NOD-like receptor pyrin domain-containing protein 3 inflammasome activation in microbiota-induced neuroinflammation: Relevance to autism and stress disorders

Abstract

The gut–brain axis has evolved into a bidirectional neuroimmune communication network linking microbial ecology, innate immunity, endocrine signaling, and central nervous system function. The NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome is a key cytosolic sensor that converts signals from microbes into pro-inflammatory pathways. Growing evidence shows that changes in microbial metabolites, intestinal permeability, and systemic immune activation caused by dysbiosis all lead to NLRP3 inflammasome signaling in microglia, astrocytes, and neurons. This neuroinflammatory response mediated by the inflammasome has been progressively associated with the pathophysiology of autism spectrum disorder (ASD) and stress-related neuropsychiatric diseases, such as anxiety and post-traumatic stress disorder. Gut microbial disturbances facilitate peripheral cytokine release, compromise the blood–brain barrier, induce mitochondrial stress, and generate reactive oxygen species—all of which are crucial upstream activators of NLRP3. The development of interleukin (IL)-1β and IL-18, which depends on inflammasomes, worsens synaptic plasticity, neurotransmitter balance, and control of the hypothalamic–pituitary–adrenal axis. In this review, we integrate novel mechanistic findings that link gut microbiota dysregulation to NLRP3-mediated neuroinflammation, clarify its involvement in ASD and stress susceptibility, and examine treatment approaches targeting microbial modulation and inflammasome suppression. Comprehending this immunometabolic axis may facilitate targeted neuroimmune therapies for neurodevelopmental and stress-related diseases.