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Caspase-11–mediated enteric neuronal pyroptosis underlies Western diet–induced colonic dysmotility
Lan Ye, … , Wenhui Hu, Shanthi Srinivasan
Lan Ye, … , Wenhui Hu, Shanthi Srinivasan
Published June 2, 2020
Citation Information: J Clin Invest. 2020;130(7):3621-3636. https://doi.org/10.1172/JCI130176.
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Research Article Gastroenterology Neuroscience

Caspase-11–mediated enteric neuronal pyroptosis underlies Western diet–induced colonic dysmotility

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Abstract

Enteric neuronal degeneration, as seen in inflammatory bowel disease, obesity, and diabetes, can lead to gastrointestinal dysmotility. Pyroptosis is a novel form of programmed cell death but little is known about its role in enteric neuronal degeneration. We observed higher levels of cleaved caspase-1, a marker of pyroptosis, in myenteric ganglia of overweight and obese human subjects compared with normal-weight subjects. Western diet–fed (WD-fed) mice exhibited increased myenteric neuronal pyroptosis, delayed colonic transit, and impaired electric field stimulation–induced colonic relaxation responses. WD increased TLR4 expression and cleaved caspase-1 in myenteric nitrergic neurons. Overactivation of nitrergic neuronal NF-κB signaling resulted in increased pyroptosis and delayed colonic motility. In caspase-11–deficient mice, WD did not induce nitrergic myenteric neuronal pyroptosis and colonic dysmotility. To understand the contributions of saturated fatty acids and bacterial products to the steps leading to enteric neurodegeneration, we performed in vitro experiments using mouse enteric neurons. Palmitate and lipopolysaccharide (LPS) increased nitrergic, but not cholinergic, enteric neuronal pyroptosis. LPS gained entry to the cytosol in the presence of palmitate, activating caspase-11 and gasdermin D, leading to pyroptosis. These results support a role of the caspase-11–mediated pyroptotic pathway in WD-induced myenteric nitrergic neuronal degeneration and colonic dysmotility, providing important therapeutic targets for enteric neuropathy.

Authors

Lan Ye, Ge Li, Anna Goebel, Abhinav V. Raju, Feng Kong, Yanfei Lv, Kailin Li, Yuanjun Zhu, Shreya Raja, Peijian He, Fang Li, Simon Musyoka Mwangi, Wenhui Hu, Shanthi Srinivasan

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Figure 1

Increased neuronal pyroptosis in colonic myenteric neurons in overweight and obese subjects compared with normal-weight controls.

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Increased neuronal pyroptosis in colonic myenteric neurons in overweight...
Sections of human colons obtained as described in the Methods. (A) Immunostaining for cleaved caspase-1 (CC1, green), Tuj-1 (red), and DAPI staining (blue) in myenteric plexus. Arrows show the pyroptotic enteric neurons. Scale bars: 100 μm. Bottom left: Histogram shows the percentage of Tuj-1+ neurons that are CC1+. Normal subjects, n = 13. Overweight subjects, n = 7. Obese subjects, n = 7. Bottom right: The correlation analysis between the percentage of enteric neuronal pyroptosis and BMI. R2 = 0.6791; P < 0.0001. (B) Immunostaining for CC1, nNOS, and ChAT and DAPI in human colon sections from normal-weight and obese individuals. Scale bars: 100 μm. Histograms show the percentage of nNOS+ and ChAT+ neurons that are CC1+. n = 5 per group. Data presented as the mean ± SEM. *P < 0.05; **P < 0.001; ***P < 0.001; ****P < 0.0001 by 1-way ANOVA with Dunnett’s multiple-comparisons test and Bartlett’s test of equal variances (A) or unpaired t test with F test comparison of variances (B).

Copyright © 2021 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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