Old Friends Hypothesis

The "old friends" hypothesis was proposed by Graham Rook in 2003 as an alternative to or refinement of the hygiene hypothesis, originally brought forward by Strachan in 1989 as an explanation for the rise in allergic disease.

This hypothesis places an emphasis on the vital microbes that have been present throughout human existence as microbiota, tolerated latent infections, or in carrier states.

This differs from exposure to other microbiotic infections that are responsible for causing colds, influenza, measles and similar childhood illnesses.

It is believed that the immune system depends on certain microbes that evolved together with the human organism. Thus their absence may cause abnormal functionality of the immune system.

Shortcomings of the Hygiene Hypothesis

The hygiene hypothesis is unable to explain several factors about the epidemiology of allergic disease. This includes;

  • Allergic asthma is on the rise in "unhygienic"' cities in America.
  • Migrants in some large European cities show a lower incidence of allergic disease than the natives.
  • Airborne virus "crowd infections" are unable to prevent allergic sensitization
  • Inefficiency of probiotics for prevention or treatment.
  • Inconsistency in research findings as to the role played by some viruses in protecting against allergy.

Therefore, the hygiene hypothesis and particular microbial agents that may play a protective role in the prevention of allergic diseases should be reconsidered.

Common childhood illness and infections, many of which are referred to as "crowd infections", that lead to either death or immunization, are not believed to have existed in early human history.

These infections began to surface following the Neolithic agricultural revolution, consequent on the increased population size and density.

The "old friends" hypothesis is currently considered to be the strongest hypothesis to explain the link between bacterial species and the immune system.

"Old Friends"

There are some microbes that are believed to have existed throughout history, with evidence of their having been around in hunter-gatherer times, and thus having been present during the evolution of the human immune system.

The microbes that evolved alongside the mammalian immune system, known as "old friends," are thought to have been intricately involved with the human immune defense development. Thus the human and the microbes depend on each other to function properly.

Rook proposed that these significant microbes include:

  • Ambient species that co-exist in the environment with humans.
  • Species that inhabit the skin, gut, respiratory tract of humans and surrounding animals.
  • Organisms (e.g. viruses and helminthes) that reside in a chronic or carrier state in humans, and can be tolerated by the immune system.

Examples of these may be the mycobacteria that are present in soil, water and food found in the surrounding environment. They are believed to have a transient impact on the human immune system, but an effect that is needed for proper function, nonetheless. Thus, consistent exposure to these, chiefly through oral intake, is a must for immunologic maturity.

Other similarly important pathogens include listeria and salmonella, all of which, like the mycobacteria, cause protective T-helper type 1 responses to occur by interacting with the antigen-presenting cells of the gut mucosa.  

In 2008, Grammatikos expanded this hypothesis to include symbiotic bacteria and parasites as "old friends" that may assist in the function of the immune system.

It has also been suggested that the lack of such beneficial exposures during intrauterine and early neonatal life account for dysfunctional responses to psychosocial stress agents in later life, leading to the development of various psychoses.

Again, the deficiency of these agents in adulthood leads to poor or defective immunoregulation, so that the impact of any stressor produces a magnified response resulting in mental illness.

Genetic polymorphisms, or differences in gene structure and function between individuals, may account for different responses to the same level of exposure, according to several studies of gene linkages in allergic disorders.

Impact of Evolution

More than 90% of mammalian evolution is believed to have taken place in isolated hunter-gatherer and farming communities, in an environment of mud and rotting vegetation.

Given this, the evolution of the human immune system was dependent on the presence of certain microbial exposure, and utilized these organisms to serve a purpose in the protective mechanisms.

Unlike the organisms associated with the original hygiene hypothesis, there is some research to indicate that lactobacilli, saprophytic environment mycobacteria and helminthes were present in vegetation, mud and water throughout the so-called evolution history of humans.

Mechanism of Action

Several different mechanisms have been proposed to explain the action of the "old friends" microorganisms in the prevention of allergic and autoimmune diseases.

One suggestion involves the reciprocal relationship between the "old friends" microbes and the human immune system, which involving the distinct microbial antigens.

These antigens may stimulate stronger immune responses in respect to the weaker autoantigens and allergens associated with autoimmune and allergic diseases.

Alternatively, there may be an effect linked to competition for cytokines, major histocompatibility complex (MHC) receptors and growth factors that are required for an immune response to occur.

Another proposed mechanism of action involves immunoregulatory interactions with the host toll-like receptors (TLRs).


Further Reading

Last Updated: Feb 26, 2019

Yolanda Smith

Written by

Yolanda Smith

Yolanda graduated with a Bachelor of Pharmacy at the University of South Australia and has experience working in both Australia and Italy. She is passionate about how medicine, diet and lifestyle affect our health and enjoys helping people understand this. In her spare time she loves to explore the world and learn about new cultures and languages.


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