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Altered microbiota caused by disordered gut motility leads to an overactivation of intestinal immune system in APC1638T mice

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Abstract

Adenomatous polyposis coli (APC) is recognized as an antioncogene related to familial adenomatous polyposis and colorectal cancers. However, APC is a large protein with multiple binding partners, indicating APC has diverse roles besides as a tumor suppressor. We have ever studied the roles of APC by using APC1638T/1638T (APC1638T) mice. Through those studies, we have noticed stools of APC1638T mice were smaller than those of APC+/+ mice and hypothesized there be a disturbance in fecal formation processes in APC1638T mice. The gut motility was morphologically analyzed by immunohistochemical staining of the Auerbach’s plexus. Gut microbiota was analyzed by terminal restriction fragment length polymorphism (T-RFLP). IgA concentration in stools was determined by enzyme-linked immunosorbent assay (ELISA). As results, macroscopic findings suggestive of large intestinal dysmotility and microscopic findings of disorganization and inflammation of the plexus were obtained in APC1638T mice. An alteration of microbiota composition, especially increased Bacteroidetes population was observed. Increases in IgA positive cells and dendritic cells in the ileum with high fecal IgA concentration were also confirmed, suggesting over-activation of gut immunity. Our findings will contribute to our understanding of APC’s functions in the gastrointestinal motility, and lead to a development of novel therapies for gut dysmotility-related diseases.

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All data generated or analyzed during this study are included in this published article.

References

  1. Kinzler KW, Nilbert MC, Su LK, Vogelstein B, Bryan TM, Levy DB, Smith KJ, Preisinger AC, Hedge P, McKechnie D et al (1991) Identification of FAP locus genes from chromosome 5q21. Science 253(5020):661–665

    Article  CAS  PubMed  Google Scholar 

  2. Fodde R (2003) The multiple functions of tumour suppressors: it’s all in APC. Nat Cell Biol 5(3):190–192

    Article  CAS  PubMed  Google Scholar 

  3. Senda T, Iizuka-Kogo A, Onouchi T, Shimomura A (2007) Adenomatous polyposis coli (APC) plays multiple roles in the intestinal and colorectal epithelia. Med Mol Morphol 40(2):68–81

    Article  PubMed  Google Scholar 

  4. Smits R, Kielman MF, Breukel C, Zurcher C, Neufeld K, Jagmohan-Changur S, Hofland N, van Dijk J, White R, Edelmann W, Kucherlapati R, Khan PM, Fodde R (1999) Apc1638T: a mouse model delineating critical domains of the adenomatous polyposis coli protein involved in tumorigenesis and development. Genes Dev 13(10):1309–1321

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Onouchi T, Kobayashi K, Sakai K, Shimomura A, Smits R, Sumi-Ichinose C, Kurosumi M, Takao K, Nomura R, Iizuka-Kogo A, Suzuki H, Kondo K, Akiyama T, Miyakawa T, Fodde R, Senda T (2014) Targeted deletion of the C-terminus of the mouse adenomatous polyposis coli tumor suppressor results in neurologic phenotypes related to schizophrenia. Mol Brain 7:21

    Article  PubMed  PubMed Central  Google Scholar 

  6. Li C, Onouchi T, Hirayama M, Sakai K, Matsuda S, Yamada NO, Senda T (2020) Morphological and functional abnormalities of hippocampus in APC(1638T/1638T) mice. Med Mol Morphol 54(1):31–40

    Article  PubMed  Google Scholar 

  7. Wang T, Onouchi T, Yamada NO, Matsuda S, Senda T (2017) A disturbance of intestinal epithelial cell population and kinetics in APC1638T mice. Med Mol Morphol 50(2):94–102

    Article  CAS  PubMed  Google Scholar 

  8. Wenduerma YNO, Wang T, Senda T (2021) A further study on a disturbance of intestinal epithelial cell population and kinetics in APC1638T mice. Med Mol Morphol. 54:203–215

    Article  CAS  PubMed  Google Scholar 

  9. Yokoyama A, Nomura R, Kurosumi M, Shimomura A, Onouchi T, Iizuka-Kogo A, Smits R, Fodde R, Itoh M, Senda T (2012) Some fine-structural findings on the thyroid gland in Apc1638T/1638T mice that express a C-terminus lacking truncated Apc. Med Mol Morphol 45(3):161–167

    Article  CAS  PubMed  Google Scholar 

  10. Nakajima A, Sasaki T, Itoh K, Kitahara T, Takema Y, Hiramatsu K, Ishikawa D, Shibuya T, Kobayashi O, Osada T, Watanabe S, Nagahara A (2020) A soluble fiber diet increases bacteroides fragilis group abundance and immunoglobulin a production in the gut. Appl Environ Microbiol. https://doi.org/10.1128/AEM.00405-20

