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Eric Gershwin M.D. University of California at Davis
Eric Gershwin M.D.University of California at Davis
If I had only known.. sigh
David Strachan Graham Rook
Before I proceed with the exciting graphs and charts, In a nut shell
The hypothesis is-------
It is proposed, there may be less autoimmunity and allergy (as well as other diseases) if we are exposed at an early age to a wide variety of organisms that abound in our surroundings (in basic dirt etc.) in our normal life.
Hygiene Hypothesis
Hygiene Hypothesis
Although proposed in the early 90’s Hygiene Hypothesis is still a work in progress.
Delving into the inner workings of the Hypothesis has proved to be a lot more complicated and controversial that appears on the surface.
Evolution takes Time
Nobody knows the consequences of these actions.
Rate of change of evolution pressures is accelerated.
Most experts think that we have a “body” that would be great if we lived about 5000 years ago..
A lag time may exist between man and modernity.
Our living conditions are a powerful modulator to our immune system…. Let’s look back.
Paleolithic10,000 years ago
Neolithic3000 years ago
Modern
Hunter gathers, nomadic, small groups
Agrarian, domestication, settlements, large groups, sanitation issues
Cities, concrete, soaps/detergents, antibiotics
Diverse exposure to microbes and some worms
Less diverse exposure to microbes and many worms
Little exposure to microbes and no wormsAseptic living conditions!!
Modern Disease and Civilization
There is a strong evidence that the leading disease killers parallel the advance of modern civilization
Similar to this phenomena, Autoimmune Disease is also affected.
Epidemiology evidence
Several studies have shown that living with--pets, large families, rural farm environment (especially farm animals)IS PROTECTIVE
Infections…mycoplasma, tuberculosis and helminthes etc.
IS PROTECTIVE
There is significant increase of allergic diseases in the last 50 years which is paralleled by a decrease in incidence and prevalence of bacterial, viral and parasitic diseases in the same time period.
Migration studies, showing that subjects migrating from a low-incidence to a high-incidence country acquire the immune disorders with a high incidence at the first generation.
Average Family size has been declining.
Over the last couple of centuries, family size has diminished
In most western countries, fertility (birth rate) has declined compared to the 1960’s
Average Family size has been declining.
Over the last couple of centuries, family size has diminished
In most western countries, fertility (birth rate) has declined compared to the 1960’s
We have---
Wall to wall air conditioning
We find antibiotics---- everywhere
The Immune SystemThe Immune system is analogous to a Symphony Orchestra. When coordinated it sounds great… upset the rhythm and ……..
Oh No a Crisis!!!!!
Asthma, Hay fever and Eczema are increasing over the last 50 years
Multiple sclerosis
Crohn’s disease
Type 1 diabetes
Asthma
19501900 2000
400
200
100
Bach JF. N Engl J Med. Sep 2002;347(12):911–920
Incidence of Autoimmune Disease –Epidemic??
There is an ominous upward trend in the average incidence of autoimmunity.
Strachan studied 17000 English children born in one week in 1953 and followed them till age 23. His initial observations was a 2 page paper in 1989. The unexpected results surprised him!
David Strachan
20.4 % of children with no older siblings reported having hay fever.
8.6 % of children with four older sibling reported having hay fever.
6.1 % of children with no older siblings reported eczema.
2.8 % of children with four older sibling reported having eczema.
His conclusion was that young children were exposed to more environmental and infectious challenges from contact with his sibling and most likely tired parents!
① The incidence of inflammatory bowel diseases (IBD), such as Crohn's disease or ulcerative colitis and primary biliary cirrhosis is also rising.
② Part of the increased incidence of these diseases may be attributed to better diagnosis or improved access to medical facilities in economically developed countries.
③ However, this cannot explain the marked increase in immunological disorder prevalence that has occurred over such a short period of time particularly for diseases which can be diagnosed easily, such as T1D or MS.
④ In parallel, there is also an increase in the prevalence of autoimmune diseases such as T1D, which now occurs earlier in life than in the past.
