Sex hormones, the gut microbiome, and neurodegenerative diseases: Lifespan perspective

Dec 30, 2025Neural regeneration research

How Sex Hormones and Gut Bacteria Relate to Brain Diseases Across the Lifespan

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Abstract

Disruptions in the gut-brain axis may correlate with the onset and progression of neurodegenerative diseases such as Parkinson's, Alzheimer's, and multiple sclerosis.

Steroid hormones influence gut microbiota composition, intestinal permeability, and immune responses, which can affect brain function and behavior.
Sex-specific differences in steroid hormone levels and immune responses are associated with variations in disease prevalence and symptom severity.
Emerging evidence highlights the hormonal regulation of the gut microbiome as a factor in neuroinflammation and neuronal vulnerability.
Intestinal dysbiosis and impaired intestinal barrier function are significant factors in the pathophysiology of Alzheimer’s disease and multiple sclerosis.
The interactions between hormones and the gut-brain axis require targeted investigation to inform sex-specific therapeutic strategies for neurodegenerative diseases.

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The gut-brain axis represents a highly integrated communication network, connecting the gastrointestinal tract and the central nervous system via neural, immune, endocrine, and metabolic pathways. Steroid hormones, such as estrogens, androgens, and glucocorticoids, play a pivotal role in modulating these interactions across the lifespan. These hormones influence the composition of microbiota, intestinal permeability, and neuroimmune responses, thereby shaping brain function and behavior. Emerging evidence suggests a correlation between disruptions in the gut-brain axis and the onset and progression of neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease, and multiple sclerosis. The diseases exhibit distinct sex-specific patterns in terms of prevalence, symptomatology, and progression. These patterns are often the consequence of differences in steroid hormone levels, receptor distribution, and immune responses. Despite these differences, the role of sex as a biological variable remains underrepresented in experimental and clinical research. This review synthesizes current evidence on how steroid hormones modulate gut-brain axis interactions and how these mechanisms contribute to neurodegeneration in a sex-specific manner. We highlight recent findings on hormonal regulation of the gut microbiome and its impact on neuroinflammation and neuronal vulnerability. This overview focuses not only on Parkinson's disease, in which genetic variations in the gene for brain-derived neurotrophic factor have been observed among others as triggers for dopaminergic neurodegeneration. In addition, Alzheimer's disease and multiple sclerosis are also considered, in which the prevalence of intestinal dysbiosis and impaired intestinal barrier function have been identified as significant influencing factors. This review provides a comprehensive framework for understanding the gender-specific neurobiology of gut-brain axis by integrating perspectives from the fields of endocrinology, neuroimmunology, and microbiome research. It is argued that a targeted investigation of the interactions between hormones and gut-brain axis is essential for the development of sex-specific therapeutic strategies for neurodegenerative diseases.

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Sex hormones, the gut microbiome, and neurodegenerative diseases: Lifespan perspective

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