Abstract
Microvillus inclusion disease (MVID) is a rare congenital severe malabsorptive and secretory diarrheal disease characterized by blunted or absent microvilli with accumulation of secretory granules and inclusion bodies in enterocytes. The typical clinical presentation of the disease is severe chronic diarrhea that rapidly leads to dehydration and metabolic acidosis. Despite significant advances in our understanding of the causative factors, to date, no curative therapy for MVID and associated diarrhea exists. Prognosis mainly relies on life-long total parenteral nutrition (TPN) and eventual small bowel and/or liver transplantation. Both TPN and intestinal transplantation are challenging and present with many side effects. A breakthrough in the understanding of MVID emanated from seminal findings revealing mutations in MYO5B as a cause for MVID. During the last decade, many studies have thus utilized cell lines and animal models with knockdown of MYO5B to closely recapitulate the human disease and investigate potential therapeutic options in disease management. We will review the most recent advances made in the research pertaining to MVID. We will also highlight the tools and models developed that can be utilized for basic and applied research to increase our understanding of MVID and develop novel and effective targeted therapies.
Highlights
Microvillus inclusion disease (MVID) is a rare congenital severe malabsorptive and secretory diarrheal disease characterized by blunted or absent microvilli with accumulation of secretory granules and inclusion bodies in enterocytes
An important factor which should be accounted for during histological evaluation of Differential diagnosis There are several features that differentiate MVID from other diarrheal conditions with similar clinical presentation including the onset at birth, absence of inflammation, presence of vacuoles containing granules with the characteristic periodic acid Schiff (PAS) and CD10 positive stain observed under light microscopy, and presence of microvillus inclusions (MIs) (Table 1)
Understanding the pathophysiological mechanisms of malabsorption should improve current management protocols and immensely enhance our knowledge regarding intestinal physiology. In this regard, increased understanding of the intriguing malabsorptive disorders of childhood such as MVID should offer new insights at the cellular and molecular levels to unravel the link between cellular trafficking and epithelial absorptive processes
Summary
MTTP (microsomal triglyceride transfer protein)[19] Fat vacuoles with foamy cytoplasm and normal villi enterocytes distinguishes tufting enteropathy from MVID. Similar to studies in cell lines and patients with MVID, intestinal tissues from MYO5B-knockout mice showed decreased localization of apical protein NHE3 but not CFTR42. Because of the presence of all types of epithelial cells and the self-renewing capacity of the enteroids, Caenorhabditis elegans nematode model very simple, consisting of only a few enterocytes, the C. elegans nematode model possesses a close resemblance to human intestinal epithelium with distinct polarization of apical and basolateral membranes with a prominent microvillus brush border In this regard, by silencing various components in the V-ATPase complex (an important regulator of cellular trafficking), the authors identified that specific subunits of the protein complex, in particular V0, are upstream of other genetic defects which leads to a MVID-like phenotype in this model[45]. Dipeptidyl peptidase-4 (DPPIV) enzyme was mistrafficked and the liver bile canaliculi lacked branching, highlighting the importance of MYO5B in studying liver dysfunction associated with MVID patients[49]
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