Autoimmune Disease in general is epidemic
Autoimmune disease incidence
Helminthes (worms) infestation
Helminthes Infections
Worms may be a clue explaining the low incidence of inflammatory bowel diseases in Sub-Saharan Africa compared to Americans of African decent
Autoimmunity: The worm returnsJoel V. WeinstockNature 491, 183–185 (08 November 2012)
Auto reactive T cell
Activate regulatory T cells
Regulatory dendritic cells and macrophages prevent the switching on of dangerous effector T cells
Alter the bacterial composition of intestinal flora
X X
X
Helminthes Infections
Autoimmunity: The worm returnsJoel V. WeinstockNature 491, 183–185 (08 November 2012)
Activate regulatory T cells
Regulatory dendritic cells and macrophages prevent the switching on of dangerous effector T cells
Alter the bacterial composition of intestinal flora
X X
X
Helminthes Infections
Asthma
AUTOIMMUNE DISEASE AND INFECTION
Type 1 Diabetes
AUTOIMMUNE DISEASE AND INFECTION
AUTOIMMUNE DISEASE AND INFECTION
TB
Contrast with infectious TB
Gut environment and dietPlant polysaccharides and other phytonutrients
Diverse Bacterial off products
Short chain Fatty acid
Th1 T cells
Treg T cells
Th2 T cellsinhibited
Innate immunity response
Microbial load play an important role in immunoprotection—
depending on the types of microbe
colonization site (skin and mucosal surface)
chronicity
and occurrence in early life.
Naïve T cell
The crucial role of TLR’s
Immune repertoire IS SHAPED by early challenges and diet
Gut environment and dietPlant polysaccharides and other phytonutrients
Diverse Bacterial off products
Short chain Fatty acid
Th1 T cells
Treg T cells
Th2 T cellsinhibited
Innate immunity response
Microbial load play an important role in immunoprotection—
depending on the types of microbe
colonization site (skin and mucosal surface)
chronicity
and occurrence in early life.
Naïve T cell
The crucial role of TLR’s
Immune repertoire IS SHAPED by early challenges and diet
Gut environment and dietPlant polysaccharides and other phytonutrients
Diverse Bacterial off products
Short chain Fatty acid
Th1 T cells
Treg T cells
Th2 T cellsinhibited
Innate immunity response
Microbial load play an important role in immunoprotection—
depending on the types of microbe
colonization site (skin and mucosal surface)
chronicity
and occurrence in early life.
Naïve T cell
The crucial role of TLR’s
Immune repertoire IS SHAPED by early challenges and diet
Gut environment and dietPlant polysaccharides and other phytonutrients
Diverse Bacterial off products
Th1 Cytokines, TGF-β, tolerogenicmessengers
Short chain Fatty acid
Th1 T cells
Treg T cells
Th2 T cellsinhibited
Innate immunity response
Microbial load play an important role in immunoprotection—
depending on the types of microbe
colonization site (skin and mucosal surface)
chronicity
and occurrence in early life.
Naïve T cell
The crucial role of TLR’s
Immune repertoire IS SHAPED by early challenges and diet
Gut environment and dietPlant polysaccharides and other phytonutrients
Diverse Bacterial off products
Th1 Cytokines, TGF-β, tolerogenicmessengers
Short chain Fatty acid
Th1 T cells
Treg T cells
Th2 T cellsinhibited
Innate immunity response
Microbial load play an important role in immunoprotection—
depending on the types of microbe
colonization site (skin and mucosal surface)
chronicity
and occurrence in early life.
Naïve T cell
The crucial role of TLR’s
Immune repertoire IS SHAPED by early challenges and diet
Window of Opportunity
Window of Opportunity
Prenatal influencesDiplacental transfer of:AntigensIgGCytokines &mediatorsImmune cellsOther environmental factors
Early Postnatal influencesIndoor and outdoor environmentFood antigensRespirable antigensMicroorganisms and their componentsGut colonization with commensal bacteria
Epidemiological and immunological evidence for the hygiene hypothesis Holger Garn, , Harald Renz ImmBio. Volume 212, Issue 6, 27 June 2007, Pages 441–452
Tole
ranc
e
Risk of allergy (and other autoimmune diseases)
BirthConception
First months
For thousands of years the human immune system has been developing a relationship with many bacteria and other creatures
• Help metabolize food• Provide nutrients and vitamins• Eliminate bad bugs • AND SHAPE OUR IMMUNE SYSTEM
In this coexistence, we are home for trillions of bacteria.
① There are thousands of different bacterial species, growing in and on us at any given time.
② The composition of this colony changes all the time.
③ All bugs secret chemicals that help in their survival. i.e. antibiotics. The physiological immune modulating implications of these compounds is only now being elucidated.
④ Our immune system has evolved to recognize some these signals and use them to give us an early warning system (innate immune system).
