Question continued: I am aware of the “hygiene hypothesis” in general, but is there evidence that group exposure is either positive or negative in immune system development? Also, everything I have read on the hygiene hypothesis is basically statistical and correlative. Is there any good research suggesting a direct causal explanation for how different levels or types of exposure affect children’s immune development?
Aside from applicable research, I would also be interested in opinions from people in the field.
Tirumalai Kamala’s answer: Let’s start with that easily misappropriated word, pathogen. Some, not all, microbes are pathogens. After all, microbes and pathogens aren’t synonymous. That now-untenable and always erroneous concept merely resulted from the historical accident that Pasteur and Koch discovered microbes in the context of human diseases. Why untenable and erroneous?
- Developing in utero, we are largely mammalian but by the still largely unfathomed process of immediate post-birth microbial colonization, each one of us is transformed into an ecosystem where microbial cells and their genes outnumber mammalian ones by at least a factor of 10:1.
- To move beyond the obsolete notion of microbes as our enemies, we need to assimilate the fact that each and every one of us who ever existed, exists today, will exist tomorrow was, is and will be part human-part microbe, an idea that challenges our notion of what it means to be human like little else.
Our skin and mucosal surfaces, all profoundly and permanently changed post-birth from mammalian tissues into co-evolved mammalian-microbial ecosystems.
- That’s just the part more easily detected by modern technologies.
- Less tangible are the myriad ways in which microbial colonization affects every aspect of our physiology. Already studies conservatively suggest that up to a third of the metabolic products in our circulatory system is microbial in origin (1, 2, 3).
- A third! And in our circulation, meaning our local microbial inhabitants are endowed with the capacity to influence distant and disparate systems such as cerebrospinal and endocrine, and anything and everything else in between.
- Hygiene hypothesis? Conceived in the 1970s, formulated in the 1980s, its premise was too narrow, how history of infections influenced allergy risk. Our knowledge of the human-microbe ecosystem has moved far beyond its purview, and we need much stronger and more compelling concepts to help instill the change in mindset necessary to unreservedly accept the inherently microbial aspect of our biological identity.
These microbes that become part of us immediately post-birth? Many of them become our lifelong microbial partners through health and disease. Certainly some of them may be pathogens or at the very least opportunists seeking to get more for less, which in the process may cause tangible and even irreversible harm.
- How do our newborn bodies distinguish friend from foe? That’s still largely a mystery. Our understanding of the process by which our newly born bodies incorporate microbes is itself still in its infancy.
- An abundance of correlative data suggests that sequence and dose of our microbial partners, i.e., which species colonize us and in what sequence, sets the stage for proper immune system training.
- So for example, C-sections tend to have long-term consequences such as higher risks for chronic diseases like asthma and IBD. Obviously initial microbes that colonize C-sections are considerably different from those of the natural born*.
- The ‘small world‘ idea (4) underpins this process. Initial species, aka keystone or starter species, colonize first and create a milieu favorable for other specific microbes to colonize. This is how an exquisitely intricate daisy chain of specific microbial species colonizes each of our bodies.
How to tease apart mammalian and microbial strands that evolution has woven together so intimately? That’s how I interpret this question. Some scientists have turned to history to help unravel this co-evolutionary partnership. Let’s zoom in to look at one such co-evolutionary partnership and then zoom out to take in a broader perspective.
Helicobacter pylori, an ancient microbial partner of humans, has much to teach us about human-microbe co-evolution.
- The human is the only known host of H. pylori.
- Precursor of the modern H. pylori likely existed inside human ancestors with evidence of its human association dating thousands of years (5).
- In particular, the specific H. pylori strain, HpAfrica2, has apparently lived peacefully in the stomachs of specific human populations longer than other H. pylori strains (6).
- Detected even in a pre-Colombian Mexican mummy, dating back ~1350AD (7).
- More compelling is its presence among isolated South American tribes (8).
