clinical Imbalances
Hormonal and Neurotransmitter Imbalances
Redox Imbalance + Oxidative Stress + Mitochondropathy
Digestive/Absorptive and Microbiological Imbalance
Structural Integrity Imbalance
- Outside the cell
- Inside the cell
2. Bioenergetics/Energy Transformation
4. Elimination of Waste
Fundamental Physiological Processes
Mind and Spirit
Experiences, Attitudes, Beliefs
Functional Medicine and GI
Gut flora, Gut Barrier and
What is “Leaky Gut”?
Leaky gut is a form of gut
dysfunction which refers to abnormal
Intestinal or bowel hyper-permeability
which occurs when the intestinal
barrier is broken down.
Major Role of the Gastrointestinal Tract is
To act as a barrier to finely regulate the trafficking of
macromolecules between the external (food/microbes) and
internal environment (systemic, cells, tissues, etc)
When this complex barrier is broken, foreign
macromolecules can enter, interact with the immune
system, and result in an inflammatory response which can
lead to a multitude of local intestinal and systemic
Fasano and Shea-Donohue,
NATURE CLINICAL PRACTICE GASTROENTEROLOGY & HEPATOLOGY SEPTEMBER 2005 VOL 2 NO 9
Why is “Leaky Gut”
Leaky gut is associated with numerous acute and
Systemic inflammatory response syndrome (SIRS)
Inflammatory bowel disease
more recently, obesity and metabolic syndrome
Cytoskeletal changes disrupt the TIGHT
JUNCTIONS between the epithelial
cells leading to intestinal hyper-
What Causes Leaky Gut ?
GI inflammation and leaky gut initiate a cascadeGI inflammation and leaky gut initiate a cascade
of signaling events that can increase inflammationof signaling events that can increase inflammation..
Scharz B, et al. Intestinal ischemic reperfusion syndrome: pathophysiology, clinical
significance, therapy: Wien Klin Wochenschr1999;111(14):539-48.
Digestion & BarrierDigestion & Barrier
Integrity ProblemsIntegrity Problems
Liver Stress/Liver Stress/
Kupffer CellKupffer Cell
Kupffer Cells Increase Inflammation
By Up-regulation of Immune Activity
Blatties CM, Li S, Perlik V, Feleder C. Signaling the brain in systemic
inflammation:the role of complement. Front Biosci 2004;9:915-31.
Altern Med Rev. 2004 Sep;9(3):297-307.
Medical nutrition therapy as a potential complementary treatment for psoriasis--five case
Brown AC, Hairfield M, Richards DG, McMillin DL, Mein EA, Nelson CD.
This research evaluated five case studies of patients with psoriasis following a dietary regimen.
There is no cure for psoriasis and the multiple treatments currently available only attempt to
reduce the severity of symptoms. Treatments range from topical applications, systemic
therapies, and phototherapy; while some are effective, many are associated with significant
adverse effects. There is a need for effective, affordable therapies with fewer side effects that
address the causes of the disorder. Evaluation consisted of a study group of five patients
diagnosed with chronic plaque psoriasis (two men and three women, average age 52 years;
range 40-68 years) attending a 10-day, live-in program during which a physician assessed
psoriasis symptoms and bowel permeability. Subjects were then instructed on continuing the
therapy protocol at home for six months. The dietary protocol, based on Edgar Cayce
readings, included a diet of fresh fruits and vegetables, small amounts of protein from
fish and fowl, fiber supplements, olive oil, and avoidance of red meat, processed foods,
and refined carbohydrates. Saffron tea and slippery elm bark water were consumed daily.
The five psoriasis cases, ranging from mild to severe at the study onset, improved on all
measured outcomes over a six-month period when measured by the Psoriasis Area and
Severity Index (PASI) (average pre- and post-test scores were 18.2 and 8.7, respectively), the
Psoriasis Severity Scale (PSS) (average pre- and post-test scores were 14.6 and 5.4,
respectively), and the lactulose/mannitol test of intestinal permeability (average pre- and post-
test scores were 0.066 to 0.026, respectively). These results suggest a dietary regimen
based on Edgar Cayce's readings may be an effective medical nutrition therapy for the
complementary treatment of psoriasis; however, further research is warranted to
confirm these results.
J Dermatol Sci. 1991 Jul;2(4):324-6.
Intestinal permeability in patients with psoriasis.
Humbert P, Bidet A, Treffel P, Drobacheff C, Agache P.
A possible relationship between intestinal structure and function in the pathogenesis
of psoriasis has recently brought about considerable interest. The purpose of this
study was to evaluate the intestinal permeability in psoriatic patients by comparing it
with healthy controls. 15 psoriatic patients and 15 healthy volunteers entered the
study. Intestinal permeability was evaluated using the 51Cr-labeled EDTA absorption
test. The 24-h urine excretion of 51Cr-EDTA from psoriatic patients was 2.46 +/-
0.81%. These results differed significantly from controls (1.95 +/- 0.36%; P less than
0.05). The difference in intestinal permeability between psoriatic patients and
controls could be due to alterations in the small intestinal epithelium of
Q J Med. 1985 Sep;56(221):559-67.
Small intestinal permeability in dermatological disease.
Hamilton I, Fairris GM, Rothwell J, Cunliffe WJ, Dixon MF, Axon AT.
