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].