Aberrant enteric neuromuscular system and dysbiosis in amyotrophic lateral sclerosis

Amyotrophic Lateral Sclerosis is a neuromuscular disease characterized by the progressive death of motor neurons and muscle atrophy. The gastrointestinal symptoms in ALS patients were largely ignored or underestimated. The relationship between the enteric neuromuscular system and microbiome in ALS p...

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Autores principales:	Yongguo Zhang, Destiny Ogbu, Shari Garrett, Yinglin Xia, Jun Sun
Formato:	article
Lenguaje:	EN
Publicado:	Taylor & Francis Group 2021
Materias:	autoimmune disease enteric neuromuscular system fals lachnospiraceae bacterium a4 butyrate-producing bacteria neuromuscular disease colonoids protein aggregation sals Diseases of the digestive system. Gastroenterology RC799-869
Acceso en línea:	https://doaj.org/article/876974bf8f694e6fad4cede288b9bc5d
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spelling	oai:doaj.org-article:876974bf8f694e6fad4cede288b9bc5d2021-11-26T11:19:48ZAberrant enteric neuromuscular system and dysbiosis in amyotrophic lateral sclerosis1949-09761949-098410.1080/19490976.2021.1996848https://doaj.org/article/876974bf8f694e6fad4cede288b9bc5d2021-01-01T00:00:00Zhttp://dx.doi.org/10.1080/19490976.2021.1996848https://doaj.org/toc/1949-0976https://doaj.org/toc/1949-0984Amyotrophic Lateral Sclerosis is a neuromuscular disease characterized by the progressive death of motor neurons and muscle atrophy. The gastrointestinal symptoms in ALS patients were largely ignored or underestimated. The relationship between the enteric neuromuscular system and microbiome in ALS progression is unknown. We performed longitudinal studies on the enteric neuron system (ENS) and microbiome in the ALS human-SOD1G93A (Superoxide Dismutase 1) transgenic mice. We treated age-matched wild-type and ALS mice with butyrate or antibiotics to investigate the microbiome and neuromuscular functions. We examined intestinal mobility, microbiome, an ENS marker GFAP (Glial Fibrillary Acidic Protein), a smooth muscle marker (SMMHC, Smooth Muscle Myosin Heavy Chain), and human colonoids. The distribution of human-G93A-SOD1 protein was tested as an indicator of ALS progression. At 2-month-old before ALS onset, SOD1G93A mice had significantly lower intestinal mobility, decreased grip strength, and reduced time in the rotarod. We observed increased GFAP and decreased SMMHC expression. These changes correlated with consistent increased aggregation of mutated SOD1G93A in the colon, small intestine, and spinal cord. Butyrate or antibiotics treated SOD1G93A mice had a significantly longer latency to fall in the rotarod test, reduced SOD1G93A aggregation, and enhanced enteric neuromuscular function. Feces from 2-month-old SOD1G93A mice significantly enhanced SOD1G93A aggregation in human colonoids transfected with a SOD1G93A-GFP plasmid. Longitudinal studies of microbiome data further showed the altered bacterial community related to autoimmunity (e.g., Clostridium sp. ASF502, Lachnospiraceae bacterium A4), inflammation (e.g., Enterohabdus Muris,), and metabolism (e.g., Desulfovibrio fairfieldensis) at 1- and 2-month-old SOD1G93A mice, suggesting the early microbial contribution to the pathological changes. We have demonstrated a novel link between the microbiome, hSOD1G93A aggregation, and intestinal mobility. Dysbiosis occurred at the early stage of the ALS mice before observed mutated-SOD1 aggregation and dysfunction of ENS. Manipulating the microbiome improves the muscle performance of SOD1G93A mice. We provide insights into the fundamentals of intestinal neuromuscular function and microbiome in ALS.Yongguo ZhangDestiny OgbuShari GarrettYinglin XiaJun SunTaylor & Francis Grouparticleautoimmune diseaseenteric neuromuscular systemfalslachnospiraceae bacterium a4butyrate-producing bacterianeuromuscular diseasecolonoidsprotein aggregationsalsDiseases of the digestive system. GastroenterologyRC799-869ENGut Microbes, Vol 13, Iss 1 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	autoimmune disease enteric neuromuscular system fals lachnospiraceae bacterium a4 butyrate-producing bacteria neuromuscular disease colonoids protein aggregation sals Diseases of the digestive system. Gastroenterology RC799-869