- Once present in almost every adult human stomach, now rapidly disappearing due to breakneck changes in lifestyle and copious antibiotic use.
- The dominant bacterial species in human stomach (9), now found in <10% of children in USA (10).
- That’s enormous demographic change in just a handful of generations. Consequences?
- Losing protection against GERD (gastroesophageal reflux disease) and consequential esophageal carcinoma. How? H. pylori affects gastric-acid secretion (11). As a result, these diseases are rising wherever H.pylori is disappearing from human stomachs (10).
- H. pylori carriage is associated with reduced asthma and allergy, at least in the developed world.
- H. pylori affects gastric hormones leptin and ghrelin, and its disappearance is now also linked to increase in metabolic syndrome, type II diabetes and obesity (12).
- Of course, our H. pylori association isn’t cost-free either, peptic ulcers and adenocarcinomas the price we pay for choosing to engage so intimately with this member of the microbial world. A double-edged sword, though, as this figure (from 10) clearly shows, the benefits of human stomachs harboring H. pylori far outweigh the costs.
- More recent research also warns us against resorting to simplistic binaries of good versus bad, and health versus disease. In Malaysia, the Malay population’s consistently found to have lower H. pylori prevalence compared to ethnic Indian and Chinese. Yet consistently lower percentage of Indians with H. pylori have peptic ulcers compared to Malays (13). Such epidemiological data imply that carriage of H. pylori by Indians somehow protects them against peptic ulcers. Obviously mammalian genetic polymorphisms determine differences in microbial colonizations between ethnicities. Keystone species differences in particular endow differences in adaptive health benefits.
- H. pylori also provides compelling evidence for modern diseases arising from the disruption of ancient partnerships. Two Colombian populations have similar H. pylori carriage but different gastric cancer rates. Difference? The coastal African ancestry communities that tend to harbor ancestral African-type H. pylori strains have lower gastric cancer rates. OTOH, the mountainous mestizo communities with greater European ancestries, whose ancestral Amerindian H. pylori strains had been replaced by European H. pylori strains, have higher gastric cancer rates (14).
- So is H. pylori a human stomach commensal or pathogen? No question H. pylori is associated with peptic ulcers. So the answer should be straightforward, except it isn’t because of the simple fact that more than half the world’s population is estimated to harbor H. pylori yet only a tiny proportion develop diseases that implicate it.
Zoom out, and we could make a similar case for another microbe, Mycobacterium tuberculosis **. Two microbes that we understood until fairly recently to be nothing but harmful pathogens. Now a toss-up, at least among evolutionary biologists, if not yet among clinicians and clinical microbiologists. Environmental microbiologists were always in the know anyway. Clinicians and clinical microbiologists would be as well, if not for the silos that separate specializations. Bacteria like H. pylori, M. tuberculosis, viruses like Hepatitis A, worms such as helminths. The microbiologist, Graham Rook calls them our ‘old friends‘ (15). They co-evolved with us, and our association is not happenstance. Rather it’s essential for proper functioning of our immune system.
OTOH, in the time since we invented agriculture and started living together in ever larger groups, a process that really accelerated with the Industrial Revolution, we have what Graham Rook calls ‘Crowd Infections‘ (17). These microbes don’t train our immune function the same way that our ‘old friends‘ do. However, these are the ones we get exposed to in places like day cares and schools. And recent studies show they don’t really protect us from allergies (16), autoimmunity or IBD (17). Why such difference between our ‘old friends‘ and ‘crowd infections‘? See figure below (from 17) for details.
- We co-evolved with these microbes.
- They persisted among small isolated hunter-gatherer humans.
- Include both harmless (commensal and environmental) and opportunist (can cause infections).
- Can mould human immunity away from pathology, i.e., allergies/autoimmunity/IBD, etc.
- We have lost or are rapidly losing them world-wide.
- We didn’t co-evolve with them.
- Mainly viruses like measles.
