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Gastrointestinal Tract Pathology in a BALB/c Niemann–Pick Disease Type C1 Null Mouse Model

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Abstract

Background

Niemann–Pick disease, type C (NPC) is a rare lysosomal storage disorder characterized by progressive neurodegeneration, splenomegaly, hepatomegaly, and early death. NPC is caused by mutations in either the NPC1 or NPC2 gene. Impaired NPC function leads to defective intracellular transport of unesterified cholesterol and its accumulation in late endosomes and lysosomes. A high frequency of Crohn disease has been reported in NPC1 patients, suggesting that gastrointestinal tract pathology may become a more prominent clinical issue if effective therapies are developed to slow the neurodegeneration. The Npc1nih mouse model on a BALB/c background replicates the hepatic and neurological disease observed in NPC1 patients. Thus, we sought to characterize the gastrointestinal tract pathology in this model to determine whether it can serve as a model of Crohn disease in NPC1.

Methods

We analyzed the gastrointestinal tract and isolated macrophages of BALB/cJ cNctr-Npc1m1N/J (Npc1−/−) mouse model to determine whether there was any Crohn-like pathology or inflammatory cell activation. We also evaluated temporal changes in the microbiota by 16S rRNA sequencing of fecal samples to determine whether there were changes consistent with Crohn disease.

Results

Relative to controls, Npc1 mutant mice demonstrate increased inflammation and crypt abscesses in the gastrointestinal tract; however, the observed pathological changes are significantly less than those observed in other Crohn disease mouse models. Analysis of Npc1 mutant macrophages demonstrated an increased response to lipopolysaccharides and delayed bactericidal activity; both of which are pathological features of Crohn disease. Analysis of the bacterial microbiota does not mimic what is reported in Crohn disease in either human or mouse models. We did observe significant increases in cyanobacteria and epsilon-proteobacteria. The increase in epsilon-proteobacteria may be related to altered cholesterol homeostasis since cholesterol is known to promote growth of this bacterial subgroup.

Conclusions

Macrophage dysfunction in the BALB/c Npc1−/− mouse is similar to that observed in other Crohn disease models. However, neither the degree of pathology nor the microbiota changes are typical of Crohn disease. Thus, this mouse model is not a good model system for Crohn disease pathology reported in NPC1 patients.

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Abbreviations

NPC1:

Niemann–Pick disease, type C1

IBD:

Inflammatory bowel disease

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Acknowledgments

We thank Dr. Laetitia Dorso and Dr. Jerome Abadie (Oniris, Atlampole-La Chanterie, Nante, France) for the pathological analysis. We thank the NICHD Molecular genomic core for the 16S sequencing and analysis of the results.

Funding

This work was supported by the intramural research program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. C.A.W. is an NIH/Oxford Scholar.

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Author notes

  1. Antony Cougnoux and Miyad Movassaghi have equally contributed to this work.

Authors and Affiliations

  1. Department of Health and Human Services, National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD, 20892, USA

    Antony Cougnoux, Miyad Movassaghi, Jaqueline A. Picache, James R. Iben, Alexander Salman, Kyle Martin, Nicole Y. Farhat, Celine Cluzeau, Wei-Chia Tseng, Kathryn Burkert, Caitlin Sojka, Christopher A. Wassif, Niamh X. Cawley & Forbes D. Porter

  2. Department of Health and Human Services, National Institutes of Health, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, MD, 20892, USA

    Fatemeh Navid

  3. Microbes, Inflammation, Intestin et Susceptibilité de l’Hôte (M2iSH), Inserm U1071, INRA USC2018, Clermont Université, Université d’Auvergne, Clermont-Ferrand, France

    Richard Bonnet

  4. Laboratoire de Bactériologie, Center Hospitalier Universitaire, Clermont-Ferrand, France

    Richard Bonnet

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  1. Antony Cougnoux
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  2. Miyad Movassaghi
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Contributions

AC and MM performed and analyzed the experiments. JAP, FN, AS, KM, NYF, CC, W-CT, KB, CS, CAW, and NXC provided experimental and technical support. JRI performed bioinformatics analysis. RB organized the pathological analysis and provided experimental advice. FDP provided experimental input. AC, MM, NXC, FN, RB, and FDP participated in the writing of the manuscript. All authors approved the final manuscript.

Corresponding author

Correspondence to Forbes D. Porter.

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Cougnoux, A., Movassaghi, M., Picache, J.A. et al. Gastrointestinal Tract Pathology in a BALB/c Niemann–Pick Disease Type C1 Null Mouse Model. Dig Dis Sci 63, 870–880 (2018). https://doi.org/10.1007/s10620-018-4914-x

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