Passive small intestinal permeability was investigated in 62 patients with atopic
eczema, 29 with psoriasis and 18 with dermatitis herpetiformis, using the
cellobiose/mannitol differential sugar absorption test. Urinary recovery of
cellobiose and mannitol in patients with both psoriasis and eczema were similar to
values in a control population, and were not affected by the extent or activity of
skin disease. The cellobiose/mannitol recovery ratio was abnormally high in seven
patients with eczema, six of whom underwent jejunal biopsy. Jejunal mucosal
morphology was normal in five, and one patient was found to have coeliac
disease. Cellobiose/mannitol recovery ratio was also abnormal in seven patients
with psoriasis, and in 11 with dermatitis herpetiformis, seven of whom had a
normal jejunal biopsy. These findings demonstrate that the passive permeability
of the small intestine is normal in the majority of patients with atopic eczema and
psoriasis. Increased absorption of macromolecules from the gut lumen cannot be
ascribed to defective intestinal integrity, and is unlikely to be relevant to the
pathogenesis of eczema. Abnormal intestinal permeability may be a more
sensitive manifestation of gluten-sensitive enteropathy than jejunal biopsy in
J Pediatr. 2004 Nov;145(5):612-6.
Effect of probiotics on gastrointestinal symptoms and small intestinal
permeability in children with atopic dermatitis.
Rosenfeldt V, Benfeldt E, Valerius NH, Paerregaard A, Michaelsen KF.
OBJECTIVE: To determine whether probiotic lactobacilli may alleviate small
intestinal inflammation and strengthen the intestinal barrier function in children with
STUDY DESIGN: In a double-blinded, placebo-controlled, cross-over study,
probiotic lactobacilli (Lactobacillus rhamnosus 19070-2 and L reuteri DSM 12246)
were administered for 6 weeks to 41 children with moderate and severe atopic
dermatitis. Gastrointestinal symptoms were registered before and during treatment
and small intestinal permeability was measured by the lactulose-mannitol test.
RESULTS: During Lactobacillus supplementation, there was a significant decrease
in the frequency of gastrointestinal symptoms (39% during the placebo period versus
10% during active treatment, P=.002). There was a positive association between the
lactulose to mannitol ratio and the severity of the eczema (r=0.61, P=.02 after
placebo and r=0.53, P=.05 after active treatment). After probiotic treatment, the
lactulose to mannitol ratio was lower (0.073) than after placebo (0.110, P=.001).
CONCLUSIONS: Impairment of the intestinal mucosal barrier appears to be
involved in the pathogenesis of atopic dermatitis. The study suggests that
probiotic supplementation may stabilize the intestinal barrier function and
decrease gastrointestinal symptoms in children with atopic dermatitis.
Identify the Initiator
• Poor diet
• Toxins (metals, molds)
• Inadequate digestive enzymes, hypochlorhydria, and
• Imbalanced ecology
• Impaired intestinal permeability
• Altered neuroendocrine balance and autonomic function
The 4R Program for
Remove (the initiator)
Replace (restore proper digestion)
– Stomach acid if necessary
– Pancreatic Enzymes if necessary
Reinoculate (change the gut ecology)
Repair (provide proper nutrition to heal gut tissue)
– Support of mucosal repair (gut nutrition)
Nutrients that InfluenceNutrients that Influence
GUT FunctionGUT Function
• Fermentable fibers (e.g., fruits, vegetables, inulin)Fermentable fibers (e.g., fruits, vegetables, inulin)
• Low allergy protein sourcesLow allergy protein sources
• Specific amino acids (e.g., glutamine)Specific amino acids (e.g., glutamine)
• Specific fractions of ColostrumSpecific fractions of Colostrum
• Plantain extractPlantain extract
• EPA (Fish Oils)EPA (Fish Oils)
• Aloe vera concentrateAloe vera concentrate
• Rosemary fractionsRosemary fractions
• Hop-derived iso-alpha and reduced iso-alpha acidsHop-derived iso-alpha and reduced iso-alpha acids
Hla T. Dietary factors and immunological consequences.Hla T. Dietary factors and immunological consequences.
Science. 2005;309:1682-1683Science. 2005;309:1682-1683..
Verein für Laktoseintoleranz / Die Zeit)
31 August 2008 (last version)
IS MILK GOOD FOR YOU?
Most common food
• Milk and derivates
• Products with yeast (wine, vinegar, breads)
• Tomatoes, eggplants, peppers, potatoes)
• Citrus fruit (oranges, grapefruits,etc)
Arch Dis Child. 1982 October; 57(10): 742–747.
Food intolerance and food allergy in children: a review of 68 cases.
A M Minford, A MacDonald, and J M Littlewood
The clinical and laboratory features of 68 children with food intolerance or food allergy are
reviewed. Young children were affected the most with 79% first experiencing symptoms
before age 1 year. Forty-eight (70%) children presented with gastrointestinal symptoms
(vomiting, diarrhoea, colic, abdominal pain, failure to thrive), 16 (24%) children with skin
manifestations (eczema, urticaria, angioneurotic oedema, other rashes), and 4 (6%) children
with wheeze. Twenty-one children had failed to thrive before diagnosis. A single food (most
commonly cows' milk) was concerned in 28 (41%) cases. Forty (59%) children had multiple
food intolerance or allergy; eggs, cows' milk, and wheat were the most common. Diagnosis
was based on observing the effect of food withdrawal and of subsequent rechallenge.
In many children food withdrawal will mean the use of an elimination diet which
requires careful supervision by a dietician. Laboratory investigations were often
unhelpful in suggesting or confirming the diagnosis.
Elimination diet for 6-8 weeks
• Vegetables and fruit
• Whole grain rice
• Fish (wild)
• Olive oil
Dysregulation of the GI system resulting in
gut hyper-permeability (Leaky Gut) can
have a profound and far reaching impact
on health and disease.