Discussion
To briefly summarize, the PHM hypothesis proposes that a subset of
microbes that have increased in our environment due to a
post-hunter-gatherer era lifestyle are able to colonize human tissues
under certain circumstances. This could lead to immune reactions to the
colonizing microbes inside the body and the cross-reacting microbes and
other antigens in the environment and food. PHMs’ cross-reactions with
self-tissue could lead to autoimmunity, especially in genetically
predisposed individuals. Subsequent hypersensitivity reactions, stress
responses and immune dysregulation could promote barrier breakdown and
susceptibility to opportunistic pathogens, exacerbating inflammation
further.
Although much of the research supporting this hypothesis could be
explained by other hypotheses, this is not seen as a drawback. In fact,
the diversity and complexity of the microbial and immune system
interactions means that many other explanations and mechanisms are
likely to be important. These other explanations may often be
complementary to the PHM hypothesis. Many observed mechanistic
explanations might be describing downstream or late-stage consequences
of the effects of PHMs on aspects of microbial communities and human
physiology.
The broad scope, unifying power and consistency with diverse
observations makes this hypothesis worth consideration. This is
especially important because, in many cases, lower abundance PHMs with
patchy distributions will not be detected unless research uses methods
that focus on improving resolution. Examples of attempts to improve
resolution are the focused approach used to assess Yersinia spp
abundance[41], culturomics approaches[25,328] and approaches
arising from methodological advances[329–331].
It is interesting to reflect on mast cells, which are best known for two
types of activities. The historically recognized role of mast cells is
in hypersensitivity reactions. Their more recently understood role is
their part in the defense against numerous pathogens, including
bacteria[332]. IgE, basophils and eosinophils are also involved in
allergy and increasingly being recognized for their roles in fighting
infection by many pathogens, not just parasites[95,333–335]. The
dual role of the other 3 traditionally recognized non-IgE types of
immune hypersensitivity reactions is also known, as they all can be
involved in infections and hypersensitivity[336].
The PHM hypothesis is consistent with the idea that in many cases, these
two roles (anti-infection and hypersensitivity) are really the same. The
main difference, according to the PHM hypothesis, is that in diseases
attributed primarily to hypersensitivity reactions or chronic
inflammation, the causal microbes have not yet been identified and/or
recognized.
Low level colonization may have a disproportionately large effect via
cross-reactions with self-tissue, environmental microbes/substances and
food components. In addition, there may be many PHMs involved, with
additive effects. These features, which could allow low abundance
microbes to have substantial effects, are proposed to be a large part of
the reason that the effects of PHMs have been previously underestimated.
In the case of autoimmune disease, the potential role for cross-reacting
microbes has long been appreciated. This is mainly due to the well-known
example of Streptococcus pyogenes cross-reacting with heart tissue,
which has been associated with tissue destruction in rheumatic heart
disease[35].
In the case of allergy, cross-reactions between inhalants and foods are
widely recognized in the form of oral allergy syndromes[337]. And
there has been a growing appreciation of microbial allergy, as discussed
in previous sections.
The PHM hypothesis posits that many, or possibly most CIDs could stem
from PHM colonization that develops and increases over the years. The
frequency of cross-reactions and diversity of microbial species/strains
suggests that there may be foods, inhalants, self-tissues, colonizing
and environmental microbes involved in a single reaction in some cases.
Although there is much evidence that is consistent with the PHM
hypothesis, there is not enough evidence to validate it. The point of
this article is to bring awareness to the plausibility and explanatory
potential of the PHM hypothesis so that it can be evaluated.
Diverse treatment approaches are worth examining in relation to the PHM
hypothesis, including antimicrobials, immune modulating medications,
allergen specific immunotherapy, probiotics, diet, lifestyle, stress
reduction techniques and altering environmental exposures. Approaches
that have several components might be the most broadly effective, like
combining antimicrobial approaches with diet and lifestyle approaches.
The best approach in each disease would probably vary.
It would be important to distinguish between approaches that eliminate
PHM colonization and those that just reduce reactions to PHMs. If
elimination of PHM colonization is not feasible, other approaches that
mitigate damaging effects might be emphasized.
If the PHM hypothesis is validated, the challenges that would ensue
might not be as difficult as they might seem initially. If the
identities and characteristics of the important PHMs and the immune
responses to them are better understood, then more effective treatment
approaches can be crafted. If the health problems associated with
westernization are microbial in origin, there is likely a wide array of
approaches available due to the power of the immune system, microbiotas
and the treatments that affect them.
In conclusion, the PHM hypothesis proposes that colonization by microbes
associated with a post-hunter-gatherer lifestyle, and especially a
westernized lifestyle, underlie many CIDs. Additionally, immune
hypersensitivities, cross-reactions, stress effects and opportunistic
infections would typically result from PHM colonization and exacerbate
the disease processes.
The PHM hypothesis arguably accounts for more of the basic research and
clinical trial results in varied chronic inflammatory diseases than any
other hypothesis. Given the adaptability of microbes, the changes in
microbial exposures, the selection pressures for more
polyextremotolerant microbes, and the frequency of cross-reactions, it
seems reasonable to test the PHM hypothesis. If validated, it could lead
to reduced morbidity and mortality through treatment approaches that
could also minimize the need for permanent diet/lifestyle changes.