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This review attempts to provide some mechanistic insight (Figures 1–3) into how the bi-directional network between the gut microbiota and the brain can not only protect but also trigger and aid chronic gut inflammation, promote a global pro-inflammatory state, modify and contribute to protein misfolding processes, dysregulate the autophagic-lysosomal protein clearance mechanism, differentiate T-cell subsets to facilitate a deleterious autoimmune response, and finally modulate immune recruitment and BBB status