Abstract
Accumulated evidence indicates that the gut microbiota affects brain function and may be altered in neurological diseases. In this study, we analyzed the gut microbiota in Cln1R151X and Cln2R207X mice, models of the childhood neurodegenerative disorders, infantile CLN1 and late infantile CLN2 Batten diseases. Significant alterations were found in the overall gut microbiota composition and also at the individual taxonomic ranks as compared to wild-type mice. The disease-specific alterations in the gut microbiota of Cln1R151X and Cln2R207X mice may contribute to the disease phenotypes observed in these mouse models. We also compared the gut microbiota composition of three wild-type mouse strains frequently used in transgenic studies: 129S6/SvEv, C57BL/6J and mixed 129S6/SvEv × C57BL/6J. Our results show that the gut microbiota of 129S6/SvEv and C57BL/6J mice differs remarkably, which likely contributes to the known, pronounced differences in behavior and disease susceptibility between these two wild-type mouse strains.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Availability of data and materials
The 16S rRNA gene sequencing data were deposited into the Sequence Read Archive (SRA) of NCBI (https://www.ncbi.nlm.nih.gov/sra). The SRA accession number is PRJNA627907 for the sequencing data of Cln1R151X, Cln2R207X, C57BL/6J and mixed 129S6/SvEv × C57BL/6J wild-type mice. The sequencing data for 129S6/SvEv wild-type mice is available at the PRJNA627956 SRA accession number.
Abbreviations
- CNS:
-
Central nervous system
- OTUs:
-
Operational taxonomic units
- WT:
-
Wild type
References
Asano Y et al (2012) Critical role of gut microbiota in the production of biologically active, free catecholamines in the gut lumen of mice. Am J Physiol Gastrointest Liver Physiol 303:G1288–G1295. https://doi.org/10.1152/ajpgi.00341.2012
Balogh SA, McDowell CS, Stavnezer AJ, Denenberg VH (1999) A behavioral and neuroanatomical assessment of an inbred substrain of 129 mice with behavioral comparisons to C57BL/6J mice. Brain Res 836:38–48
Bilovocky NA, Romito-DiGiacomo RR, Murcia CL, Maricich SM, Herrup K (2003) Factors in the genetic background suppress the engrailed-1 cerebellar phenotype. J Neurosci 23:5105–5112
Bravo JA et al (2011) Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve. Proc Natl Acad Sci U S A 108:16050–16055. https://doi.org/10.1073/pnas.1102999108
Campbell JH et al (2012) Host genetic and environmental effects on mouse intestinal microbiota. ISME J 6:2033–2044. https://doi.org/10.1038/ismej.2012.54
Carcel-Trullols J, Kovacs AD, Pearce DA (2015) Cell biology of the NCL proteins: what they do and don’t do. Biochim Biophys Acta 1852:2242–2255. https://doi.org/10.1016/j.bbadis.2015.04.027
Chen Y et al (2011) Characterization of fecal microbial communities in patients with liver cirrhosis. Hepatology 54:562–572. https://doi.org/10.1002/hep.24423
Chen J et al (2016) Multiple sclerosis patients have a distinct gut microbiota compared to healthy controls. Sci Rep 6:28484. https://doi.org/10.1038/srep28484
Collins S, Martin TL, Surwit RS, Robidoux J (2004) Genetic vulnerability to diet-induced obesity in the C57BL/6J mouse: physiological and molecular characteristics. Physiol Behav 81:243–248. https://doi.org/10.1016/j.physbeh.2004.02.006
Cook MN, Bolivar VJ, McFadyen MP, Flaherty L (2002) Behavioral differences among 129 substrains: implications for knockout and transgenic mice. Behav Neurosci 116:600–611