⑤ It is now, thought that early in life, a persistent recognition of bacterial off products and other environmental/diet stimuli (tolerangenic factors) shape our immune system
THE MICROBIOME
A hypothesis was suggested that immune responses elicited by the strong antigens carried by infectious agents compete for consumption of homeostatic factors with the immune responses elicited by weak antigens, such as self-antigens and allergens
IL-7
IL-2
IL-7IL-7
IL-2IL-7
IL-2
Strong Bacterial antigen Weak Self antigen
homeostatic factors
Competition effect for Homeostatic Factors
(Bach 2002). This hypothesis is strong, although as yet there is little experimental evidence to support it.
A hypothesis was suggested that immune responses elicited by the strong antigens carried by infectious agents compete for consumption of homeostatic factors with the immune responses elicited by weak antigens, such as self-antigens and allergens
IL-7
IL-2
IL-7IL-7
IL-2IL-7
IL-2
Strong Bacterial antigen Weak Self antigen
homeostatic factors
Competition effect for Homeostatic Factors
(Bach 2002). This hypothesis is strong, although as yet there is little experimental evidence to support it.
A hypothesis was suggested that immune responses elicited by the strong antigens carried by infectious agents compete for consumption of homeostatic factors with the immune responses elicited by weak antigens, such as self-antigens and allergens
IL-7
IL-2
IL-7IL-7
IL-2IL-7
IL-2
Strong Bacterial antigen Weak Self antigen
homeostatic factors
Competition effect for Homeostatic Factors
(Bach 2002). This hypothesis is strong, although as yet there is little experimental evidence to support it.
A hypothesis was suggested that immune responses elicited by the strong antigens carried by infectious agents compete for consumption of homeostatic factors with the immune responses elicited by weak antigens, such as self-antigens and allergens
Strong Bacterial antigen Weak Self antigen
homeostatic factors
Competition effect for Homeostatic Factors
(Bach 2002). This hypothesis is strong, although as yet there is little experimental evidence to support it.
Bystander suppression
Bacterial antigen
TregAuto reactive T cell
Autoantigen It is a phenomenon by which regulatory cells induced by a given antigen extend their suppression to immune responses against antigens distinct from the ones that induced them.
Bystander suppression
Bacterial antigen
Treg
Autoantigen
X
SUPPRESSIVE CYTOKINES
CTLA4, IL-10- and TGF-β
It is a phenomenon by which regulatory cells induced by a given antigen extend their suppression to immune responses against antigens distinct from the ones that induced them.
SUPPRESSION
Experimental Evidence in Animal Models support the Hygiene Hypothesis
Type 1 diabetes Allergy & Asthma
ColitisMy work in PBC
Worm infection
Type 1 diabetes NOD mice model
Transfer of male microbiome to female pups protected them from getting Type 1 Diabetes.
weeks
Females with female bugs
Females with male bugs
Female controls
Schistosoma mansoni blocked the development of type 1 diabetes. 5 weeks of age.
Cooke, A. et al., 1999. Infection with Schistosomamansoni prevents insulin dependent diabetes mellitus in non-obese diabetic mice. Parasite Immunology 21: 169-176.
Science 1 March 2013: Vol. 339 no. 6123 pp. 1084-1088 Sex Differences in the Gut MicrobiomeDrive Hormone-Dependent Regulation of AutoimmunityJanet G. M. Markle1,2, Daniel N. Frank3, Steven Mortin-Toth1, Charles E. Robertson4, Leah M. Feazel3, Ulrike Rolle-Kampczyk5, Martin von Bergen5,6,7, Kathy D. McCoy8, Andrew J. Macpherson8, Jayne S. Danska1,2,9,*
Overall lung extension, peribronchial and perivascular cellular infiltration, and interstitial edema were the parameters considered for histological scoring
1.) Mice were infected with Salmonella
2.) Immunized with ovalbumin and were repeatedly challenged
A longitudinal study by Pelosi et al has demonstrated reduced frequency and incidence of asthma in children who reported a prior infection with Salmonella.
Similar studies have used different bacteria such as H pylori and bacterial adjuvants with similar results.
Previous Infections Athsma/ allergy
Salmonella infections showed protection
Mice were exposed to eggs of the helminth Schistosoma mansoni and then challenged rectally with trinitrobenzesulfonic acid (TNBS) to induce colitis
Schistosome egg exposure decreased colonic IFN-gamma but increased IL-10 mRNA expression in TNBS-treated mice.
David E. Elliott , Jie Li , Arthur Blum , Ahmed Metwali , Khurram Qadir , Joseph F. Urban Jr., Joel V. WeinstockAmerican Journal of Physiology - Gastrointestinal and Liver PhysiologyPublished 1 March 2003Vol. 284no. 3,
Colitis model and Helminthes eggs
TGF-β dnTGFbetaRII mice.A model for PBC. Anecdotal observation.
