Vitamin D research is discussed in light of the hypothesis that the lower average levels of vitamin D frequently observed in autoimmune disease are not a sign of deficiency. Instead, it is proposed that the lower levels result from chronic infection with intracellular bacteria that dysregulate vitamin D metabolism by causing vitamin D receptor (VDR) dysfunction within phagocytes. The VDR dysfunction causes a decline in innate immune function that causes susceptibility to additional infections that contribute to disease progression. Evidence has been accumulating that indicates that a number of autoimmune diseases can be reversed by gradually restoring VDR function with the VDR agonist olmesartan and subinhibitory dosages of certain bacteriostatic antibiotics. Diseases showing favorable responses to treatment so far include systemic lupus erythematosis, rheumatoid arthritis, scleroderma, sarcoidosis, Sjogren's syndrome, autoimmune thyroid disease, psoriasis, ankylosing spondylitis, Reiter's syndrome, type I and II diabetes mellitus, and uveitis. Disease reversal using this approach requires limitation of vitamin D in order to avoid contributing to dysfunction of nuclear receptors and subsequent negative consequences for immune and endocrine function. Immunopathological reactions accompanying bacterial cell death require a gradual elimination of pathogens over several years. Practical and theoretical implications are discussed, along with the compatibility of this model with current research.

Diverse hypotheses exist to explain allergic and autoimmune diseases. There are 3 factors common to most, if not all, of these diseases: 1. Microbial imbalances, microbial triggers and/or infections, 2. Allergy/hypersensitivity to food and/or environmental substances and 3. Stress. The post-hunter-gatherer era microbe hypersensitivity-enhanced colonization/infection (PHMHEC) hypothesis presented here proposes that these factors are part of a phenomenon that involves an extension of the altered microbiota hypothesis, which is the current leading hypothesis to explain the increase in allergic and autoimmune diseases in the last 75 years in association with westernization. The category of post-hunter-gatherer era microbes (PHM), as defined here,

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The human microbiome, especially the microbiomes of the gastrointestinal and respiratory tracts, are potentially important in determining susceptibility to COVID-19 and the immunopathology that leads to severe disease. Data is beginning to be gathered on the risk factors for severe disease in the coronavirus disease of 2019 . This data will be discussed in connection with some highlights of what is being learned about the human microbiome and its relationship with viral illnesses and inflammation-related chronic diseases. In particular, possible roles for diet, lifestyle, and microbiota manipulation as means of reducing rates of severe viral disease will be explored. Some potential pharmaceutical approaches to treating severe COVID-19 disease, involving the microbiome, mast cells and hypersensitivity responses, are also discussed. It is proposed that chronic low-grade infections and/or dysbiosis may underlie the age-related diseases that are risk factors for severe disease from SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2). It is also suggested that the connection between these chronic diseases and COVID-19 may have implications for understanding some of the reasons for the severity of COVID-19 in a proportion of patients. Whether or not the hypothesis of a causal role for dysbiosis or prior infection is correct, some of the suggested treatment approaches might still be worth investigating.

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.