This article proposes an extension of the hygiene hypothesis to explain
chronic inflammatory diseases (CIDs) and their increase with
westernization. Instead of emphasizing microbes that are missing/reduced
due to westernization, a hypothesis is proposed that emphasizes the
importance of microbes that are relatively novel. Environmental microbes
encountered in association with a pre-agricultural lifestyle would
presumably be the most coevolved with the human immune system and thus
less likely to promote chronic disease. Post-hunter-gatherer era
microbes (PHMs) are microbes that are encountered more frequently and/or
at higher levels since humans ceased to live as nomadic
hunter-gatherers. It is hypothesized that some PHMs, particularly those
increasing with westernization, colonize human tissues and
dysregulate/suppress the immune system. This hypothesized colonization
of PHMs could cause allergy/hypersensitivity reactions leading to
physiological stress, attacks on self-tissue, hypersensitivity reactions
to similar cross-reacting environmental microbes and other
allergens/antigens, greater vulnerability to diverse infections (e.g.,
COVID-19) and CIDs. Low-level colonization with diverse PHMs could
explain high levels of comorbidities among CIDs, allergic responses to
self-tissue (auto allergy), allergies to varied microbial taxa and
allergen-initiated stress effects. Allergic reactions and the stress
they cause might be adaptive by promoting expulsion and avoidance of
potentially dangerous microbes. This is consistent with the observation
that selective IgE deficiency leads to increased levels of diseases such
as asthma, chronic rhinosinusitis, otitis media and autoimmune disease.
PHMs that could be related to CIDs include microbes in tobacco smoke,
increased Candida albicans and Aspergillus fumigatus that occurs in some
situations, and increased exposure to Pseudomonas fluorescens and
Yersinia spp. Additionally, fungi that tolerate multiple extreme
environments have been found to be more likely to be opportunistic
pathogens. This might suggest that microbes associated with
human-created novel and extreme environments (e.g., antibiotics,
xenobiotics) would have an increased ability to colonize and persist in
humans. The PHM hypothesis could help explain contradictory findings on
diet, why many chronic inflammatory diseases resemble chronic infections
and why stress and xenobiotics are associated with CID incidence and
exacerbations. Four foundations and 11 related hypotheses are discussed.
Examples discussed include sarcoidosis, inflammatory bowel disease,
asthma, long-term COVID-19 and Kawasaki disease.