4 Autism Research and Treatment Genetics, epigenetics, “triggers” Allergy, autoimmunity, chronic inﬂammation Risk of cognitive dysfunction Postindustrial culture toilets, water treatment, modern medicine Indoor work, soap, Exercise not shampoo, bathing essential for survival Biome depletion Vitamin D deﬁciency Uncontrolled stress Immune hypersensitivity and/or destabilization Metabolic dysfunction, toxicity issues, oxidative stress Alteration of transport and Phase I/Phase II metabolism A wide range of demands on transport and Phase I/Phase II metabolism Pretherapeutic zone Optimal therapeutic zone Postoptimal therapeutic zone Figure 1: The pathogenesis of epidemics of allergic, inﬂammatory, and autoimmune disease. Cultural mismatches with human biology (the pretherapeutic zone) have consequences that can be readily avoided (the optimal therapeutic zone). If biome depletion in particular is not avoided, the individual is left susceptible to a wide range of often complex immune-related diseases (the postoptimal therapeutic zone), sometimes associated with imbalances in metabolite transport and/or Phase I/Phase II metabolism. Other consequences such as vitamin D deﬁciency and uncontrolled stress may, in some but not all cases, add to the problem. Factors contributing to disease which are often naturally occurring and generally diﬃcult or impossible to avoid are underlined and ﬁt within the postoptimal therapeutic zone. (iv) Addition of helminths to humans cures inﬂamma- tory bowel disease [48] and stops the progression of multiple sclerosis [49]. (v) The eﬀects of biome depletion on the immune system are not necessarily instantaneous because long-term eﬀects of immune interactions with the biome can span decades or, through epigenetics, even generations [1]. Nevertheless, the epidemiology of hyperimmune disease reveals an inverse correlation between helminths and disease. (vi) Humans with helminths and rodents colonized with helminths have profoundly less reactive immune sys- tems than do either without helminths [44, 50, 51]. (vii) A long coevolutionary history of helminths and ver- tebrates, in conjunction with the potent immunoreg- ulatory eﬀects of the former, is consistent with the idea that the human immune system is literally, physically dependent on helminths [1]. We propose that biome depletion is changing the immune system at a population-wide level, which in turn will undoubtedly impact the brain, particularly dur- ing sensitive periods of development. Importantly, this model does not compete with any prior hypotheses or known risk factors for neuroinﬂammatory conditions, but rather complements them. For instance, biome deple- tion may set the stage for exaggerated levels of neu- roinﬂammation, which interacts with other known risk factors or triggers (psychological or metabolic stress, infection, genetics or epigenetics) in the induction of autism. 8. Mismatches between Normal Human Genetics and Post-Industrial Culture Leading to Hyperimmune Epidemics: Vitamin D Deﬁciency Based on the available information outlined above, it seems very likely that biome depletion is by far the most signiﬁcant and most profoundly inﬂuential consequence of genetic/cultural mismatches in postindustrial society. However, other consequences which apparently exacerbate the eﬀects of biome depletion are evident. For example, vitamin D deﬁciency has reached epidemic proportions in postindustrial society, is known to impact inﬂammation during early development [52], and, like biome depletion, has been linked to a spectrum of allergic, autoimmune, and inﬂammatory diseases [53–55]. Further, epidemiology and other circumstantial evidence link vitamin D deﬁciency to autism [56, 57]. Interestingly, the widely publicized asso- ciation between rainfall and autism [58] can be accounted for, perhaps more than in part, by decreased exposure to sunshine in areas with high rainfall, and the subsequent impact of lower vitamin D levels. Vitamin D deﬁciency is another consequence of postindustrial culture’s mismatches with human biology (Figure 1). Vitamin D production requires exposure of oils on the body’s surface to sunlight. The resulting photochem- ical reaction and production of vitamin D is greatly reduced