    Article  PubMed  PubMed Central  Google Scholar 

  11. Yanagibashi T, Hosono A, Oyama A, Tsuda M, Hachimura S, Takahashi Y, Itoh K, Hirayama K, Takahashi K, Kaminogawa S (2009) Bacteroides induce higher IgA production than Lactobacillus by increasing activation-induced cytidine deaminase expression in B cells in murine Peyer’s patches. Biosci Biotechnol Biochem 73(2):372–377

    Article  CAS  PubMed  Google Scholar 

  12. Yanagibashi T, Hosono A, Oyama A, Tsuda M, Suzuki A, Hachimura S, Takahashi Y, Momose Y, Itoh K, Hirayama K, Takahashi K, Kaminogawa S (2013) IgA production in the large intestine is modulated by a different mechanism than in the small intestine: Bacteroides acidifaciens promotes IgA production in the large intestine by inducing germinal center formation and increasing the number of IgA+ B cells. Immunobiology 218(4):645–651

    Article  CAS  PubMed  Google Scholar 

  13. Nagashima K, Hisada T, Sato M, Mochizuki J (2003) Application of new primer-enzyme combinations to terminal restriction fragment length polymorphism profiling of bacterial populations in human feces. Appl Environ Microbiol 69(2):1251–1262

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Baker GC, Smith JJ, Cowan DA (2003) Review and re-analysis of domain-specific 16S primers. J Microbiol Methods 55(3):541–555

    Article  CAS  PubMed  Google Scholar 

  15. Hayashi H, Sakamoto M, Benno Y (2004) Evaluation of three different forward primers by terminal restriction fragment length polymorphism analysis for determination of fecal bifidobacterium spp in healthy subjects. Microbiol Immunol 48(1):1–6

    Article  CAS  PubMed  Google Scholar 

  16. Phillips RJ, Hargrave SL, Rhodes BS, Zopf DA, Powley TL (2004) Quantification of neurons in the myenteric plexus: an evaluation of putative pan-neuronal markers. J Neurosci Methods 133(1–2):99–107

    Article  PubMed  Google Scholar 

  17. Bishop AE, Carlei F, Lee V, Trojanowski J, Marangos PJ, Dahl D, Polak JM (1985) Combined immunostaining of neurofilaments, neuron specific enolase, GFAP and S-100. A possible means for assessing the morphological and functional status of the enteric nervous system. Histochemistry 82(1):93–97

    Article  CAS  PubMed  Google Scholar 

  18. Butovsky O, Jedrychowski MP, Moore CS, Cialic R, Lanser AJ, Gabriely G, Koeglsperger T, Dake B, Wu PM, Doykan CE, Fanek Z, Liu L, Chen Z, Rothstein JD, Ransohoff RM, Gygi SP, Antel JP, Weiner HL (2014) Identification of a unique TGF-beta-dependent molecular and functional signature in microglia. Nat Neurosci 17(1):131–143

    Article  CAS  PubMed  Google Scholar 

  19. Swanson MEV, Murray HC, Ryan B, Faull RLM, Dragunow M, Curtis MA (2020) Quantitative immunohistochemical analysis of myeloid cell marker expression in human cortex captures microglia heterogeneity with anatomical context. Sci Rep 10(1):11693

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Koizumi T, Kerkhofs D, Mizuno T, Steinbusch HWM, Foulquier S (2019) Vessel-associated immune cells in cerebrovascular diseases: from perivascular macrophages to vessel-associated microglia. Front Neurosci 13:1291

    Article  PubMed  PubMed Central  Google Scholar 

  21. Leyh J, Paeschke S, Mages B, Michalski D, Nowicki M, Bechmann I, Winter K (2021) Classification of microglial morphological phenotypes using machine learning. Front Cell Neurosci 15:701673

    Article  PubMed  PubMed Central  Google Scholar 

  22. Kohrgruber N, Halanek N, Groger M, Winter D, Rappersberger K, Schmitt-Egenolf M, Stingl G, Maurer D (1999) Survival, maturation, and function of CD11c- and CD11c+ peripheral blood dendritic cells are differentially regulated by cytokines. J Immunol 163(6):3250–3259

    Article  CAS  PubMed  Google Scholar 

  23. Qualai J, Li LX, Cantero J, Tarrats A, Fernandez MA, Sumoy L, Rodolosse A, McSorley SJ, Genesca M (2016) Expression of CD11c Is associated with unconventional activated T cell subsets with high migratory potential. PLoS ONE 11(4):e0154253

