The Post-hunter-gatherer Era Microbes (PHM) Hypothesis
Although the reduction of some microbes is likely important, the PHM hypothesis focuses primarily on the increase in certain microbes, the post-hunter-gatherer era microbes, that might contribute to disease processes. In this section, the PHM hypothesis will be outlined, saving more detailed evaluation and supporting information for later sections.
Post-hunter-gatherer era microbes are microbes that are encountered more frequently and/or at higher levels since the advent of agriculture. Some PHMs are novel, such as mutated strains found in association with newer products/substances or relatively novel conditions. Other microbes are PHMs because human exposure to them has increased due to changing lifestyles (e.g., increases in microbes related to food storage or refrigeration). The third category, the “crowd/virulent” PHMs are the causes of infections that arose after agriculture and cause acute diseases in healthy individuals (e.g., smallpox). The last category will not be discussed further. Here the focus is on PHMs that typically have effects via colonization or less obvious infectious processes.
The microbial communities that humans have been exposed to have changed throughout the millennia as human activities have changed. PHMs were likely added with each advance (e.g., agriculture, the mining of metals). There were presumably selective pressures acting on human populations that led to some degree of toleration of the changing microbiotas. However, the PHM hypothesis proposes that in recent years the microbiota changes have occurred so rapidly that the newer PHMs have caused or contributed to the above-mentioned disease increases.
The human genetic makeup largely evolved during the more than 500 million years during which our ancestors lived as hunter-gatherers or gatherers. The microbial exposures associated with those lifestyles would presumably be the most conducive to optimal human functioning. The PHM hypothesis proposes that humans are increasingly exposed to a novel microbial environment[2]. A subset of these PHMs are proposed to colonize or infect human tissues leading to immune system dysregulation, allergy/hypersensitivity reactions, dysbiosis, chronic stress and CIDs.
Colonization and infection are terms that are used differently by different authors[16]. As used here, colonization will refer to a microbial strain’s existence in some tissues at a low level that typically would not result in microbial abundances and host reactions that would be recognized as an infection. However, according to the PHM hypothesis, these colonizers can sometimes contribute to symptoms and disease processes.
The PHM hypothesis includes an important role for an extension of the toxin hypothesis of allergy. Rather than allergies being a mistake by the immune system, the toxin hypothesis proposes that allergy is an important defense mechanism that protects the host from harmful environmental substances, e.g., venoms and toxins[17,18]. More recent research continues to support this hypothesis[19,20]. It has also been extended to include allergic reactions serving to promote avoidance of certain microbes[21,22]. The PHM hypothesis proposes that the microbes that produce allergic reactions include numerous PHMs.
In addition to causing allergic symptoms, the PHM hypothesis proposes that PHM-associated allergens would also produce a stress response. Thus, the observed stress effects that occur in many CIDs could be at least partly due to stress responses resulting from PHMs and other sources of allergens. Chronic allergen-induced physiological stress could create and exacerbate psychological stress and lead to damaging stress-related and inflammation-related effects.
Cross-reactions play an important role in the PHM hypothesis. The effects of allergic reactions to PHMs would be magnified by cross-reactions with multiple allergens from other microbes, self-tissue or environmental substances. Also, one would expect cross-reactions between the PHMs that have colonized the human body and closely-related microbes in the environment.
Similar to what occurs in most infections, the PHM hypothesis proposes that the locations the microbes colonize largely determine the type and location of the symptoms. For instance, low abundance, hard-to-detect PHMs colonizing the skin might lead to atopic dermatitis.
In addition, in many of these CIDs there is a waxing and waning of symptoms. A major contributor to symptom increases could be explained by increases in exposure to antigens in food and the environment that cross-react with the colonizing PHMs and thus increase inflammation.
There are many means by which immune dysregulation and/or suppression might occur as a result of PHM colonization. For instance, some PHMs might produce substances that dysregulate or suppress the immune system. Also, PHMs that colonize the human body could undergo antigenic changes that increase their survival and reproductive potential. These antigenic changes could also reduce the ability of the immune system to eliminate them. This might be partly because exposure to the cross-reacting environmental PHMs bias the immune system toward responding to the environmental PHMs’ slightly different antigens. This could reduce the accuracy of the immune system’s targeting of the PHMs that have already colonized the tissues. This might be seen as analogous to the situation that can occur in heterologous infections[23] when the immune response to one infecting microbial strain interferes with the response to another microbial strain. However, in this case, one of the strains is found in the environment and is encountered primarily in the mucosa.
Thus, the PHM hypothesis proposes that colonization or infection with a variety of PHMs could lead to various diseases that involve immune hypersensitivity reactions. These reactions may be directed against self-tissues, colonizing PHMs and cross-reacting environmental microbes/antigens that come into contact with the skin and mucosal surfaces. Stress responses and secondary infections often play a role in CID pathogenesis and are proposed to at least partly stem from PHM colonization. Varied genetic susceptibility factors would play a role in determining the type and severity of diseases that develops.
The PHM hypothesis proposes that CIDs might develop in the following way. PHMs from the environment colonize one or more tissues, sometimes after a higher-than-usual environmental exposure (e.g., through a skin or mucosal break and/or disruption). Acute infections, physical/psychological stressors and other factors might serve as additional triggers. Inflammation and barrier breakdown are among the changes that could result. In a proportion of cases, this could be followed by a vicious cycle of increasing PHM colonization, hypersensitivity reactions, increased physiological stress, increasing mucosal barrier breakdowns, secondary infections and tissue damage.
Susceptibility to acute infections that might result from PHM-induced immune dysregulation is part of the PHM hypothesis. The occurrence of repeated acute infections has been reported to be related to the onset or exacerbation of a number of CIDs[2,5,24].
One can postulate alternatives to this hypothesis that might also fit the overall framework presented here. One alternative involves a primary role for hunter-gatherer era microbes (non PHMs alternative). This alternative hypothesis seems less likely since humans would be presumably more adapted to tolerate such microbes and one would not expect the increase in chronic disease rates. However, it might be other factors related to westernization, like the loss of commensal microbes or the increase of xenobiotic exposures that account for a possible increase in susceptibility to non PHMs.
Another alternative is that the implicated microbes do not actually colonize the tissues and instead are just present in the mucus or the gastrointestinal lumen (non colonization alternative). However, most of the other components of the PHM hypothesis might still be applicable to both these alternatives, and thus the overall hypothesis is still relevant. The situation likely varies among diseases and could even involve a mixture of microbes fitting the different alternatives just mentioned.
The idea that PHMs that might contribute to CIDs could be associated with at least some foods/beverages, pollutants and products associated with a westernized lifestyle might appear to be problematic. However, there is increasing recognition of the role of a westernized lifestyle in CIDs[3]. In addition, lifestyle interventions, such as dietary changes that improve disease outcomes and/or symptoms, are gaining support, as will be discussed later. If the PHM hypothesis is validated, a better understanding of the role of PHMs could lead to improvements in interventions, leading to more effective lifestyle and pharmaceutical approaches. Also, the negative effects of PHMs would generally only occur when a trigger occurs that causes the disease process to pass a certain threshold. Lifestyle and pharmaceutical approaches could reduce the PHMs or reduce the consequences of their presence.