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Licensed Unlicensed Requires Authentication Published by De Gruyter April 12, 2022

Gut dysbiosis and homocysteine: a couple for boosting neurotoxicity in Huntington disease

Juan Carlos Martínez-Lazcano , Edith González-Guevara , Catherine Boll and Graciela Cárdenas ORCID logo EMAIL logo


Huntington’s disease (HD), a neurodegenerative disorder caused by an expansion of the huntingtin triplet (Htt), is clinically characterized by cognitive and neuropsychiatric alterations. Although these alterations appear to be related to mutant Htt (mHtt)-induced neurotoxicity, several other factors are involved. The gut microbiota is a known modulator of brain-gut communication and when altered (dysbiosis), several complaints can be developed including gastrointestinal dysfunction which may have a negative impact on cognition, behavior, and other mental functions in HD through several mechanisms, including increased levels of lipopolysaccharide, proinflammatory cytokines and immune cell response, as well as alterations in Ca2+ signaling, resulting in both increased intestinal and blood-brain barrier (BBB) permeability. Recently, the presence of dysbiosis has been described in both transgenic mouse models and HD patients. A bidirectional influence between host brain tissues and the gut microbiota has been observed. On the one hand, the host diet influences the composition and function of microbiota; and on the other hand, microbiota products can affect BBB permeability, synaptogenesis, and the regulation of neurotransmitters and neurotrophic factors, which has a direct effect on host metabolism and brain function. This review summarizes the available evidence on the pathogenic synergism of dysbiosis and homocysteine, and their role in the transgression of BBB integrity and their potential neurotoxicity of HD.

Corresponding author: Graciela Cárdenas, Departamento de Neurología y Enfermedades Neuro-Infecciosas, Instituto Nacional de Neurología y Neurocirugía “Manuel Velasco Suárez”, Insurgentes Sur 3877, La Fama, Mexico, Mexico City 14269, Mexico, E-mail:

  1. Author contribution: · Study concept and design: Cárdenas G, González-Guevara E, Boll C, Martínez-Lazcano JC· Data acquisition: Cárdenas G, González-Guevara E, Boll C, Martínez-Lazcano JC· Data analysis and interpretation: Cárdenas G, González-Guevara E, Boll C, Martínez-Lazcano JC.· Manuscript drafting: Cárdenas G, González-Guevara E, Boll C, Martínez-Lazcano JC· Critical revision of the manuscript for important intellectual content: Cárdenas G.

  2. Research funding: This research received no specific grant from any funding agency in the public, commercial, nor not-for-profit sectors.

  3. Conflict of interest statement: The authors declare that no conflict of interest exists.


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Received: 2021-12-03
Accepted: 2022-03-11
Published Online: 2022-04-12
Published in Print: 2022-10-26

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