Project description:The maintenance of tissue-specific chronic inflammation results from the interplay of genetic and unidentified environmental factors. Here, we describe an immunoregulatory role for an environmentally driven microbial metabolite in Card14E138A/+-induced spontaneous psoriasis. Through metabolite screening, we demonstrate chronic skin inflammation is accompanied by alterations microbial metabolite. Notably, depletion of gut, not skin, microbes alleviates disease symptoms. We further identify indoxyl sulfate (I3S), a bacteriogenic metabolite, as a key driver of psoriatic inflammation and confirm that gut-resident indole-producing microbiota mediate this process. Mechanistically, indole-producing microbiota promote host I3S biothsynthesis via a metabolic relay, and I3S potentiates skin inflammation by reshaping chromatin accessibility in skin Th17 cells through AHR signaling. In human psoriasis cohorts, serum I3S levels correlate with disease severit. In summary, our study uncovers a mechanistic link between gut microbial factors and type 3 skin inflammation, highlighting targeting gut microbiota as a strategy for mitigating skin inflammation.
Project description:The spread of inflammation from the skin to the joints is a key issue in the pathogenesis of psoriatic arthritis (PsA). Psoriasis (PsO), one of the most common skin diseases, usually precedes joint manifestations, suggesting skin-joint disease spread, which occurs in about 30% of psoriasis patients. Until now, it has been unclear why the inflammatory process remains restricted to the skin in some patients with PsO, whereas it spreads to tendons and joints in others. Using a preclinical model of PsA, we aimed to elucidate the skin-joint axis, i.e. the spread of psoriatic inflammation from the skin to the joints. KAEDE transgenic mice expressing a photo-convertible fluorescent reporter were used to assess cell trafficking from inflamed skin to other organs in the mouse model of IL-23 overexpression (IL-23OE) induced PsA. Psoriatic skin lesions were irradiated with UV light to induce the photoswitch from KAEDE-GREEN to KAEDE-RED. Migrating cells were characterised by scRNAseq.
Project description:Vitiligo is a common autoimmune skin disorder. We constructed an induced vitiligo mouse model and performed bulk-RNA sequencing on the skin and 16S rRNA sequencing of feces from vitiligo mice and uninduced mice. Next, we performed skin bulk-RNA sequencing after treatment using ABX. Lastly, we subjected gut microbe-related metabolite hippuric acid to control mice and performed bulk-RNA sequencing on the skin to observe oxidative stress-related gene expression changes.
Project description:In this study we evaluated the role of hyaluronan (HA) in reactive adipogenesis, a local expansion of preadipocytes that provides host defense by release of antimicrobial peptides. We observed that HA accumulated during maturation of adipocytes in vitro and was associated with increased expression of preadipocyte factor 1 (Pref-1), Zinc finger protein 423 (Zfp423) and early B cell factor 1 (Ebf1). Although HA is normally abundant in the extracellular matrix, a further increase in HA staining occurred in mice at sites of reactive adipogenesis following injury of colon by dextran sodium sulfate or injury of skin from infection with S. aureus. HA also abundantly accumulated around adipocytes seen in the colon of patients with inflammatory bowel disease. This HA was necessary for adipocyte maturation since digestion of HA by administration of soluble hyaluronidase or transgenic expression of hyaluronidase 1 inhibited adipogenesis in vitro and in vivo. Furthermore, hyaluronidase also suppressed inflammation of both skin and colon and decreased antimicrobial peptide expression by developing preadipocytes. This resulted in increased bacterial transit across the epithelial barrier despite decreased tissue injury from inflammation. These observations suggest HA plays an important role in reactive adipogenesis and host defense after injury.