Darby TM et al (2019) Lactococcus Lactis Subsp cremoris Is an Efficacious Beneficial Bacterium that Limits Tissue Injury in the Intestine. Science 12:356–367. https://doi.org/10.1016/j.isci.2019.01.030
De Angelis M et al (2013) Fecal microbiota and metabolome of children with autism and pervasive developmental disorder not otherwise specified. PLoS ONE 8:e76993. https://doi.org/10.1371/journal.pone.0076993
Edgar RC, Haas BJ, Clemente JC, Quince C, Knight R (2011) UCHIME improves sensitivity and speed of chimera detection. Bioinformatics 27:2194–2200. https://doi.org/10.1093/bioinformatics/btr381
Emoto T et al (2017) Characterization of gut microbiota profiles in coronary artery disease patients using data mining analysis of terminal restriction fragment length polymorphism: gut microbiota could be a diagnostic marker of coronary artery disease. Heart Vessels 32:39–46. https://doi.org/10.1007/s00380-016-0841-y
Finegold SM et al (2010) Pyrosequencing study of fecal microflora of autistic and control children. Anaerobe 16:444–453. https://doi.org/10.1016/j.anaerobe.2010.06.008
Freeman HC, Hugill A, Dear NT, Ashcroft FM, Cox RD (2006) Deletion of nicotinamide nucleotide transhydrogenase: a new quantitive trait locus accounting for glucose intolerance in C57BL/6J mice. Diabetes 55:2153–2156. https://doi.org/10.2337/db06-0358
Friswell MK et al (2010) Site and strain-specific variation in gut microbiota profiles and metabolism in experimental mice. PLoS ONE 5:e8584. https://doi.org/10.1371/journal.pone.0008584
Fung TC, Olson CA, Hsiao EY (2017) Interactions between the microbiota, immune and nervous systems in health and disease. Nat Neurosci 20:145–155. https://doi.org/10.1038/nn.4476
Geraets RD et al (2017) A tailored mouse model of CLN2 disease: a nonsense mutant for testing personalized therapies. PLoS ONE 12:e0176526. https://doi.org/10.1371/journal.pone.0176526
Hildebrand F et al (2013) Inflammation-associated enterotypes, host genotype, cage and inter-individual effects drive gut microbiota variation in common laboratory mice. Genome Biol 14:R4. https://doi.org/10.1186/gb-2013-14-1-r4
Inoue T et al (2018) Gut Dysbiosis Associated With Hepatitis C Virus Infection. Clin Infect Dis 67:869–877. https://doi.org/10.1093/cid/ciy205
Jalanko A, Braulke T (2009) Neuronal ceroid lipofuscinoses. Biochim Biophys Acta 1793:697–709. https://doi.org/10.1016/j.bbamcr.2008.11.004
Jangi S et al (2016) Alterations of the human gut microbiome in multiple sclerosis. Nat Commun 7:12015. https://doi.org/10.1038/ncomms12015
Jiang H (2015) Altered fecal microbiota composition in patients with major depressive disorder. Brain Behav Immun 48:186–194. https://doi.org/10.1016/j.bbi.2015.03.016
Johnson KR, Erway LC, Cook SA, Willott JF, Zheng QY (1997) A major gene affecting age-related hearing loss in C57BL/6J mice. Hear Res 114:83–92
Johnson TB, Langin LM, Zhao J, Weimer JM, Pearce DA, Kovacs AD (2019) Changes in motor behavior, neuropathology, and gut microbiota of a Batten disease mouse model following administration of acidified drinking water. Sci Rep 9:14962. https://doi.org/10.1038/s41598-019-51488-z
Kelly MA et al (1998) Locomotor activity in D2 dopamine receptor-deficient mice is determined by gene dosage, genetic background, and developmental adaptations. J Neurosci 18:3470–3479
Keshavarzian A et al (2015) Colonic bacterial composition in Parkinson’s disease. Mov Disord 30:1351–1360. https://doi.org/10.1002/mds.26307
Koike H, Arguello PA, Kvajo M, Karayiorgou M, Gogos JA (2006) Disc1 is mutated in the 129S6/SvEv strain and modulates working memory in mice. Proc Natl Acad Sci U S A 103:3693–3697. https://doi.org/10.1073/pnas.0511189103