Dis
ease
seve
rity
CHINAUCDEAST COAST
In performing experiments to understand the mechanisms of Primary Biliary Cirrhosis using dnTGFbetaRII mice…..
we noticed that our TGF-β mice showed less disease severity and with less AMA autoantibodies compared to our collaborators.
On further inspection, we ruled out many technical and observational factors.
The mice were genetically identical, same diet with the only differences were the housing facilities.
Infant gut microbiota and the hygiene hypothesis of allergic disease: impact of household pets and siblings on microbiota composition and diversity
Gut microbiome changes
Infant gut microbiota and the hygiene hypothesis of allergic disease: impact of household pets and siblings on microbiota composition and diversity
Start to get more diversity with more exposure
Gut microbiome changes
Low gut diversity is associated with later Asthma
Yes = develops Asthma by age 7
De Filippo C et al. PNAS 2010;107:14691-14696
Diet difference in gut Microbiome from children in Italy and that from rural Sub-Saharan Africa
Italy
Africa
De Filippo C et al. PNAS 2010;107:14691-14696
Diet difference in gut Microbiome from children in Italy and that from rural Sub-Saharan Africa
Helminth TherapyUse of ProbioticsDiet TherapyPreventive Therapy
Therapy
Paleodiet
As of now, no hygiene-related treatments are part of the standard of care
Diet
① Reintroducing a varied diet with less processed food will generally produce a more diverse microbiome.
② This will help in preventing most deficiencies (zinc, vitamin D etc.) that have been proven to cause immune effects.
③ Secondly, a healthy intestine and colon (where a majority of immune cells reside) will provide a correct environment for homeostasis.
④ However, certain autoimmune diseases (type 1 diabetes, celiac disease, IBD etc) with accompanied medications will affect the diet, eating habits and the microbiome, so extra care must be factored when trying to modify those individuals diets.
One thing most people in the autoimmunity field agree on is that there’s a lack of evidence-based information about dietary treatments for autoimmune diseases.
Probiotics Probiotics are microorganisms that provide health benefits when consumed.
Many studies have been performed showing some minorimprovement in a variety of afflictions especially diarrhea.Probiotic therapy may also help people with Crohn’s disease and irritable bowel syndrome. However, clinical trial results are mixed.
Problem is knowing what is the deficiency in the patient group and what specific probiotic(s) can be used to correct it. In most cases it is a guessing game.
There is a problem with what species to give, the standardization, dosage and length of treatment. There is usually no requirement to demonstrate safety, purity, or potency before marketing OTC probiotics.
Caution in the use of probiotics should be advised when administered to infants and immune compromised patients.
Many studies are now being conducted and new techniques elucidating patients microbiome will help answer critical questions.
Helminth Therapy
Some clinical trials for MS and IBD using Trichurasuis ova or Necator americanus larvae are being conducted for safety and efficacy.
No conclusions can be drawn at this time as to the effectiveness of these treatments.
The cross over from animal studies (which are very promising) to human therapy will take time and some massaging of the techniques
The hope is to provide remission that is related to the modulating the autoimmune response and allergic inflammatory responses.
Lifestyle changes could increase microbial exposure, but whether this on balance improves the balance of risks remains the subject of research.
Proposals include----Natural childbirth,
Sustained breast feeding
Physical interaction between siblings/other children
Spend more time in "uncleaned" outdoor environments. Yes get dirty…..
Preventive therapy
The providing live infectious agents is a possibility, especially in the case of probiotics. ( But its effectiveness is still unclear)
Deaths from infectious diseases are on the declineInfant mortality is slowly declining.Humans are living longer
Today’s Ethics
So why mess with the current system?
The administration of pathogenic infectious agents or agents suspected of developing into pathogens is harder to imagine. (However, we vaccinate with live pathogens in some cases)
As we understand the Hygiene Hypothesis, perhaps in the future we could see the development of therapies that mimic the beneficial effects of “infection”, encouraging early exposure of infants to a “standard” disease-preventing collection of germ mimics and naturally letting children play in dirt.
The providing live infectious agents is a possibility, especially in the case of probiotics. ( But its effectiveness is still unclear)
Deaths from infectious diseases are on the declineInfant mortality is slowly declining.Humans are living longer
Today’s Ethics
So why mess with the current system?
The administration of pathogenic infectious agents or agents suspected of developing into pathogens is harder to imagine. (However, we vaccinate with live pathogens in some cases)