Project description:The migratory locust, Locusta migratoria, is a serious agricultural pest and important insect model to study insect digestion and feeding behavior. The gut is one of the primary interfaces between the insect and its environment. Nevertheless, knowledge on the gut transcriptome of L. migratoria is still very limited. With the development of two EST databases from L. migratoria (whole body and central nervous system (CNS)) and one EST database from Schistocerca gregaria (CNS), an abundance of transcript data was made available for locusts. In addition, the genome of Locusta was also recently published in an effort to create a better understanding of swarm formation and flight behavior (Wang et al., 2014). While the transcript composition of nervous tissue was relatively well studied after the development of the specific CNS-derived EST-databases from both L. migratoria and S. gregaria, little transcript profiling information is available for the digestive system at the moment. Locusts are, however, widely used as physiological model organisms regarding the regulation and control of feeding and digestion, and improved knowledge on the gut transcriptome could contribute significantly to a better understanding of their gut physiology. Therefore, we aimed to use the available sequence data to specifically identify gut-expressed transcripts in 5th larval locusts. By means of two independent self-self microarray hybridizations for two distinct tissues, the gut and the brain, a selection could be made of those ESTs that are present in the gut and/or the brain. Here, sequences that were found to be expressed in gut but not brain were further functionally annotated to shed new light on the complex physiology of the locust digestive system. Since the gut is the single most important organ in digestion, and both tissues are assumed to be involved in the regulation thereof, the resulting subset of sequences can also be valuable for further in-depth studies on the regulation of digestion. In addition, the method allowed us to rank the signal intensities, using them as a rough indicator to compare relative transcript abundance in the gut. Therefore, the data complement previously published transcript and genomic data, and provide a clear overview of the expressed portion of the genome in the gut. Taken together, the present data provide significant insight into locust larval gut physiology, and will be valuable for future studies on the insect gut. Self-self hybridisation of Cy5- and Cy3-labeled samples. One biological repeat per tissue type, i.e., brain and gut. Gut is a combination of foregut, midgut, gastric caeca and hindgut. Per tissue type, a pool was made from RNA from 3 pools of 5 locusts, and this for 3 different feeding conditions, resulting in samples derived from a total of 45 locust larvae. Feeding conditions were normally fed, fed with diet containing additional protease inhibitors (PIs), and starved locusts.
Project description:Dysbiosis in the gut microbiota impacts several systemic diseases. One possible mechanism is the migration of perturbed intestinal immunocytes to extra-intestinal tissues. Combining the Kaede photoconvertible mouse model and single-cell genomics, we generated a detailed map of migratory trajectories from the colon, at baseline and during intestinal and extra-intestinal inflammation. All colonic lineages emigrated from the colon in an S1P-dependent manner, dominated by B lymphocytes with a large continuous circulation of follicular B cells, which carried a gut-imprinted transcriptomic signature. T cell emigration was more selective, with distinct groups of RORg+ cells and IEL-like CD160+ T cells in the spleen. Gut inflammation curtailed emigration, except for DCs disseminating to lymph nodes. Colon emigrating cells distributed differentially to tumor, skin inflammation, or arthritic synovium, the former dominated by myeloid cells in a chemokine-dependent manner. These results thus reveal specific cellular trails originating in the gut, influenced by microbiota, which can shape peripheral immunity.
Project description:Patients diagnosed with cutaneous and/or gastrointestinal aGvHD provide a unique opportunity to perform an in-depth comparison of activated human CD8+ T cells homing to the gut and skin, in some cases even within the same host, at the same time, acting as key players in the same human disease, and exerting their effector functions in these two tissue environments. This study aims at the identification of novel biomarkers associated with skin- and gut-homing CD8+ T cells in general, and CD8+ T cell markers possibly linked to CTL-mediated skin- and gut damage in aGvHD in particular.
Project description:The migratory locust, Locusta migratoria, is a serious agricultural pest and important insect model to study insect digestion and feeding behavior. The gut is one of the primary interfaces between the insect and its environment. Nevertheless, knowledge on the gut transcriptome of L. migratoria is still very limited. With the development of two EST databases from L. migratoria (whole body and central nervous system (CNS)) and one EST database from Schistocerca gregaria (CNS), an abundance of transcript data was made available for locusts. In addition, the genome of Locusta was also recently published in an effort to create a better understanding of swarm formation and flight behavior (Wang et al., 2014). While the transcript composition of nervous tissue was relatively well studied after the development of the specific CNS-derived EST-databases from both L. migratoria and S. gregaria, little transcript profiling information is available for the digestive system at the moment. Locusts are, however, widely used as physiological model organisms regarding the regulation and control of feeding and digestion, and improved knowledge on the gut transcriptome could contribute significantly to a better understanding of their gut physiology. Therefore, we aimed to use the available sequence data to specifically identify gut-expressed transcripts in 5th larval locusts. By means of two independent self-self microarray hybridizations for two distinct tissues, the gut and the brain, a selection could be made of those ESTs that are present in the gut and/or the brain. Here, sequences that were found to be expressed in gut but not brain were further functionally annotated to shed new light on the complex physiology of the locust digestive system. Since the gut is the single most important organ in digestion, and both tissues are assumed to be involved in the regulation thereof, the resulting subset of sequences can also be valuable for further in-depth studies on the regulation of digestion. In addition, the method allowed us to rank the signal intensities, using them as a rough indicator to compare relative transcript abundance in the gut. Therefore, the data complement previously published transcript and genomic data, and provide a clear overview of the expressed portion of the genome in the gut. Taken together, the present data provide significant insight into locust larval gut physiology, and will be valuable for future studies on the insect gut.