The "Old Friends" Hypothesis

Modern humans (as all mammals) have co-evolved with different bacteria, viruses and parasites. Until the development of vaccines and hygiene, these organisms lived in the human body in relatively constant amounts, varying between geographical regions and specific events. Infectious diseases were, together with violent deaths and accidents, the main cause of death for primitive humans. Before the development of modern medical practices, most infectious diseases were lethal. Even while this reduced greatly the impact of different pathogens on death rates, infectious diseases are still in the top 10 causes of death in the world (1). 

Mutualism and evolved dependence

Mutualism refers to a type of biological interaction between two organisms in which each individual derives a fitness benefit. Putting it simply, both organisms benefit from the presence of the other. On the other hand, evolved dependence refers to the situation in which two organisms have evolved together, so they have adapted and become dependent on each other for survival and proper functioning. We can quantify this parameter as "the performance difference between the genotype that is adapted to the partner's absence and the genotype that is adapted to its presence, both measured in the absence of the partner"(2). This is illustrated in the following figure (here mutualism is referred as "proximate mutualism/response"):

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If we have this data, we can calculate:

a. The proximate response of the organism to partner removal for individual genotypes: FGp/p - FGp/a (genotype adapted to the partner) and FGa/p - FGa/a (genotype adapted to the absence of the partner).

b. The ultimate response of the organism to removal of the partner: FGp/p - FGa/a. This reflects performance between genotypes. 

c. Evolved dependence: FGa/a - FGp/a (performance difference in the absence of the partner). 

The Old Friends

Paleolithic populations carried several types of organisms as for example, "heirloom species" inherited from their primate ancestors. They would have also been exposed to zoonoses that they picked up during carrion scavenging. In addition, they would have consumed several miligrams of harmless environmental saprophytes daily. Rook has termed these organisms as "pseudocommensals" (or "the Old Friends") (3). The shift to agriculture and husbandry will have had little effect on exposure to "pseudocommensals" or to the heirloom species, but the more sedentary lifestyle increased orofecal transmission and caused prolonged contact with animals. The latter led to adaptation to several animal viruses. However, evolved dependence between humans and neolithic viruses is unlikely, as Rook remarks:

"(...) the viruses acquired during the Neolithic era, such as influenza (B and C), smallpox, mumps and measles, cannot have become endemic until populations were large enough. This required communities of several hundreds of thousands, which did not occur until the appearance of cities 2,000–3,000 years ago. Since this represents only 100–150 generations, extremely strong selection pressure would have been required for evolved dependence to appear, and this seems unlikely. Moreover, most humans did not live in such large groups, and these viruses were, for example, absent from pre-Columbian American populations."

The neolithic transition did not result in loss of exposure to the Old Friends as until the modern era, more than 97% of the population still lived in rural environments, close to mud, animals and feces, which are the sources of these organisms. Since the mid-19th century, as public health measures and antibiotics appeared, the exposure to many of the old friends has been drastically diminished or delayed. 

Evolved dependence between humans and the Old Friends

The main evolutionary principle relevant for the Old Friends Hypothesis is that the presence of the Old Friends would have led to adaptations by the host. Rather than provoking damaging aggresive immune responses, an anti-inflammatory equilibrium is established. If an aggresive and exaggerated immune response is developed, the survival of both the host and parasite would be compromised. 

Applying the concepts mentioned above, evolved dependence implies that a genotype has adapted to the partner. This is the case for human-parasite co-evolution. Accordingly, Fumagalli et al (4) found a high frequency of SNPs in interleukin/interleukin receptor genes in geographical areas with the highest number of endemic helminth species. Additionally, they report that six of nine risk alleles for IBD and celiac disease were significantly correlated with micropathogen richness*. Of all interleukin genes analyzed, most members of the IL-1 signaling pathway correlated with pathogen richness. IL-1A and IL-1B are pleiotropic cytokines that play a central role in immunity and inflammation. Macropathogen richness also correlated strongly with IL4, IL4R and IL10 (Th2 response) and IL19, IL20 (known to induce skin inflammatory responses) SNPs. Finally, SNPs in IL2B, IL15 and IL15RA were correlated with macropathogen richness. IL-2B and IL-RA are part of a trimeric complex which binds IL-15, which has been related to immune protection of gut tissues by stimulating tight junction formation. 

This findings show that pathogens, and more specifically helminths are a major selective force for interleukin genes. The Old Friends modulate dendritic cells (DC) towards Treg, attenuating the immune response. The genetic variants and SNPs shown responsive to helminths suggest that the adaptation to the constitutive presence of these pathogens is reflected by an increase in pro-inflammatory cytokines, so the inflammation equilibrium is achieved. The lack of this background anti-inflammatory stimuli due to absence of pathogens by the modern lifestyle shifts the balance towards excessive inflammation. 

Mutualism and gut flora

Human gut microbiota is the perfect example of mutualism. The composition of gut flora is dynamic, responsive to environmental factors and geographical location. Bacteria are also transmitted between humans and other animals, shaping the composition of microbial communities in populations and families. 

Many attributes that were assumed to be human traits might in fact be the result of human-microbe interactions. Ongoing research is demonstrating the importance of the composition of gut microbial communities for human health. There is more that we dont know than what we know about specific bacteria in the human gut. This is why for example, prebiotics and probiotics (applies to also the so-called "probiotic diets") assumed to be healthy by increasing the population of certain species might not be healthy in the long term, because the effect on other species is not known. This also affects the human gut virome, which is a very recent area of research. Finally, interactions between different pathogens (ie. helminths) with gut microbiota/viruses represent another potential factor for immune regulation. 

* Pathogen richness refers to the number of different pathogen species/genera in a specific geographic location. In the study, micropathogens included bacteria, viruses, fungi and protozoa. Macropathogens included insects, arthropods and helminths, but because parasitic worms were the most abundant class (90% of species/genera), the term basically meant helminths.