AbstractThis article discusses a variant of the altered microbiota hypothesis, the leading hypothesis to explain the increase in allergic/autoimmune/inflammatory diseases with westernization. Instead of emphasizing the microbes that are missing/reduced due to westernization, this article focuses on those 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 they would be less likely to promote debilitating chronic disease. Post-hunter-gatherer era microbes (PHM) are microbes that are encountered more frequently and/or at higher levels since humans ceased to live as nomadic hunter-gatherers. Research will be discussed that suggests that some PHM suppress/dysregulate the immune system, potentially causing chronic inflammatory diseases and increased vulnerability to severe infections. PHM colonization or infection, hypersensitivity reactions and associated chronic stress could significantly impact multiple diseases. Exploration of this hypothesis might generate insights into pathogenic mechanisms and improved treatment approaches.IntroductionThis article proposes an extension of the altered microbiota hypothesis[1], which is the dominant hypothesis to explain the increase in many chronic inflammatory diseases in the last 75 years in association with westernization. The altered microbiota hypothesis is an updated version of the hygiene hypothesis. The hygiene hypothesis suggested that the recent increase in allergies is due to reduced exposure to pathogens. Instead, the altered microbiota hypothesis proposes that it is primarily a reduction of commensal and environmental microbes that we coevolved with that is responsible for increased rates of chronic inflammatory diseases.The absence/reduction of certain coevolved microbes likely plays an important role; however, this article focuses on microbes that are relatively novel. The category of post-hunter-gatherer era microbes (PHM), as discussed here, comprises microbes that are encountered more frequently and/or at higher levels since the advent of agriculture and permanent settlements.The microbial communities (microbiotas) that humans have been exposed to have changed as human activities have changed. The most intense and rapid changes in these microbiotas likely occurred recently in association with westernization and industrialization. A large proportion of the human genetic makeup evolved during the 200 million years during which humans and their mammalian ancestors lived as hunter-gatherers or gatherers. Microbes commonly encountered in that era would presumably be the most coevolved with the human immune system and would thus tend to cause less disease and/or be beneficial. In contrast, humans are now exposed to many microbes that they did not coevolve with[1]. It is proposed here, in the PHM hypothesis, that some proportion of the less coevolved PHM suppress/dysregulate the immune system, contribute to multiple chronic inflammatory diseases and increase vulnerability to severe outcomes in acute infections through their colonization or infection and accompanying hypersensitivity reactions and chronic stress.Microbes could be considered to be PHM due to being novel, such as mutated strains found in association with newer products/substances or novel conditions[1]. Alternatively, microbial species or strains could be PHM due to being increased by changing lifestyles (e.g., intestinal Candida albicans overgrowth due to factors such as high dietary refined carbohydrates and antibiotics).The PHM hypothesis focuses on the sources of microbes that may contribute to disease and emphasizes microbes’ cross-reactions with varied internal and external antigens. In addition, it integrates the environmental chemical (xenobiotic) hypothesis with the PHM hypothesis by noting the likelihood of PHM being associated with chemicals from certain occupations and air pollution from burning fossil fuels[1]. In addition, it is compatible with the cold chain hypothesis that links Crohn’s disease with cold-tolerant bacteria (e.g., Yersinia spp and Listeria spp) in refrigerated food[2]. PHM are more likely to be present in certain types of food consumed commonly in westernized societies, including refrigerated and ultra-processed foods/beverages[1]. Microbes associated with food additives are also potential sources of PHM (e.g., halophilic Archaea from salt[1,3]).The term westernization, as used here, refers to factors associated with a modern lifestyle that may be associated with health effects. It includes a sedentary lifestyle and increased exposure to xenobiotics/pollutants. New exposures from western medicine, like antibiotics, are also included. The westernized diet typically includes increased consumption of animal products, fat (especially saturated animal-derived fat and vegetable oils), sugar, ultra-processed foods/beverages, salt, and food additives.The role of other hypotheses and mechanistic explanations could be complementary to the role of the PHM or be related to the processes that stem from the effects of the PHM.
