microbiome and type 1 diabetes, etc

the NY Times had a recent story looking at the role of the microbiome (sorry to those microbiome-phobic) in the development of type 1 diabetes (T1D), see http://www.nytimes.com/2016/06/05/opinion/sunday/educate-your-immune-system.html?smprod=nytcore-iphone&smid=nytcore-iphone-share . this article was based on a recent clinical study (see microbiome type1 diabetes cell2016 in dropbox, or doi.org/10.1016/j.chom.2015.01.001).

--33 infants genetically predisposed to T1D through specific HLA alleles, following changes in their gut microbiota frequently

--though microbiota varied greatly between individuals, it remained stable throughout infancy in each individual

--after 3 years, 4 of the children developed T1D

--at the time of T1D diagnosis, there was a marked 25% drop in diversity of the microbiome occurring after anti-islet cell autoantibody development/seroconversion (not found in those who did not seroconvert) but 1 year before clinical T1D, along with spikes in inflammation-favoring organisms, gene functions and serum plus stool metabolites.

commentary:

--initial colonization of the human gut begins in utero, is influenced by microbial exposure at birth, then gets gradual increase in diversity in part related to the introduction of table foods. The microbiome largely stabilizes at approximately 3 years of age

--T1D: an autoimmune disorder resulting from T cell-mediated destruction of insulin-producing pancreatic b-cells. 70% of T1D cases carry HLA high risk alleles for T1D, yet only 3-7% of children with those alleles develop T1D. the incidence of T1D has been increasing rapidly over the past few decades. All of this suggests that there are important non-genetic factors influencing the development of clinical T1D. In Finland, the incidence of T1D is particularly high: 1 in 120 children develop T1D before age 15 (the US is about 1 in 300).

--mouse data show that in those susceptible to T1D, changing the gut microbiota can lead to protection from T1D.

--other studies have found a decreased intestinal microbial diversity in children with long-lasting b-cell autoimmunity, as well as in inflammatory bowel disease and C difficile-associated diarrhea (in mice, decreased diversity is associated with increased in IgE levels and predisposition to immune-mediated disorders).

--the probability of progression to T1D after positivity of 2 islet autoantibodies is >80% after 15-year followup, though there is significant variability as to when this happens. so even though in the above study the microbiome seemed to influence the development of clinical T1D but not the autoantibody seroconversion, it does suggest that the effect of an adverse microbiome is associated at least with earlier development of clinical disease.

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a followup of the above but now larger study looked the "hygiene hypothesis" in general, which posits that early exposure to specific microorganisms/parasites in infancy benefits the development of the immune system, leading to protection from the development of allergic and immunologic disease. This study looked at microbiome changes in North Karelia, Finland, where those from the same genetic pool but living on the Russian side have about 1/5 the development of early-onset autoimmune diseases as the European side, and noting important microbiome changes, which might explain these clinical differences (see microbiome and autoimmune disease finland cell2016 in dropbox, or Vatanen T. Cell 2016; 165: 842). 

--background:

    --several studies have shown that improved sanitation seems to be associated with increased incidence of type 1 diabetes (T1D), multiple sclerosis, and early childhood infections

    --rates of asthma, hayfever and allergic sensitization are decreased in kids growing up on traditional farms

    --mice with their gut colonized by with protective microbiota have decreased risk of autoimmune diabetes and allergies

    --there is a 2- to 6-fold increase in allergies and 5- to 6-fold increase in T1D and other autoimmune disorders in the Finnish vs Russian sides of North Karelia; in nearby Estonia, the incidence of T1D and atopy are transitioning with economic development from rates historically similar to the Russian side to the Finnish side

--the study:

    --approx 1000 infants in the three areas (Russian Karelia, Finnish Karelia, and Estonia) were followed from birth to 3 yo with monthly stool samples, with metagenomic characterization of 785 gut microbial communities. These 3 areas have similar genetic makeup as well as similar climate and latitude.

    --74 kids were selected from each country based on similar HLA risk class distribution and gender, getting monthly stool samples and information on breastfeeding, diet, allergies, infections, family history, etc.

--results:

    --the resident country was the major source of variation of gut microbiome, especially during the first year of life. The diversity of the microbiome overall increased with age. The specific microbiome findings below are corrected for major confounding factors or birth mode, breastfeeding and other dietary factors, antibiotic use and age            

        --the Finnish and Estonian kids harbored more Bacteroides species and enrichment in lipopolysaccharide (LPS) biosynthesis-encoding genes; Russian kids had more Bifidobacterium species (esp B. bifidum)

        --the abundance of Bacteroides correlated with serum insulin autoantibody levels  

        --more lipopolysaccharides (endotoxins) were produced in Finnish and Estonian kids,

        --this LPS differed from that in the Russian kids, which developed almost exclusively from E coli. (And, the Bacteroides LPS inhibits immune stimulation and inflammatory cytokine responses to E coli LPS in human cells.) This Russian-side LPS, unlike that from Bacteroides as in the Finnish and Estonian kids, elicits endotoxin tolerance (further studies in mice of the specific endotoxins found that the LPS from E coli, as in the Russian kids, also increased their immune tolerance and decreased diabetes): ie, different LPS produce different constituents in the human gut microbiome, with either stimulatory or inhibitory activity on components of the immune system (though, of note, the specific LPS differences are quite different in mice and human gut microbiomes) 

        --assessment of T1D anti-b cell autoantibody seropositivity revealed a gradient: 16 in Finland, 14 in Estonia and 4 in Russia

Commentary

--this article and the NY Times commentary reinforce that the microbiome is a major mediator of the environment into human disease. Colonization by different bacteria in the first year of life leads to changes in attendant lipopolysaccharides, which seem to have a direct effect on immune tolerance/susceptibility, and seems to be related to diabetes autoantibody seropositivity (not found in the first study) and potentially to the increased incidence in T1 diabetes in certain areas. One of the important components of this study is that the potential genetic differences between these communities is pretty much mitigated, since they all derive from a common gene pool and only recently had such dramatic differences in environmental exposures.

