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.