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.