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, 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. 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. 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. 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. PHM are more likely to be present in certain types of food consumed commonly in westernized societies, including refrigerated and ultra-processed foods/beverages. 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.