 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, includes many microbes that are encountered much more frequently since humans ceased to live as nomadic hunter-gatherers and began living an agricultural or urban lifestyle. The microbial communities (microbiotas) that humans have been exposed to have changed as human activities have changed. It is postulated that the most intense and rapid changes in these microbiotas have occurred in recent decades in association with westernization. Human genetic makeup evolved largely during the 200 million years during which humans and their mammalian ancestors lived as hunter-gatherers or gatherers. It is proposed here that environmental microbes commonly encountered in association with that lifestyle in a pre-agricultural age would be the most coevolved with the human immune system, and thus the immune system would generally respond to these microbes without leading to debilitating chronic disease. In contrast, according to the PHMHEC hypothesis, at least some of the microbes newly encountered or encountered at higher levels during the post-hunter-gatherer era, the PHM, would be more likely to evade the immune system and/or cause hypersensitivity reactions. A mechanism called hypersensitivity-enhanced colonization/infection (HEC) is postulated to be one means by which low abundance microbes cause disease. Microbes sometimes cause hypersensitivity reactions in a manner that increases their virulence, and these reactions could be enhanced by increased exposure to similar or identical microbes in the environment. Slight differences between antigens of environmental and colonizing microbes could make the colonizing microbes even more difficult for the immune system to effectively target. Multiple secondary opportunistic infections resulting from PHM-induced immune dysregulation/suppression could exacerbate disease processes. Vulnerability to more severe acute infections (e.g., severe COVID-19) could also be increased. The long-term colonization/infection of multiple PHM and accompanying hypersensitivity reactions could contribute to physiological and psychological stress and tax the immune system and other systems of the body and be an underlying factor leading to many allergic, autoimmune and chronic inflammatory diseases. The united holobiont disease hypothesis, which is analogous to the united airway disease hypothesis, is discussed, as well as the view that the concept of sterile inflammation needs revision and perhaps should be replaced with “inflammation without apparent infection” (IWAI) in light of the potential role of low abundance microbes. The relationship between the PHMHEC hypothesis and other hypotheses is discussed for a variety of diseases, ending with a discussion of implications for research and treatment.
Abstract 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, includes many microbes that are encountered much more frequently since humans ceased to live as nomadic hunter-gatherers and began living an agricultural or urban lifestyle. The microbial communities (microbiotas) that humans have been exposed to have changed as human activities have changed. It is postulated that the most intense and rapid changes in these microbiotas have occurred in recent decades in association with westernization. Human genetic makeup evolved largely during the 200 million years during which humans and their mammalian ancestors lived as hunter-gatherers or gatherers. It is proposed here that environmental microbes commonly encountered in association with that lifestyle in a pre-agricultural age would be the most coevolved with the human immune system, and thus the immune system would generally respond to these microbes without leading to debilitating chronic disease. In contrast, according to the PHMHEC hypothesis, at least some of the microbes newly encountered or encountered at higher levels during the post-hunter-gatherer era, the PHM, would be more likely to evade the immune system and/or cause hypersensitivity reactions. A mechanism called hypersensitivity-enhanced colonization/infection (HEC) is postulated to be one means by which low abundance microbes cause disease. Microbes sometimes cause hypersensitivity reactions in a manner that increases their virulence, and these reactions could be enhanced by increased exposure to similar or identical microbes in the environment. Slight differences between antigens of environmental and colonizing microbes could make the colonizing microbes even more difficult for the immune system to effectively target. Multiple secondary opportunistic infections resulting from PHM-induced immune dysregulation/suppression could exacerbate disease processes. Vulnerability to more severe acute infections (e.g., severe COVID-19) could also be increased. The long-term colonization/infection of multiple PHM and accompanying hypersensitivity reactions could contribute to physiological and psychological stress and tax the immune system and other systems of the body and be an underlying factor leading to many allergic, autoimmune and related diseases. The united holobiont disease hypothesis, which is analogous to the united airway disease hypothesis, is discussed, as well as the view that the concept of sterile inflammation needs revision and perhaps should be replaced with “inflammation without apparent infection” (IWAI) in light of the potential role of low abundance microbes. The relationship between the PHMHEC hypothesis and other hypotheses is discussed for a variety of diseases, ending with a discussion of implications for research and treatment.Keywords: Autoimmune, Allergy, Hypersensitivity, Microbiota, Hygiene Hypothesis, Cross-Reaction, Occupational Health, Plant-based DietTakeaway pointsMicrobes in food, in the air and on the skin that humans have had greater exposure to since the hunter-gatherer period, especially in the last 75 years, may be contributing to the rise in allergic, autoimmune and related diseases associated with westernization.Allergic and autoimmune diseases could stem from direct negative effects of PHM colonization/infection and/or the immune system’s defensive reactions against PHM antigens that cross-react with food, pollen and other environmental antigens as well as self-antigens. Various treatments may be aiding the elimination of the PHM, e.g., dietary changes, anti-microbial treatments, microbiota manipulation, allergen avoidance, stress reduction methods and allergen-specific immunotherapy.Research into mechanisms and treatments might benefit from investigating the potential role of PHM in light of the PHMHEC hypothesis.