Kovacs AD, Pearce DA (2015) Finding the most appropriate mouse model of juvenile CLN3 (Batten) disease for therapeutic studies: the importance of genetic background and gender. Dis Model Mech 8:351–361. https://doi.org/10.1242/dmm.018804
Laukens D, Brinkman BM, Raes J, De Vos M, Vandenabeele P (2016) Heterogeneity of the gut microbiome in mice: guidelines for optimizing experimental design. FEMS Microbiol Rev 40:117–132. https://doi.org/10.1093/femsre/fuv036
Ley RE, Backhed F, Turnbaugh P, Lozupone CA, Knight RD, Gordon JI (2005) Obesity alters gut microbial ecology. Proc Natl Acad Sci U S A 102:11070–11075. https://doi.org/10.1073/pnas.0504978102
Ley RE, Turnbaugh PJ, Klein S, Gordon JI (2006) Microbial ecology: human gut microbes associated with obesity. Nature 444:1022–1023. https://doi.org/10.1038/4441022a
Lloret A et al (2006) Genetic background modifies nuclear mutant huntingtin accumulation and HD CAG repeat instability in Huntington’s disease knock-in mice. Hum Mol Genet 15:2015–2024. https://doi.org/10.1093/hmg/ddl125
Magara F et al (1999) Genetic background changes the pattern of forebrain commissure defects in transgenic mice underexpressing the beta-amyloid-precursor protein. Proc Natl Acad Sci U S A 96:4656–4661
Marin IA et al (2017) Microbiota alteration is associated with the development of stress-induced despair behavior. Sci Rep 7:43859. https://doi.org/10.1038/srep43859
McMurdie PJ, Holmes S (2013) phyloseq: an R package for reproducible interactive analysis and graphics of microbiome census data. PLoS ONE 8:e61217. https://doi.org/10.1371/journal.pone.0061217
Miller BH, Schultz LE, Gulati A, Su AI, Pletcher MT (2010) Phenotypic characterization of a genetically diverse panel of mice for behavioral despair and anxiety. PLoS ONE 5:e14458. https://doi.org/10.1371/journal.pone.0014458
Miller JN, Kovacs AD, Pearce DA (2015) The novel Cln 1(R151X) mouse model of infantile neuronal ceroid lipofuscinosis (INCL) for testing nonsense suppression therapy. Hum Mol Genet 24:185–196. https://doi.org/10.1093/hmg/ddu428
Naseribafrouei A et al (2014) Correlation between the human fecal microbiota and depression. Neurogastroenterol Motil 26:1155–1162. https://doi.org/10.1111/nmo.12378
Paigen B, Morrow A, Brandon C, Mitchell D, Holmes P (1985) Variation in susceptibility to atherosclerosis among inbred strains of mice. Atherosclerosis 57:65–73
Parekh PI, Petro AE, Tiller JM, Feinglos MN, Surwit RS (1998) Reversal of diet-induced obesity and diabetes in C57BL/6J mice. Metabolism 47:1089–1096
Paulus MP, Dulawa SC, Ralph RJ, Mark AG (1999) Behavioral organization is independent of locomotor activity in 129 and C57 mouse strains. Brain Res 835:27–36
Rothhammer V et al (2016) Type I interferons and microbial metabolites of tryptophan modulate astrocyte activity and central nervous system inflammation via the aryl hydrocarbon receptor. Nat Med 22:586–597. https://doi.org/10.1038/nm.4106
Schaible TD, Harris RA, Dowd SE, Smith CW, Kellermayer R (2011) Maternal methyl-donor supplementation induces prolonged murine offspring colitis susceptibility in association with mucosal epigenetic and microbiomic changes. Hum Mol Genet 20:1687–1696. https://doi.org/10.1093/hmg/ddr044
Schaubeck M et al (2016) Dysbiotic gut microbiota causes transmissible Crohn’s disease-like ileitis independent of failure in antimicrobial defence. Gut 65:225–237. https://doi.org/10.1136/gutjnl-2015-309333
Scheperjans F et al (2015) Gut microbiota are related to Parkinson’s disease and clinical phenotype. Mov Disord 30:350–358. https://doi.org/10.1002/mds.26069