- Don’t persist among small isolated hunter-gatherer humans, either kill the human/get KO-ed by strong immunity.
- Need dense human populations of the type that slowly started to develop with agriculture.
- Don’t mould human immunity away from pathology.
Problem is modern living has more or less eliminated ‘old friends‘ from our midst, especially in the developed world. See figure below (from 17) for details on how we did this, largely inadvertently. They include factors such as
- Certain types of sanitation systems that disproportionately eliminate environmental microbes we co-evolved with.
- Diets that contain a lot of processed food.
- Diminished/practically non-existent contact with a variety of animals and plants, essentially nature.
- Dense living in environments that predispose to high circulation of ‘crowd infections‘.
- Wikoff, William R., et al. “Metabolomics analysis reveals large effects of gut microflora on mammalian blood metabolites.” Proceedings of the National Academy of Sciences 106.10 (2009): 3698-3703.
- Swann, Jonathan R., et al. “Systemic gut microbial modulation of bile acid metabolism in host tissue compartments.” Proceedings of the National Academy of Sciences 108.Supplement 1 (2011): 4523-4530. ;
- Nicholson, Jeremy K., et al. “Host-gut microbiota metabolic interactions.” Science 336.6086 (2012): 1262-1267.
- Baquero, Fernando, and César Nombela. “The microbiome as a human organ.” Clinical Microbiology and Infection 18.s4 (2012): 2-4.
- Linz, Bodo, et al. “An African origin for the intimate association between humans and Helicobacter pylori.” Nature 445.7130 (2007): 915-918.
- Moodley, Yoshan, et al. “Age of the association between Helicobacter pylori and man.” PLoS pathog 8.5 (2012): e1002693.
- Castillo-Rojas, Gonzalo, Marco A. Cerbón, and Yolanda López-Vidal. “Presence of Helicobacter pylori in a Mexican pre-Columbian mummy.” BMC microbiology 8.1 (2008): 119.
- Sitaraman, Ramakrishnan. “Allergies, Helicobacter pylori and the continental enigmas.” Name: Frontiers in Microbiology 6 (2015): 578.
- Bik, Elisabeth M., et al. “Molecular analysis of the bacterial microbiota in the human stomach.” Proceedings of the National Academy of Sciences of the United States of America 103.3 (2006): 732-737.
- Blaser, Martin J. “Who are we? Indigenous microbes and the ecology of human diseases.” EMBO reports 7.10 (2006): 956.
- Peek, Richard M., and Martin J. Blaser. “Helicobacter pylori and gastrointestinal tract adenocarcinomas.” Nature Reviews Cancer 2.1 (2002): 28-37.
- Blaser, Martin J., and John C. Atherton. “Helicobacter pylori persistence: biology and disease.” Journal of Clinical Investigation 113.3 (2004): 321.
- Goh, Khean-Lee, and N. Parasakthi. “The racial cohort phenomenon: seroepidemiology of Helicobacter pylori infection in a multiracial South-East Asian country.” European journal of gastroenterology & hepatology 13.2 (2001): 177-183.
- Kodaman, Nuri, et al. “Human and Helicobacter pylori coevolution shapes the risk of gastric disease.” Proceedings of the National Academy of Sciences 111.4 (2014): 1455-1460.
- Rook, G. A. W., and L. R. Brunet. “Microbes, immunoregulation, and the gut.” Gut 54.3 (2005): 317-320.
- Dunder, Teija, et al. “Infections in child day care centers and later development of asthma, allergic rhinitis, and atopic dermatitis: prospective follow-up survey 12 years after controlled randomized hygiene intervention.” Archives of pediatrics & adolescent medicine 161.10 (2007): 972-977.
- Rook, G. A. W., C. L. Raison, and C. A. Lowry. “Microbial ‘old friends’, immunoregulation and socioeconomic status.” Clinical & Experimental Immunology 177.1 (2014): 1-12.