the profound impact of factors produced in the small intestine upon processes required in the colon. The rise in bacterial load in the colon matched the overgrowth of Enterobacteriaceae, a finding commonly observed among models of intestinal inflammation and colitis. Therefore, the measured increase in abundance of LPS-P in the colon is likely due to a combination of reduced IAP activity and increased numbers of Gram-negative Enterobacteriaceae. What causes the bloom of Enterobacteriaceae remains to be established. Nevertheless, LPS-P is permeable to the mucosal barrier therefore higher LPS-P levels are likely to generate increased TLR4-dependent inflammation required for disease onset and progression in this recurrent food poisoning model of colitis. Neu3 induction following oral ST infection links an inflammatory mechanism to a chronic environmental trigger that may explain the origin of colitis among some human populations. Increased levels of intestinal Neu3 and reduced levels of IAP have also been observed in human colitis while inborn genetic deficiency of IAP in humans causes IBD, together providing support for oral IAP augmentation strategies in clinical trials5). Neu inhibition provides an equally efficacious approach in the mouse and possibly in humans1,4). Neu3 inhibition may be also therapeutic in cancers of the colon, renal, and prostate tissues; moreover, Neu3 deficiency in mice resulted in fewer colitis-associated colonic tumors2,6). In the context of the colitis model studied herein, the onset of disease signs and tissue damage spans multiple compartments and is more complex than can be explained simply by elevated LPS-P abundance and Tlr4 activation. Dysbiosis among the commensal Gram-negative microbiota and the erosion of the protective mucin barrier are hallmarks of colitis in mice and humans yet they cannot be explained at present by the currently known functions of Neu3, IAP, and TLR4, indicating that other ReferencesProgress after the Grant PeriodSince the grant award period ended, this research has continued and expanded to include investigations of the molecular mechanisms causing erosion of the mucin barrier of the colon in the onset and progression of colitis. The breakdown of the colonic mucin barrier, made up primarily of Mucin-2, is a key event in the pathogenesis of colitis among both mouse and human species. Mucin barrier erosion results in bacterial access to epithelial cells and greatly increases the inflammatory damage resulting in tissue ulceration, damage, and poor prognosis. The mechanism of mucin barrier erosion, which is modulated by Neu3 deficiency in our model system, remains an important but unresolved pathogenic factor. Our current studies are focused on identifying the factors involved in mucin barrier erosion. Future PerspectiveThe discovery that IAP is regulated in the intestinal tract and thereby linked to health and disease has provided significant corroboration for ongoing clinical studies focused on treating human inflammatory diseases (sepsis and colitis, for example) with alkaline phosphatase augmentation using recombinant IAP. In addition, our studies demonstrating that either neuraminidase inhibitors or Neu3 deficiency are similarly protective reveals another therapeutic approach that may be possible with the development of orally administered Neu3 inhibitors. (support for this research included the Mizutani Foundation for Glycoscience). 5) Lukas M, Drastich P, Konecny M, Gionchetti P, Urban O, Cantoni F, Bortlik M, Duricova D, Bulitta M. Exogenous alkaline phosphatase for the treatment 1) Yang, WH, Heithoff, DM, Aziz, PV, Sperandio, M, Nizet, V, Mahan, MJ, Marth, JD. Recurrent infection disables host protection against intestinal inflammation, Science (358): doi: 10.1126/science.aao5610, 2017. 2) Yamaguchi K, Shiozaki K, Moriya S, Koseki K, Wada T, Tateno H, Sato I, Asano M, Iwakura Y, Miyagi T. Reduced susceptibility to colitis-associated colon carcinogenesis in mice lacking plasma membrane-associated sialidase. PLoS One, (7): doi:10.1371/journal.pone.0041132, 2012. 3) Yang WH, Aziz PV, Heithoff DM, Mahan MJ, Smith JW, Marth JD. An intrinsic mechanism of secreted protein aging and turnover, Proc. Natl. Acad. Sci. USA (112): 13657-13662, 2015. 4) Yang WH, Westman JS, Heithoff DM, Sperandio M, Cho JW, Mahan MJ, Marth JD. Neu3 neuraminidase induction triggers intestinal inflammation and colitis in a model of recurrent human food poisoning. Proc. Natl. Acad. Sci. USA (118): doi: 10.1073/pnas.2100937118, 2021. of patients with moderate to severe ulcerative colitis. Inflamm. Bowel Dis. (16): 1180–1186, 2010.6) Kakugawa Y, Wada T, Yamaguchi K, Yamanami H, Ouchi K, Sato I, Miyagi M. Up-regulation of plasma membrane-associated ganglioside sialidase (Neu3) in human colon cancer and its involvement in apoptosis suppression. Proc. Natl. Acad. Sci. USA (99): 10718–10723, 2002. pathogenic mechanisms remain to be identified. Nevertheless, our identification of Neu3 as an essential component of pathogenesis indicates its potential value as a selective target for inhibition for the prevention and treatment of intestinal inflammation and colitis. 77
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