AbstractThe 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 (COVID-19). 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.Keywords: microbiome, COVID-19, Westernized diet, exercise, stress, mast cells, cytokine storm, IL-6, plant-based diet, inflammation, dysbiosisIntroductionResearchers are rapidly gaining knowledge about COVID-19 to help address the current global pandemic, with a focus on treatment and prevention of the spread of the disease[1–3]. This article has two primary aims. The first aim is to examine the characteristics of the disease and the individuals who are most susceptible to severe disease to see if they can help reveal how humans can become less susceptible. A second aim is to explore whether these considerations might suggest treatment approaches that have potential to help at least some of those who are already suffering from severe disease. It is hoped that this review will be able to suggest areas of research that could be helpful in dealing with both the current pandemic and with other similar diseases or future epidemics.The emphasis here will be on the human microbiome and the diet, lifestyle and medical intervention factors that often affect it. This emphasis arises from the increasing research showing the profound impact of the human microbiome on immune function and many aspects of diverse disease processes[4,5]. The human genetic makeup is certainly important; however, the microbiotas inhabiting different parts of the human body are increasingly being shown to be crucial factors. It has been estimated that there are as many bacterial cells in the human body as human cells[6], and numerous microbial metabolites from the microbiome reach the blood stream and are increasingly being investigated[7]. This has led to the human microbiome being called the second genome[8]. One advantage of focusing on this second genome is that studies are showing that it can be altered much more easily than the human genome, apparently with beneficial effects, such as in the treatment of antibiotic-associated diarrhea due to Clostridiodes dificile infection using fecal microbiota transplants[9].The rapid changes in diet, lifestyle, environmental exposures and medical interventions in the last 75 years has led to changes in the human microbiome that may not be optimally compatible with our evolved immune responses to pathogens. This perspective is closely related to the hygiene hypothesis[10] and its newer forms, such as the altered microflora hypothesis[11] and an extension of these earlier hypotheses that focuses on the potentially pathogenic microbes within the post-hunter-gatherer era microbiota (PHM)[12]. Throughout this review, attention will be paid to factors that might lead to the establishment of these potentially pathogenic microbes, which include environmental microbes that are less coevolved with their human hosts and thus could have greater immune suppressing/dysregulating potential.
Abstract 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, includes many microbes that are encountered much more frequently since humans ceased to live as nomadic hunter-gatherers and began living an agricultural or urban lifestyle. The microbial communities (microbiotas) that humans have been exposed to have changed as human activities have changed. It is postulated that the most intense and rapid changes in these microbiotas have occurred in recent decades in association with westernization. Human genetic makeup evolved largely during the 200 million years during which humans and their mammalian ancestors lived as hunter-gatherers or gatherers. It is proposed here that environmental microbes commonly encountered in association with that lifestyle in a pre-agricultural age would be the most coevolved with the human immune system, and thus the immune system would generally respond to these microbes without leading to debilitating chronic disease. In contrast, according to the PHMHEC hypothesis, at least some of the microbes newly encountered or encountered at higher levels during the post-hunter-gatherer era, the PHM, would be more likely to evade the immune system and cause hypersensitivity reactions. A mechanism called hypersensitivity-enhanced colonization/infection (HEC) is postulated to be one means by which low abundance microbes cause disease. Microbes sometimes cause hypersensitivity reactions in a manner that increases their virulence, and these reactions could be enhanced by increased exposure to similar or identical microbes in the environment. Slight differences between antigens of environmental and colonizing microbes could make the colonizing microbes even more difficult for the immune system to effectively target. Multiple secondary opportunistic infections resulting from PHM-induced immunosuppression and/or immune dysregulation could exacerbate disease processes. The long-term colonization/infection of multiple PHM and accompanying hypersensitivity reactions could contribute to physiological and psychological stress and tax the immune system and other systems of the body and be an underlying factor leading to many allergic, autoimmune and related diseases. The united holobiont disease hypothesis, which is analogous to the united airway disease hypothesis, is discussed, as well as the view that the concept of sterile inflammation needs revision and perhaps should be replaced with “inflammation without apparent infection” (IWAI) in light of the potential role of low abundance microbes. The relationship between the PHMHEC hypothesis and other hypotheses is discussed for a variety of diseases, ending with a discussion of implications for research and treatment.Keywords: Autoimmune, Allergy, Hypersensitivity, Microbiota, Hygiene Hypothesis, Cross-Reaction, Occupational Health, Plant-based Diet