217: Ptpn2 Loss-of-Function Reduces Vitamin B12 Levels in Genotyped Crohn's Disease Patients and Intestinal Brush Border Expression of the B12 Transporter, Cubilin, in Mice

Manz, Salomon; Canale, Vinicius; Crawford, Meli’sa; Chaterjee, Pritha; Lei, Andy; Santos, Alina N.; Shawki, Ali; Spalinger, Marianne R.; Scharl, Michael; McCole, Declan F.

doi:10.1016/s0016-5085(22)60097-0

Cited by 1 publication

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“…It was proposed that inflammation-induced reduction in the ileal cobalamin receptor expression leads to impaired absorption of cobalamin, causing hypocobalaminemia or cobalamin deficiency in CIE [ 42 ]. Significant changes in intestinal mucosal gene and protein expression profiles are reported in IBD in people [ 43 – 45 ] and CIE in dogs [ 46 ]. As an example, proinflammatory cytokines, such as tumor necrosis factor-alpha ( TNFA ), were shown to be increased in people with IBD [ 47 ] and dogs with CIE [ 48 ].…”

Section: Introductionmentioning

confidence: 99%

Expression of the cobalamin transporters cubam and MRP1 in the canine ileum–Upregulation in chronic inflammatory enteropathy

Kather,

Kacza,

Pfannkuche

et al. 2024

PLoS ONE

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Chronic inflammatory enteropathy (CIE) in dogs, a spontaneous model of human inflammatory bowel disease (IBD), is associated with a high rate of cobalamin deficiency. The etiology of hypocobalaminemia in human IBD and canine CIE remains unknown, and compromised intestinal uptake of cobalamin resulting from ileal cobalamin receptor deficiency has been proposed as a possible cause. Here, we evaluated the intestinal expression of the cobalamin receptor subunits, amnionless (AMN) and cubilin (CUBN), and the basolateral efflux transporter multi-drug resistance protein 1 (MRP1) in 22 dogs with CIE in comparison to healthy dogs. Epithelial CUBN and AMN levels were quantified by confocal laser scanning microscopy using immunohistochemistry in endoscopic ileal biopsies from dogs with (i) CIE and normocobalaminemia, (ii) CIE and suboptimal serum cobalamin status, (iii) CIE and severe hypocobalaminemia, and (iv) healthy controls. CUBN and MRP1 expression was quantified by RT-qPCR. Receptor expression was evaluated for correlation with clinical patient data. Ileal mucosal protein levels of AMN and CUBN as well as mRNA levels of CUBN and MRP1 were significantly increased in dogs with CIE compared to healthy controls. Ileal cobalamin receptor expression was positively correlated with age, clinical disease activity index (CCECAI) score, and lacteal dilation in the ileum, inversely correlated with serum folate concentrations, but was not associated with serum cobalamin concentrations. Cobalamin receptor downregulation does not appear to be the primary cause of hypocobalaminemia in canine CIE. In dogs of older age with severe clinical signs and/or microscopic intestinal lesions, intestinal cobalamin receptor upregulation is proposed as a mechanism to compensate for CIE-associated hypocobalaminemia. These results support oral supplementation strategies in hypocobalaminemic CIE patients.

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