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.
  1. 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.
  2. 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.
  3. 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.
  4. 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.
  5. 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.
  6. 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.
  7. 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.
  8. 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.
  9. 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.
  10. 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.
  11. 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.