Sheng MH et al (1999) Histomorphometric studies show that bone formation and bone mineral apposition rates are greater in C3H/HeJ (high-density) than C57BL/6J (low-density) mice during growth. Bone 25:421–429
Sleat DE et al (1997) Association of mutations in a lysosomal protein with classical late-infantile neuronal ceroid lipofuscinosis. Science 277:1802–1805
Sun Y, Wolcott RD, Dowd SE (2011) Tag-encoded FLX amplicon pyrosequencing for the elucidation of microbial and functional gene diversity in any environment. Methods Mol Biol 733:129–141. https://doi.org/10.1007/978-1-61779-089-8_9
Turnbaugh PJ, Backhed F, Fulton L, Gordon JI (2008) Diet-induced obesity is linked to marked but reversible alterations in the mouse distal gut microbiome. Cell Host Microbe 3:213–223. https://doi.org/10.1016/j.chom.2008.02.015
van Bogaert MJ, Groenink L, Oosting RS, Westphal KG, van der Gugten J, Olivier B (2006) Mouse strain differences in autonomic responses to stress. Genes Brain Behav 5:139–149. https://doi.org/10.1111/j.1601-183X.2005.00143.x
Vesa J et al (1995) Mutations in the palmitoyl protein thioesterase gene causing infantile neuronal ceroid lipofuscinosis. Nature 376:584–587. https://doi.org/10.1038/376584a0
Wang F et al (2016) Detecting Microbial Dysbiosis Associated with Pediatric Crohn Disease Despite the High Variability of the Gut Microbiota. Cell Rep 14:945–955. https://doi.org/10.1016/j.celrep.2015.12.088
Williams BB et al (2014) Discovery and characterization of gut microbiota decarboxylases that can produce the neurotransmitter tryptamine. Cell Host Microbe 16:495–503. https://doi.org/10.1016/j.chom.2014.09.001
Yano JM et al (2015) Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis. Cell 161:264–276. https://doi.org/10.1016/j.cell.2015.02.047
Yin J et al (2015) Dysbiosis of Gut Microbiota With Reduced Trimethylamine-N-Oxide Level in Patients With Large-Artery Atherosclerotic Stroke or Transient Ischemic Attack. J Am Heart Assoc. https://doi.org/10.1161/JAHA.115.002699
Zhang H et al (2009) Human gut microbiota in obesity and after gastric bypass. Proc Natl Acad Sci U S A 106:2365–2370. https://doi.org/10.1073/pnas.0812600106
Zheng P et al (2016) Gut microbiome remodeling induces depressive-like behaviors through a pathway mediated by the host’s metabolism. Mol Psychiatry 21:786–796. https://doi.org/10.1038/mp.2016.44
Acknowledgements
We thank Logan Langin for maintaining our mouse colony.
Funding
This work was entirely supported by Sanford Health.
Author information
Authors and Affiliations
Contributions
ADK and DAP designed the study, ADK and CP performed the experiments, ADK, JZ and DAP analyzed the data and wrote the paper. All authors have read and approved the manuscript.
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Code availability
Not applicable.
Consent for publication
Not applicable.
Consent to participate
Not applicable.
Ethics approval
All animal procedures were carried out according to the guidelines of the Animal Welfare Act and NIH policies, and were approved by the Sanford Research Animal Care and Use Committee.
Additional information
Communicated by Erko Stackebrandt.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Parker, C., Zhao, J., Pearce, D.A. et al. Comparative analysis of the gut microbiota composition in the Cln1R151X and Cln2R207X mouse models of Batten disease and in three wild-type mouse strains. Arch Microbiol 203, 85–96 (2021). https://doi.org/10.1007/s00203-020-02007-6
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00203-020-02007-6