spellingShingle	autoimmune disease enteric neuromuscular system fals lachnospiraceae bacterium a4 butyrate-producing bacteria neuromuscular disease colonoids protein aggregation sals Diseases of the digestive system. Gastroenterology RC799-869 Yongguo Zhang Destiny Ogbu Shari Garrett Yinglin Xia Jun Sun Aberrant enteric neuromuscular system and dysbiosis in amyotrophic lateral sclerosis
description	Amyotrophic Lateral Sclerosis is a neuromuscular disease characterized by the progressive death of motor neurons and muscle atrophy. The gastrointestinal symptoms in ALS patients were largely ignored or underestimated. The relationship between the enteric neuromuscular system and microbiome in ALS progression is unknown. We performed longitudinal studies on the enteric neuron system (ENS) and microbiome in the ALS human-SOD1G93A (Superoxide Dismutase 1) transgenic mice. We treated age-matched wild-type and ALS mice with butyrate or antibiotics to investigate the microbiome and neuromuscular functions. We examined intestinal mobility, microbiome, an ENS marker GFAP (Glial Fibrillary Acidic Protein), a smooth muscle marker (SMMHC, Smooth Muscle Myosin Heavy Chain), and human colonoids. The distribution of human-G93A-SOD1 protein was tested as an indicator of ALS progression. At 2-month-old before ALS onset, SOD1G93A mice had significantly lower intestinal mobility, decreased grip strength, and reduced time in the rotarod. We observed increased GFAP and decreased SMMHC expression. These changes correlated with consistent increased aggregation of mutated SOD1G93A in the colon, small intestine, and spinal cord. Butyrate or antibiotics treated SOD1G93A mice had a significantly longer latency to fall in the rotarod test, reduced SOD1G93A aggregation, and enhanced enteric neuromuscular function. Feces from 2-month-old SOD1G93A mice significantly enhanced SOD1G93A aggregation in human colonoids transfected with a SOD1G93A-GFP plasmid. Longitudinal studies of microbiome data further showed the altered bacterial community related to autoimmunity (e.g., Clostridium sp. ASF502, Lachnospiraceae bacterium A4), inflammation (e.g., Enterohabdus Muris,), and metabolism (e.g., Desulfovibrio fairfieldensis) at 1- and 2-month-old SOD1G93A mice, suggesting the early microbial contribution to the pathological changes. We have demonstrated a novel link between the microbiome, hSOD1G93A aggregation, and intestinal mobility. Dysbiosis occurred at the early stage of the ALS mice before observed mutated-SOD1 aggregation and dysfunction of ENS. Manipulating the microbiome improves the muscle performance of SOD1G93A mice. We provide insights into the fundamentals of intestinal neuromuscular function and microbiome in ALS.
format	article
author	Yongguo Zhang Destiny Ogbu Shari Garrett Yinglin Xia Jun Sun
author_facet	Yongguo Zhang Destiny Ogbu Shari Garrett Yinglin Xia Jun Sun
author_sort	Yongguo Zhang
title	Aberrant enteric neuromuscular system and dysbiosis in amyotrophic lateral sclerosis
title_short	Aberrant enteric neuromuscular system and dysbiosis in amyotrophic lateral sclerosis
title_full	Aberrant enteric neuromuscular system and dysbiosis in amyotrophic lateral sclerosis
title_fullStr	Aberrant enteric neuromuscular system and dysbiosis in amyotrophic lateral sclerosis
title_full_unstemmed	Aberrant enteric neuromuscular system and dysbiosis in amyotrophic lateral sclerosis
title_sort	aberrant enteric neuromuscular system and dysbiosis in amyotrophic lateral sclerosis
publisher	Taylor & Francis Group
publishDate	2021
url	https://doaj.org/article/876974bf8f694e6fad4cede288b9bc5d
work_keys_str_mv	AT yongguozhang aberrantentericneuromuscularsystemanddysbiosisinamyotrophiclateralsclerosis AT destinyogbu aberrantentericneuromuscularsystemanddysbiosisinamyotrophiclateralsclerosis AT sharigarrett aberrantentericneuromuscularsystemanddysbiosisinamyotrophiclateralsclerosis AT yinglinxia aberrantentericneuromuscularsystemanddysbiosisinamyotrophiclateralsclerosis AT junsun aberrantentericneuromuscularsystemanddysbiosisinamyotrophiclateralsclerosis
_version_	1718409483990859776

Aberrant enteric neuromuscular system and dysbiosis in amyotrophic lateral sclerosis

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