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A recent single-cell survey of the small-intestinal epithelium suggests that mucosal pentraxin 2 (Mptx2) is a new Paneth cell marker, but its function and involved mechanism in the Paneth cell are still unknown. Therefore, we create Mptx2 knockout (Mptx2−/−) mice to investigate its precise effects on intestinal homeostasis using models of lipopolysaccharide (LPS), methicillin-resistant Staphylococcus aureus (MRSA) peritoneal infection, and dextran sulfate sodium (DSS)–induced intestinal injury and inflammation. We here find that Mptx2 is selectively expressed in Paneth cells in the small intestines of mice. Mptx2−/− mice have increased susceptibility to intestinal inflammation and injured. Mptx2 deficiency reduces Paneth cell count and expression of antimicrobial factors, leading to altered intestinal bacteria composition. Loss of Mptx2 aggravates MRSA infection–induced damage in the intestine while decreasing autophagy in Paneth cells. Mptx2−/− mice are more vulnerable to LPS-induced intestinal possibly due to inhibition of the autophagy/endoplasmic reticulum (ER) stress pathway. Mptx2−/− mice are susceptible to DSS-induced colitis that could be ameliorated by treatment with gentamicin or vancomycin antibiotics. In conclusion, Mptx2 is essential to maintain intestinal homeostasis potentially via regulation of autophagy in Paneth cells. Mucosal pentraxin 2 (Mptx2) is identified as a marker of Paneth cells, and its deficiency is shown to trigger microbiota dysbiosis and increased epithelial invasion by bacteria while also reducing secretory autophagy. [ABSTRACT FROM AUTHOR]

Background: Megacystis microcolon intestinal hypoperistalsis syndrome (MMIHS) is a rare and serious congenital disorder with poor outcomes, where a heterozygous missense mutation is present in the ACTG2 gene. Here, we aimed to investigate the pathogenesis of ACTG2 in MMIHS. Methods: A cohort with 20 patients with MMIHS was screened. Actg2R257C heterozygous mutant mice were generated using the CRISPR/Cas9 system. Gastrointestinal (GI) motility, voluntary urination, collagen gel contraction, and G‐actin/F‐actin analysis were performed. Key Results: The R257C variant of ACTG2 most frequently occurred in patients with MMIHS and demonstrated the typical symptoms of MMIHS. Actg2R257C heterozygous mutant mice had dilated intestines and bladders. The functional assay showed a prolonged total time of GI transit and decreased urine spot area. Collagen gel contraction assay and G‐actin/F‐actin analysis indicated that mutant mice showed reduced area of contraction of smooth muscle cells (SMCs) and impaired actin polymerization. Conclusions & Inferences: A mouse model demonstrating MMIHS‐like symptoms was generated. The Actg2R257C heterozygous variant impairs SMCs contraction by interfering with actin polymerization, leading to GI motility disorders. [ABSTRACT FROM AUTHOR]

Background: Megacystis microcolon intestinal hypoperistalsis syndrome (MMIHS) is a rare and serious congenital disorder with poor outcomes, where a heterozygous missense mutation is present in the ACTG2 gene. Here, we aimed to investigate the pathogenesis of ACTG2 in MMIHS., Methods: A cohort with 20 patients with MMIHS was screened. Actg2 R257C heterozygous mutant mice were generated using the CRISPR/Cas9 system. Gastrointestinal (GI) motility, voluntary urination, collagen gel contraction, and G-actin/F-actin analysis were performed., Key Results: The R257C variant of ACTG2 most frequently occurred in patients with MMIHS and demonstrated the typical symptoms of MMIHS. Actg2 R257C heterozygous mutant mice had dilated intestines and bladders. The functional assay showed a prolonged total time of GI transit and decreased urine spot area. Collagen gel contraction assay and G-actin/F-actin analysis indicated that mutant mice showed reduced area of contraction of smooth muscle cells (SMCs) and impaired actin polymerization., Conclusions & Inferences: A mouse model demonstrating MMIHS-like symptoms was generated. The Actg2 R257C heterozygous variant impairs SMCs contraction by interfering with actin polymerization, leading to GI motility disorders., (© 2022 John Wiley & Sons Ltd.)