Spontaneous mutant in threespine stickleback connects endosome trafficking disorders and inflammatory bowel diseases via changes in the gut microbiome

Abstract

Endosomes are organelles that sort and traffic materials to different cellular compartments to enable performance of other organelles. One group of organelles supported by endosomes are lysosome related organelles (LROs) - which perform specialized functions using endocytosed or recycled materials from endosomes. LROs include melanosomes, lytic granules, platelet dense granules, lamellar bodies, and more. Individuals with endosome trafficking disorders commonly present with oculocutaneous albinism due to insufficient trafficking to - and maturation of - melanosomes. While the loss of pigment is an easily identifiable phenotype, mutations in endosome trafficking can also cause multi-organ system symptoms due to more broad disruption of LROs. Different endosome trafficking mutations impact LRO maturation at different degrees of severity and can impact a subset or all LROs leading to a wide range of symptomologies. Endosome trafficking disorders can present with oculocutaneous albinism (caused by mutated melanosomes), blood diathesis (caused by mutated platelet dense granules), pulmonary fibrosis (caused by mutated lamellar bodies), or chronic inflammation and inflammatory bowel disease (IBD) (caused by mutated lytic granules), as well as other symptoms. The shared inflammatory patterns of Hermansky-Pudlak Syndrome (HPS) and Inflammatory Bowel Disease (IBD) are well studied. However, impacts of this shared gastrointestinal inflammation on the gut microbiome remain unexplored. Using a spontaneously identified mutant family of threespine stickleback fish, we characterize changes in LROs and symptoms of oculocutaneous albinism. We further demonstrate that the shared gastrointestinal phenotypes of HPS and IBD extend to the gut microbiome showing similar shifts in microbial communities consistent with IBD. We argue endosome trafficking models should be explored as models to study the gut microbiome in addition to inflammatory phenotypes in IBD, and importantly, be used to test microbial/dietary interventions for both IBD and endosome trafficking disorders.