Hypothesis of the Causal Mechanisms Between Gut Microbiota and Neurodegenerative Diseases: An Elucidation from Evolutionary Perspective and Metabolic Consideration

Tang, Guangyan; Guo, Liwen; Liu, Zhiwei; Quan, Yuan

doi:10.3390/metabo16050337

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Hypothesis of the Causal Mechanisms Between Gut Microbiota and Neurodegenerative Diseases: An Elucidation from Evolutionary Perspective and Metabolic Consideration

Hubei Key Laboratory of Agricultural Bioinformatics, College of Informatics, Huazhong Agricultural University, Wuhan 430070, China

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Metabolites 2026, 16(5), 337; https://doi.org/10.3390/metabo16050337

Submission received: 24 April 2026 / Revised: 13 May 2026 / Accepted: 15 May 2026 / Published: 18 May 2026

(This article belongs to the Section Bioinformatics and Data Analysis)

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Abstract

Growing evidence links gut microbiota dysbiosis to neurodegenerative diseases (NDs) such as Alzheimer’s disease and Parkinson’s disease, yet the field remains dominated by correlational observations rather than experimentally validated causal mechanisms. In this hypothesis-generating Perspective, we propose that causal inference in microbiota-associated neurodegeneration may be strengthened by combining two complementary lenses: evolutionary biomedicine and microbial metabolism. Because evolutionary information carries intrinsic temporal and causal structure, it can provide biological prior knowledge for inferring causal mechanisms of diseases. Human Accelerated Regions (HARs), genomic loci conserved across mammals but rapidly divergent in the human lineage, offer an anchor for identifying human-specific host–microbe co-evolutionary units relevant to NDs. We further hypothesize that microbial metabolites represent one class of mechanistically testable intermediates linking host genetic background, gut microbial ecology, and neurodegenerative phenotypes. This integrated evolutionary-metabolic perspective offers a tractable path from correlation toward mechanism in gut microbiota–ND research.

Keywords: gut microbiota; neurodegenerative diseases; human accelerated regions; metabolites; causality

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MDPI and ACS Style

Tang, G.; Guo, L.; Liu, Z.; Quan, Y. Hypothesis of the Causal Mechanisms Between Gut Microbiota and Neurodegenerative Diseases: An Elucidation from Evolutionary Perspective and Metabolic Consideration. Metabolites 2026, 16, 337. https://doi.org/10.3390/metabo16050337

AMA Style

Tang G, Guo L, Liu Z, Quan Y. Hypothesis of the Causal Mechanisms Between Gut Microbiota and Neurodegenerative Diseases: An Elucidation from Evolutionary Perspective and Metabolic Consideration. Metabolites. 2026; 16(5):337. https://doi.org/10.3390/metabo16050337

Chicago/Turabian Style

Tang, Guangyan, Liwen Guo, Zhiwei Liu, and Yuan Quan. 2026. "Hypothesis of the Causal Mechanisms Between Gut Microbiota and Neurodegenerative Diseases: An Elucidation from Evolutionary Perspective and Metabolic Consideration" Metabolites 16, no. 5: 337. https://doi.org/10.3390/metabo16050337

APA Style

Tang, G., Guo, L., Liu, Z., & Quan, Y. (2026). Hypothesis of the Causal Mechanisms Between Gut Microbiota and Neurodegenerative Diseases: An Elucidation from Evolutionary Perspective and Metabolic Consideration. Metabolites, 16(5), 337. https://doi.org/10.3390/metabo16050337

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Hypothesis of the Causal Mechanisms Between Gut Microbiota and Neurodegenerative Diseases: An Elucidation from Evolutionary Perspective and Metabolic Consideration

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