Digestive Diseases and Sciences

, Volume 63, Issue 4, pp 870–880 | Cite as

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

  • Antony Cougnoux
  • Miyad Movassaghi
  • Jaqueline A. Picache
  • James R. Iben
  • Fatemeh Navid
  • Alexander Salman
  • Kyle Martin
  • Nicole Y. Farhat
  • Celine Cluzeau
  • Wei-Chia Tseng
  • Kathryn Burkert
  • Caitlin Sojka
  • Christopher A. Wassif
  • Niamh X. Cawley
  • Richard Bonnet
  • Forbes D. PorterEmail author
Original Article



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 Npc1 nih 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.


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.


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.


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.


Niemann–Pick disease type C Gastrointestinal tract Microbiota Macrophage dysfunction Crohn disease 



Niemann–Pick disease, type C1


Inflammatory bowel disease



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.

Author’s contribution

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.


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.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no competing interests.


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Copyright information

© This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2018

Authors and Affiliations

  • Antony Cougnoux
    • 1
  • Miyad Movassaghi
    • 1
  • Jaqueline A. Picache
    • 1
  • James R. Iben
    • 1
  • Fatemeh Navid
    • 2
  • Alexander Salman
    • 1
  • Kyle Martin
    • 1
  • Nicole Y. Farhat
    • 1
  • Celine Cluzeau
    • 1
  • Wei-Chia Tseng
    • 1
  • Kathryn Burkert
    • 1
  • Caitlin Sojka
    • 1
  • Christopher A. Wassif
    • 1
  • Niamh X. Cawley
    • 1
  • Richard Bonnet
    • 3
    • 4
  • Forbes D. Porter
    • 1
    Email author
  1. 1.Department of Health and Human Services, National Institutes of HealthEunice Kennedy Shriver National Institute of Child Health and Human DevelopmentBethesdaUSA
  2. 2.Department of Health and Human Services, National Institutes of HealthNational Institute of Arthritis and Musculoskeletal and Skin DiseasesBethesdaUSA
  3. 3.Microbes, Inflammation, Intestin et Susceptibilité de l’Hôte (M2iSH), Inserm U1071, INRA USC2018Clermont Université, Université d’AuvergneClermont-FerrandFrance
  4. 4.Laboratoire de BactériologieCenter Hospitalier UniversitaireClermont-FerrandFrance

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