title: Leaky intestine and impaired microbiome in an amyotrophic lateral sclerosis mouse model.
abstract: Emerging evidence has demonstrated that intestinal homeostasis and the microbiome play essential roles in neurological diseases, such as Parkinson's disease. Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by a progressive loss of motor neurons and muscle atrophy. Currently, there is no effective treatment. Most patients die within 3-5 years due to respiratory paralysis. Although the death of motor neurons is a hallmark of ALS, other organs may also contribute to the disease progression. We examined the gut of an ALS mouse model, G93A, which expresses mutant superoxide dismutase (SOD1(G93A)), and discovered a damaged tight junction structure and increased permeability with a significant reduction in the expression levels of tight junction protein ZO-1 and the adherens junction protein E-cadherin. Furthermore, our data demonstrated increased numbers of abnormal Paneth cells in the intestine of G93A mice. Paneth cells are specialized intestinal epithelial cells that can sense microbes and secrete antimicrobial peptides, thus playing key roles in host innate immune responses and shaping the gut microbiome. A decreased level of the antimicrobial peptides defensin 5 alpha was indeed found in the ALS intestine. These changes were associated with a shifted profile of the intestinal microbiome, including reduced levels of Butyrivibrio Fibrisolvens, Escherichia coli, and Fermicus, in G93A mice. The relative abundance of bacteria was shifted in G93A mice compared to wild-type mice. Principal coordinate analysis indicated a difference in fecal microbial communities between ALS and wild-type mice. Taken together, our study suggests a potential novel role of the intestinal epithelium and microbiome in the progression of ALS.
authors.affiliation: Department of Biochemistry, Rush University Medical Center, Chicago, Illinois.
authors.forename: Shaoping
authors.initials: S
authors.lastname: Wu
authors.affiliation: Department of Physiology, Kansas City University of Medicine and Bioscience, Kansas, Missouri.
authors.forename: Jianxun
authors.initials: J
authors.lastname: Yi
authors.affiliation: Department of Biochemistry, Rush University Medical Center, Chicago, Illinois.
authors.forename: Yong-Guo
authors.initials: YG
authors.lastname: Zhang
authors.affiliation: Department of Physiology, Kansas City University of Medicine and Bioscience, Kansas, Missouri jun_sun@rush.edu jzhou@kcumb.edu.
authors.forename: Jingsong
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Department of Biochemistry, Rush University Medical Center, Chicago, Illinois jun_sun@rush.edu jzhou@kcumb.edu.
authors.forename: Jun
authors.initials: J
authors.lastname: Sun
keywords: Antimicrobial peptides; Paneth cells; ZO‐1; autophagy; cell biology; dysbiosis; intestinal permeability; microbiome; signal transduction; tight junction
references.citation: Physiol Rev. 2007 Apr;87(2):545-64
references.pmid: 17429041
references.citation: Autophagy. 2008 Feb;4(2):151-75
references.pmid: 18188003
references.citation: PLoS One. 2011;6(12 ):e28032
references.pmid: 22145021
references.citation: J Neuropathol Exp Neurol. 2011 May;70(5):349-59
references.pmid: 21487309
references.citation: Br J Nutr. 2012 Sep;108(5):820-31
references.pmid: 22676885
references.citation: Lancet Neurol. 2003 Feb;2(2):107-16
references.pmid: 12849267
references.citation: Nat Immunol. 2009 May;10(5):461-70
references.pmid: 19381141
references.citation: Front Cell Neurosci. 2013 Nov 26;7:234
references.pmid: 24324403
references.citation: J Exp Med. 2007 Dec 24;204(13):3067-76
references.pmid: 18039951
references.citation: Anaerobe. 2010 Aug;16(4):444-53
references.pmid: 20603222
references.citation: J Gastroenterol Hepatol. 2003 May;18(5):479-97
references.pmid: 12702039
references.citation: Nat Rev Neurosci. 2006 Sep;7(9):710-23
references.pmid: 16924260
references.citation: Eur J Neurol. 2009 Jun;16(6):745-51
references.pmid: 19475756
references.citation: J Biol Chem. 2008 Nov 7;283(45):30585-95
references.pmid: 18782762
references.citation: Mamm Genome. 2011 Aug;22(7-8):420-48
references.pmid: 21706386
references.citation: PLoS One. 2013 Dec 06;8(12):e82112
references.pmid: 24324755
references.citation: Nature. 2014 Oct 23;514(7523):508-12
references.pmid: 25174708
references.citation: Mol Immunol. 2014 Apr;58(2):151-9
references.pmid: 24365749
references.citation: Autophagy. 2014 Apr;10(4):588-602
references.pmid: 24441414
references.citation: Exp Mol Med. 2012 Feb 29;44(2):99-108
references.pmid: 22257885
references.citation: Annu Rev Pathol. 2013 Jan 24;8:105-37
references.pmid: 23072311
references.citation: PLoS One. 2013;8(3):e58606
references.pmid: 23505542
references.citation: Genes Dis. 2014 Dec;1(2):132-139
references.pmid: 25642449
references.citation: Nature. 2007 Oct 18;449(7164):804-10
references.pmid: 17943116
references.citation: Nat Commun. 2013;4:2163
references.pmid: 23860099
references.citation: Curr Mol Med. 2011 Apr;11(3):246-54
references.pmid: 21375489
references.citation: Physiol Rep. 2015 Jan 19;3(1):null
references.pmid: 25602021
references.citation: Neuro Endocrinol Lett. 2008 Feb;29(1):117-24
references.pmid: 18283240
references.citation: Gut. 2015 Jul;64(7):1082-94
references.pmid: 25080448
references.citation: Proc Natl Acad Sci U S A. 2006 May 2;103(18):7142-7
references.pmid: 16636275
references.citation: J Biol Chem. 2010 Jan 1;285(1):705-12
references.pmid: 19889637
references.citation: Autophagy. 2008 Apr;4(3):290-3
references.pmid: 18196963
references.citation: Cell. 2013 Dec 19;155(7):1451-63
references.pmid: 24315484
references.citation: J Biol Chem. 2011 Sep 16;286(37):32436-43
references.pmid: 21795684
references.citation: PLoS One. 2014 Oct 13;9(10):e107388
references.pmid: 25310566
references.citation: J Biol Chem. 2014 May 23;289(21):15094-103
references.pmid: 24692554
references.citation: Nature. 2014 Jan 23;505(7484):559-63
references.pmid: 24336217
references.citation: Nat Immunol. 2009 Jul;10(7):786-93
references.pmid: 19503106
references.citation: J Exp Med. 2008 Aug 4;205(8):1755-61
references.pmid: 18663129
references.citation: J Control Release. 2010 Mar 3;142(2):196-205
references.pmid: 19896996
references.citation: Am J Physiol Gastrointest Liver Physiol. 2006 Apr;290(4):G577-82
references.pmid: 16537969
references.citation: Nature. 2008 Nov 13;456(7219):259-63
references.pmid: 18849966
references.citation: Nat Immunol. 2010 Jan;11(1):76-83
references.pmid: 19855381
references.citation: Science. 1994 Jun 17;264(5166):1772-5
references.pmid: 8209258
references.citation: PLoS One. 2008 Jun 04;3(6):e2369
references.pmid: 18523661
references.citation: Gastroenterology. 2009 May;136(6):2003-14
references.pmid: 19457424
references.citation: Proc Natl Acad Sci U S A. 2014 Jan 7;111(1):197-201
references.pmid: 24344300