**4. Determinants of individual sensitivity of brain-gut axis and gut microbiome to environmental toxins; intrinsic and extrinsic components**

Studies of the human microbiome revealed that even healthy individuals differ remarkably in the microbes of the gut. The gut microbiome is regulated by both extrinsic and intrinsic factors. While much of this biodiversity remains unexplained, extrinsic factors such as diet, environ‐ ment, and early microbial exposure, and the intrinsic factors such as host genetics have been implicated (Human Microbiome Project Consortium, 2012); our own studies (Sulkowski et al., 2012) suggest that sex may play an important role. Diet-derived carbohydrates that are not fully digested in the upper gut are metabolized by bacteria in the human large intestine. These nondigestable carbohydrates influence microbial fermentation and total bacterial number in the colon. Human milk, unlike milk of other mammalian species, contains high amounts of oligosaccharides of yet unknown function, but one can speculate that dietary oligosaccharides may play an important function in the development of the microbiome in human neonates. Evidence exists that the amount and type of nondigestable carbohydrates influence the species composition of the intestinal microbiome. Individual variation in the gut microbiome may, in part reflect differences in dietary intake, but the response of the gut microbiome to dietary change can also differ among individuals (Flint, 2012)

Furthermore, an outcome of the exposure to infectious microbes or their toxins is also influ‐ enced by both microbial and host genes. Some host genes encode defense mechanisms, whereas others assist pathogen function. Extensive human diversity in cell lethality dependent on toxin binding and uptake has been observed (Martchenko et al., 2012). Furthermore, there is evidence that individuals may evolve their own specific microbiome (Clayton, 2012).

Results of our recent animal studies (Sulkowski et al, 2012; Khan et al, 2012, Xu et al, submitted; see also Fig. 2) indicate that the sensitivity of the developing CNS to both environmental toxins and infection, are both sex- and rat strain-dependent. It can be extrapolated that the sensitivity of the human microbiome is also sex-dependent. Because of this individual variability in host response it is not surprising that the results of human postmortem studies of ASD brains are difficult to interpret.
