Testing the PHM Hypothesis
Fully validating the PHM hypothesis may prove challenging initially,
since some of the microbes may be very low in abundance. In-depth
analyses of the microbiotas of man-made products, xenobiotics, air
pollution and agricultural products is needed. A more thorough
assessment of colonizing microbes is an important goal. This would allow
validation of this hypothesis through determining the sources of
colonizing microbes and their associations with symptoms and
pathogenesis.
Regarding COVID-19, studying the virus-induced effects on immune
reactions to the tissue microbiota would be of interest. The microbiotas
and immune reactions of COVID-19 patients could be compared to healthy
controls and patients with the comorbid conditions who do not have
COVID-19. One might find that those who recovered from COVID-19 more
easily had fewer potential PHMs and/or a lower or more transient immune
reaction to them.
According to the PHM hypothesis, allergies are often due to PHM
colonization. Thus, allergy-suppressing modes of treatment might be
evaluated, as discussed above, to help control excessive inflammation in
COVID-19. Both PHMs and secondary opportunistic pathogens that might be
contributing to the inflammation could be sought and potentially
targeted by antimicrobials or other approaches designed to affect the
microbiota balance. Immune modulation designed to reduce reactions to
PHMs might be appropriate. These approaches also might be investigated
in those who are symptomatic months after COVID-19.
Laboratory studies in animal models have utility in many contexts and
could help evaluate the PHM hypothesis. Animals used in studies that
model diseases would also be affected by PHMs. It would be impossible to
give them the same environmental conditions that they evolved to
tolerate. However, one could vary the degree of exposure to PHMs using
different types of food, water, soil and other exposures.
The effects of dietary interventions on health outcomes in CIDs could be
assessed. The effects of length of time since harvest and other factors
potentially affecting PHMs’ abundances could be analyzed. Ideally, high
resolution assessments of the food and human microbiomes would be
included. Antimicrobial, immune modulatory and microbiota modulatory
approaches could be assessed, alone or in combination with dietary
approaches.
It would be useful to determine if plant microbial antigens cross-react
with plant antigens to the same extent that human-associated microbes
cross-react with human tissue antigens[100]. If they do, it would
lend support to the PHM hypothesis proposal that microbes in food are
involved in allergic diseases and other CIDs. Microbes that cross-react
with particular allergens could then be sought and their relevance in
disease processes investigated.
Many other types of studies could be done to evaluate various aspects of
the PHM hypothesis[2]. For instance, epidemiological studies could
look for associations of disease with PHMs. Experiments could
investigate stress effects of PHM allergen exposure in humans or assess
effects of microbes present in xenobiotics.
With regard to stress, the ability of PHM exposure to affect the
perception and physiological effects of stress could be studied.
Research has shown that food allergic individuals have greater histamine
and tryptase release under cold pain stress[325] and this research
could be expanded to look specifically at PHM colonization effects.
If the PHM hypothesis is correct, then reducing or eliminating PHM
colonization would likely allow toleration of previously
reaction-provoking foods and environmental exposures. This could be
tested if antimicrobials, immunotherapy, probiotics, medications, diet
change or other approaches could be shown to eliminate or reduce
symptoms and the relevant PHMs. However, to be most useful, all relevant
PHMs and opportunistic infections would need to be considered. This
perspective is in accord with the increasing recognition of the
importance of polymicrobial infections[24,54,326,327].