--again, this type of study reinforces that what seems intuitive: it makes sense that being brought up in a natural environment with natural exposures, as in farming, allows for evolutionary adaptation; recent human changes, which do not allow for evolutionary accommodation, in farming and hygiene have the potential to disrupt the complex interaction between us and nature.

--some unresolved issues: is it just the microbiome? are there undetected viruses which either promote or protect from T1D development? is it when one is exposed to the virus (eg it seems that several diseases such as EBV seem to confer less likelihood of developing MS if the EBV infection happens earlier. same with the clinical results from polio infection). though the very well-controlled mice experiments seem to suggest an important role for the microbiome itself, and the effect of specific bacterial changes.

--this does not mean that modernization has no benefits: Russian Karelia has life expectancy 66.6 years, 13 yrs less than Finns. 

--the hygiene hypothesis does not mean personal cleanliness. It refers to specific environmental exposures. So, eating food off the ground is not necessarily protective....

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The Amish of Indiana and the Hutterites of South Dakota are groups of farmers who emigrated from Europe in the 1700s and 1800s during the Prostestant Reformation, have similar genetic ancestries, but very different prevalences of asthma: the Amish schoolchildren have a prevalence of 5.2% vs 21.3% in the Hutterites; and the prevalence of allergic sensitization is 7.2% vs 33.3%. This is despite similarities in many of the risk factors for asthma, including: large sibship size; high rates of childhood immunization; diets rich in fat, salt and raw milk; low rates of childhood obesity; long duration of breast-feeding; minimal exposure to tobacco and air pollution; and taboos against indoor pets. But they have very different farming styles: the Amish practice traditional farming using horses for fieldwork and transportation, and live on single-family dairy farms; the Hutterites live on large communal industrialized farms. The current study (see asthma allergy in amish vs hutterite nejm2016 in dropbox, or Stein MM. N Engl J Med 2016; 375:411) assessed environmental exposures, genetic ancestry, and immune profiles of 60 Amish and Hutterite children, measuring levels of antigens and endotoxins, and the microbial composition of indoor dust samples. They also looked at the effect of dust extracts from each grouping on the immune and airway responses in a mouse model of experimental allergic asthma. results:

--of the 30 children from each group, mean age 11, 30% girls, 14 sibs, but they found: no asthma in the 30 Amish kids and 6 cases in the Hutterites, similarly much higher allergen-specific IgE  and total serum IgE levels in the Hutterites. No other immunoglobulin differences. Also decreased peripheral eosinophils in the Amish children

--genome-wide SNPs revealed "remarkable genetic similarities" between the 2 groups of children (confirming that these groups are from similar genetic backgrounds)

--median endotoxin levels were 6.8 times as high in the Amish house dust; common allergens (cats, dogs, house dust-mites, cockroaches) were 4 times as high in the Amish homes

--there were profound differences in the microbial composition of mattress dust samples

--there were profound differences in the proportions, phenotypes, and functions of innate immune cells of the 2 groups of kids

--intranasal instillation of dust extracts from Amish but not Hutterite houses significantly inhibited airway hyperreactivity and eosinophilia in the mice

commentary:

--unfortunately they did not assess microbiome changes (both in the gut and in the respiratory tract) in these children. This study does suggest that there are profound effects of the environment (likely related to the differing farming techniques) which translate into quite dramatic differences in immune responses and ultimately into clinical allergic asthma.

--the tie-in with microbiome is a bit opaque (at least translucent) in this article, but was addressed in a Canadian study, which looked at the effect of microbiome changes associated with antibiotic exposure and the development of asthma, along with comments on other studies about T1D, gluten-sensitivity, etc (see prior blog http://gmodestmedblogs.blogspot.com/2015/10/gi-microbiome-in-little-kids-and.html  )

--so, the bottom line: there are pretty clearly very important associations between the human microbiome and an array of disorders (see http://gmodestmedblogs.blogspot.com/search/label/microbiome ); the microbiome is sometimes referred to as the "missing organ", but seems quite susceptible to external/environmental stimuli. Preserving a healthy microbiome relies on a healthy diet and exercise (and reducing the barriers to them...). And there are even some data finding that stress itself leads to changes in the microbiome and conversely that changes in the microbiome lead to changes in how the body reacts to stress through the hypothalamic-pituitary axis  (eg see Gur TL. Front Psychiatry 2015; 6:1, or the whole issue of Science from June 08, 2012, including the article by Nicholson JK. Science. 2012; 336: 1262). So, to me, this issue really does reinforce some of the current initiatives: reducing the use of antibiotics both in humans and especially in farming where farm animals get antibiotics to increase their weight; and increasing a healthier lifestyle with better nutrition, exercise, and decreasing stress (though these last ones are not really getting better....).