Foundations of the PHM hypothesis and comparison with other
hypotheses
Four foundational ideas or observations are addressed briefly in this
section. They are not novel, but it is proposed that they imply that the
PHM hypothesis is a plausible explanation that might have been missed
due to methodological limitations.
The first foundation is that a large proportion of species/strains
remain uncharacterized. A low level of colonization, particularly in a
limited area of the body, could easily be missed by current methods. The
situation has been depicted as an iceberg, with the bulk of
species/strains hidden from view[25]. This is in accord with
ecological research that finds that in most ecosystems, there are many
rare species[26,27], usually with patchy distributions[28]. And
it is now recognized that differences between strains of species can be
of crucial importance[29,30]. Thus, the relevant uncharacterized
microbial diversity is likely very large.
The second foundation is that low abundance species or strains could be
important. The low abundance oral bacteria Poryphoromonas gingivalis can
produce a toxin that affects immune function and has been implicated in
many diseases[31,32]. Hypersensitivity and cross-reactions are
additional reasons that low abundance species/strains could be
important. The additive effects of multiple colonizing species could
also increase their effect.
The third foundation is that environmental microbes have the potential
to be a significant component of the microbiota of humans[33]. Thus,
environmental microbes might comprise a significant subset of the
undetected rare species/strains likely present in humans.
The fourth foundation is that changing human activities have led to
humans being exposed to many microbial species/strains that they would
not have been exposed to at significant levels until recently. The
selective pressures from extreme conditions that human activities create
for microbes (e.g., cleaning solutions, antimicrobials, toxic chemicals,
food processing procedures, industrial pollution) could lead to an
increase in novel microbial taxa. These novel microbes would often
tolerate diverse and extreme conditions, which might include conditions
present in the human body. For instance, it has been found that fungi
that tolerate multiple types of extreme environments
(polyextremotolerant) are more likely to be opportunistic
pathogens[34].
Thus, these foundational ideas and findings in microbiology and ecology
suggest that there are far more novel PHMs inhabiting the human body
than has been recognized. They support the plausibility of the
hypothesis that relatively low virulence, low abundance PHMs might play
a significant role in CIDs.
Part of the usefulness of the PHM hypothesis is that it brings together
multiple hypotheses and observations in a way that could explain common
features of many CIDs. Some of the similarities and differences between
the PHM hypothesis and 11 related categories of hypotheses follow.
- The hygiene hypothesis[12] and altered microbiota
hypothesis[13–15] focus on the absence/reduction of microbes as
the cause of microbiota imbalances leading to disease. Although
sharing the emphasis on changes in microbial communities, the PHM
hypothesis focuses on microbes that are increased in association with
a post-hunter-gatherer lifestyle.
- The molecular mimicry hypothesis posits a cross-reaction between an
infectious agent and self-tissue as a cause of autoimmune disease.
Root-Bernstein et al[35] discusses this hypothesis and suggests
that the need for multiple exposures to pathogens or environmental
factors could explain why frequent microbial cross-reactions with
self-tissue only occasionally lead to autoimmune disease. The PHM
hypothesis also includes a role for molecular mimicry and the likely
involvement of multiple disease agents. In the PHM hypothesis, PHMs
and opportunistic pathogens that take advantage of an immune system
dysregulated by PHMs are implicated.
- The xenobiotic causation hypothesis[4] focuses on the role of
pollution and novel environmental substances in causing CIDs. The PHM
hypothesis proposes that xenobiotic-associated PHMs that colonize an
affected organ or tissue could be the primary trigger for disease in
at least some cases. Alternatively, one or more PHMs may exacerbate
the effects of the xenobiotic.
- The macronutrient emphasis of microbiome research focuses on high
sugar, high fat and low fiber diet effects on the microbiome[3].
Changes in levels of these macronutrients leading to changes in immune
function, dysbiosis, intestinal permeability and microbial
translocation are being observed[36,37]. The PHM hypothesis
includes the macronutrient role, but emphasizes how macronutrients
might affect the abundance of PHMs. The PHM hypothesis also posits
that low abundance PHMs in certain foods/beverages and inhalants
contribute to and may initiate inflammation and the resulting
dysbiosis and intestinal permeability.
- The toxin hypothesis of allergy proposes that allergic reactions occur
as a defensive response against toxins in the environment[17,18].
The PHM hypothesis includes this view of allergy but also includes
PHMs as instigators of defensive allergic reactions and proposes an
important role for PHM colonization of human tissues.
- Psychological stress has been proposed to play an important role in
the development and exacerbation of CIDs[9,38], and the PHM
hypothesis includes this. However, allergy/hypersensitivity to
microbes and other allergens is seen as a crucial and generally
overlooked source of physiological stress that can initiate or
exacerbate psychological stress.
- Hypotheses regarding chronic infection as a cause of CIDs, such as
asthma, chronic rhinosinusitis, inflammatory bowel disease and some
autoimmune diseases have been proposed[2,39,40]. The PHM
hypothesis posits that low abundance PHMs are often the cause of
immune dysregulation and/or suppression leading to the more overt
opportunistic pathogens’ increase. The observed opportunistic
pathogens may or may not be PHMs as well.
- Infection by a microbe that also involves hypersensitivity to that
microbe is not new (e.g., allergic bronchopulmonary aspergillosis,
severe asthma with fungal sensitization). The PHM hypothesis proposes
that this concept is applicable to many CIDs, but low levels of the
microbes involved are limiting their detection.
- Focal infection theory proposed that infection in one part of the body
is sometimes related to chronic disease processes in another part of
the body. The earlier view was that bacterial allergy was often
involved in symptom causation[2]. The PHM hypothesis is similar;
however, it also proposes that the microbes that are the underlying
cause are related to the post-hunter-gatherer lifestyle, and that
allergy-related stress, cross-reactions with self-tissues and
inhaled/ingested antigens are often involved.
- Daschner[22] proposed an evolution-based hypothesis for symptoms
related to fungi in damp buildings, viewing symptoms as a means of
causing avoidance of infection with fungi. The PHM hypothesis is
similar but broader, including non-fungal microbes as well as other
components, such as a primary role for microbial colonization and
relatively novel species/strains.
- A role for novel microbial exposures has been proposed in some
hypotheses. The cold chain hypothesis links Crohn’s disease to
microbes that survive well in refrigerated food[6,41]. The PHM
hypothesis includes this hypothesis in that consumption of
refrigerated food that likely contains PHMs would be a part of a
post-hunter-gatherer lifestyle. Other hypotheses that implicate human
microbiota effects from novel sources of microbes[42,43],
xenobiotics[42] and westernization-related variants of the normal
microbiota[44] also have some features in common with the PHM
hypothesis.
To summarize, the PHM hypothesis builds upon previous observations,
ideas and hypotheses. The hypothesis is consistent with much published
data, makes predictions that are testable, and could potentially lead to
clinical advances.