    Article  PubMed  PubMed Central  Google Scholar 

  24. Freytag C, Seeger J, Siegemund T, Grosche J, Grosche A, Freeman DE, Schusser GF, Hartig W (2008) Immunohistochemical characterization and quantitative analysis of neurons in the myenteric plexus of the equine intestine. Brain Res 1244:53–64

    Article  CAS  PubMed  Google Scholar 

  25. Lin Z, Gao N, Hu HZ, Liu S, Gao C, Kim G, Ren J, Xia Y, Peck OC, Wood JD (2002) Immunoreactivity of Hu proteins facilitates identification of myenteric neurones in guinea-pig small intestine. Neurogastroenterol Motil 14(2):197–204

    Article  CAS  PubMed  Google Scholar 

  26. Desmet AS, Cirillo C, Vanden BP (2014) Distinct subcellular localization of the neuronal marker HuC/D reveals hypoxia-induced damage in enteric neurons. Neurogastroenterol Motil 26(8):1131–1143

    Article  CAS  PubMed  Google Scholar 

  27. Swaminathan M, Kapur RP (2010) Counting myenteric ganglion cells in histologic sections: an empirical approach. Hum Pathol 41(8):1097–1108

    Article  PubMed  Google Scholar 

  28. Yntema CL, Hammond WS (1954) The origin of intrinsic ganglia of trunk viscera from vagal neural crest in the chick embryo. J Comp Neurol 101(2):515–541

    Article  CAS  PubMed  Google Scholar 

  29. Lake JI, Heuckeroth RO (2013) Enteric nervous system development: migration, differentiation, and disease. Am J Physiol Gastrointest Liver Physiol 305(1):G1-24

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Tsai LH, Gleeson JG (2005) Nucleokinesis in neuronal migration. Neuron 46(3):383–388

    Article  CAS  PubMed  Google Scholar 

  31. Kapitein LC, Hoogenraad CC (2015) Building the neuronal microtubule cytoskeleton. Neuron 87(3):492–506

    Article  CAS  PubMed  Google Scholar 

  32. Bennett ML, Viaene AN (2021) What are activated and reactive glia and what is their role in neurodegeneration? Neurobiol Dis 148:105172

    Article  CAS  PubMed  Google Scholar 

  33. Hattori M, Taylor TD (2009) The human intestinal microbiome: a new frontier of human biology. DNA Res 16(1):1–12

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Mabbott NA, Donaldson DS, Ohno H, Williams IR, Mahajan A (2013) Microfold (M) cells: important immunosurveillance posts in the intestinal epithelium. Mucosal Immunol 6(4):666–677

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Maynard CL, Elson CO, Hatton RD, Weaver CT (2012) Reciprocal interactions of the intestinal microbiota and immune system. Nature 489(7415):231–241

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Mearin F, Lacy BE, Chang L, Chey WD, Lembo AJ, Simren M, Spiller R (2016) Bowel disorders. Gastroenterology 150(6):1393–1407

    Article  Google Scholar 

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Acknowledgements

We are grateful to Yutaka Hattori (Keyence, Osaka, Japan) for the helpful advice on using a Biorevo fluorescence microscopy BZ-X-800.

Funding

This work was supported by JSPS KAKENHI Grant Number JP15K08132 to Senda T.

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Authors and Affiliations

  1. Department of Anatomy, Graduate School of Medicine, Gifu University, 1-1 Yanagido, Gifu, 501-1194, Japan

    Nami O. Yamada,  Wenduerma & Takao Senda

Authors
  1. Nami O. Yamada
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  2. Wenduerma
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  3. Takao Senda
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Contributions

NOY designed the study. NOY and W performed the experiments. NOY wrote the manuscript. NOY, W, and TS contributed to data interpretation and manuscript revisions. TS supervised the study. all authors read and approved the final manuscript.

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Correspondence to Nami O. Yamada.

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The authors declare that they have no competing interests.

Ethics approval and consent to participate

The animal study proposal was approved by the Committee for Ethics in Animal Experimentation at Gifu University (permission number: 2019-004). All experiments were conducted in accordance with the relevant guidelines and regulations.

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Yamada, N.O., Wenduerma & Senda, T. Altered microbiota caused by disordered gut motility leads to an overactivation of intestinal immune system in APC1638T mice. Med Mol Morphol 56, 177–186 (2023). https://doi.org/10.1007/s00795-023-00352-1

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  • DOI: https://doi.org/10.1007/s00795-023-00352-1

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