Abstract: Amyotrophic lateral sclerosis is a devastating neurodegenerative disease marked by progressive motor neuron degeneration. Despite extensive research, effective treatments remain elusive, underscoring the need to explore the molecular mechanisms driving disease progression. The amyotrophic lateral sclerosis complexity is further compounded by its large heterogeneity, encompassing both genetic and sporadic forms, diverse phenotypic presentations, and highly variable progression rates. A key pathological feature of amyotrophic lateral sclerosis is the aggregation of TAR DNA-binding protein 43, which contributes to cellular toxicity, neuroinflammation, and neuronal dysfunction. This review explores the complex interplay between TAR DNA-binding protein 43 pathology, immunity dysregulation, and the gut-brain axis, with a focus on the role of microbiome-derived metabolites in amyotrophic lateral sclerosis. Neuroinflammation, mediated by both innate and adaptive immunity, plays a central role in disease pathogenesis, with TAR DNA-binding protein 43 influencing immune signaling and exacerbating neurotoxicity. Additionally, disruptions in gut microbiota composition and intestinal barrier integrity, frequently observed in amyotrophic lateral sclerosis patients, suggest a potential role for the gut-brain axis in modulating neurodegenerative processes. By integrating evidence from emerging studies, our aim is to clarify how TAR DNA-binding protein 43 aggregation contributes to neuroinflammation and immune dysfunction while exploring the gut microbiota role as both a modulator and potential biomarker of disease. Understanding these interactions could pave the way for novel therapeutic strategies, including microbiome-targeted interventions such as probiotics, dietary modifications, or immune-modulating therapies. Finally, unraveling the TAR DNA-binding protein 43–immune system–microbiome axis may offer new avenues for personalized treatments aimed at mitigating neuroinflammation, slowing amyotrophic lateral sclerosis progression, and improving patient outcomes and life quality.

Key words: amyotrophic lateral sclerosis, immunity, microbiome, neuroinflammation, short-chain fatty acids, TAR DNA-binding protein 43