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Lubiprostone Decreases Mouse Colonic Inner Mucus Layer Thickness and Alters Intestinal Microbiota

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Abstract

Background

Lubiprostone has been used to treat constipation through its effects to stimulate Cl− secretion, resulting in water and electrolyte secretion.

Aim

Potential associated changes in intestinal mucus and the colonizing bacteria (microbiome) have not been studied. As mucus obstructions may play a role in cystic fibrosis, the hypothesis that lubiprostone alters intestinal mucus and the microbiome was investigated.

Methods

Ion transport studies were performed ex vivo. For mucus and microbiome studies, mice were gavaged daily with lubiprostone or vehicle. Mucin from intestinal sections was analyzed in Carnoy’s fixed tissues stained with Alcian blue. Microbiome composition was analyzed by 16S rRNA gene-based sequencing.

Results

Lubiprostone stimulated short circuit current in all mouse intestinal segments after both serosal and mucosal additions, albeit at lower concentrations in the latter. Current was Cl-dependent and blocked by mucosal diphenylcarboxylic acid, serosal bumetanide, and serosal Ba++. The CFTR inhibitor CFTRinh172 had a marginal effect. Mucus near epithelial cells (inner layer mucus) was not present in the small intestine of any mice. Proximal colon inner mucus layer was thicker in ∆F/∆F compared with +/∆F and +/+ mice. Lubiprostone decreased inner mucus layer thickness in both proximal and distal colon of all mice. Furthermore, lubiprostone altered the intestinal microbiome by increasing abundance of Lactobacillus and Alistipes.

Conclusions

Lubiprostone activates non-CFTR Cl− secretion and alters the colonic inner mucus layer, which is associated with changes in the composition of the enteric microbiome.

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Acknowledgments

Supported by a grant from Takeda Pharmaceuticals North America, Inc., NIH Digestive Disease Research Center grant DK-42086 (E.B.C.), NIH grant R37 DK47722 (E.B.C.), the University of Chicago Cancer Research Center (CA-01459), a fellowship grant from the Crohn’s and Colitis Foundation of America (Y.W.), NIH grant HD059123 (E.C.C.).

Conflict of interest

The authors disclose no other potential conflicts of interests or financial relationship with the organization that sponsored the research.

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Authors and Affiliations

  1. Division of Biological Sciences, Department of Medicine, The University of Chicago, 900 E. 57th St., Chicago, IL, 60637, USA

    Mark W. Musch, Yunwei Wang, Erika C. Claud & Eugene B. Chang

  2. Division of Biological Sciences, Department of Pediatrics, The University of Chicago, 900 E. 57th St., Chicago, IL, 60637, USA

    Erika C. Claud

  3. Knapp Center for Biomedical Discovery, The University of Chicago, 900 E. 57th St., Chicago, IL, 60637, USA

    Eugene B. Chang

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  1. Mark W. Musch
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  2. Yunwei Wang
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Correspondence to Eugene B. Chang.

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Musch, M.W., Wang, Y., Claud, E.C. et al. Lubiprostone Decreases Mouse Colonic Inner Mucus Layer Thickness and Alters Intestinal Microbiota. Dig Dis Sci 58, 668–677 (2013). https://doi.org/10.1007/s10620-012-2509-5

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  • DOI: https://doi.org/10.1007/s10620-012-2509-5

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