Taurodeoxycholate ameliorates DSS-induced colitis in mice.

BACKGROUND: Inflammatory bowel disease (IBD) is typically managed using medications such as 5-aminosalicylic acid (5-ASA), glucocorticoids, anti-TNFα Ab, or anti-IL-12/23 Ab. However, some patients do not respond well to these treatments or frequently experience relapses. Therefore, alternative therapeutic options are needed. Since the activation of the inflammasome is crucial to the pathogenesis of IBD, inhibiting the inflammasome may be beneficial for patients. MATERIALS AND METHODS: We tested the efficacy of taurodeoxycholate (TDCA), which is a known G-protein coupled receptor 19 (GPCR19) agonist, in a mouse colitis model induced by dextran sodium sulfate (DSS). RESULTS: In the mouse colitis model, TDCA prevented loss of body weight, shortening of the colon, production of pro-inflammatory cytokines, infiltration of pro-inflammatory cells, and mucosal ulceration in the colon. In vitro, TDCA inhibited the activation of NF-κB in bone marrow-derived macrophages (BMDMs) by activating the cAMP-PKA axis. TDCA downregulated the expression of purinergic receptor P2X7 (P2X7R) and enhanced the colocalization of P2X7R with GPCR19, and inhibited the Ca2+ mobilization of BMDMs when stimulated with ATP or BzATP, which plays a pivotal role in activating the NLRP3 inflammasome (N3I) via P2X7R. TDCA inhibited the oligomerization of NLRP3-ASC and downregulated the expression of NLRP3 and ASC, as well as suppressed the maturation of pro-caspase-1 and pro-IL-1ß. TDCA also increased the percentage of M2 macrophages while decreasing the number of M1 macrophages, Th1, Th2, and Th17 cells in the colon. CONCLUSION: TDCA ameliorated DSS-induced colitis in mice, possibly by inhibiting both the priming phase (via the GPCR19-cAMP-PKA-NF-κB axis) and the activation phase (via the GPCR19-P2X7R-NLRP3-Caspase 1-IL-1ß axis) of N3I signaling.

Detection of Salmonella genes in stool samples of children aged 5 years and younger in urban and rural areas of Bangladesh.

INTRODUCTION: Typhoid incidence in children is higher in urban areas than in rural areas of Bangladesh. This study examined whether healthy urban children harboured higher levels of Salmonella genes than healthy rural children. METHODOLOGY: Stool samples from 140 children were studied: 70 from rural areas and 70 from urban metropolitan areas. RESULTS: The stool samples of urban children contained more Salmonella genes (median 4, IQR 3-4) than those of rural children (median 3, IQR 3-4). This suggests that urban Bangladeshi children have more Salmonella genes in their guts than rural children. Especially, in those under 12 months of age, the Salmonella gene prevalence in urban children was unique. They had more Salmonella genes (median 4, IQR 4-5) than rural children in the same age group (median 3, IQR 2.5-4). We also found more Salmonella genes in urban children who drank tap water (median 4, IQR 3-5) than in rural children whose water source was tube well water (median 3, IQR 2-4) and boiled pond water (median 3, IQR 3-3.5). However, there was no significant difference of Salmonella genes between urban children who drank tap-water and children whose water source was a tube well (median 4, IQR 3-4). CONCLUSIONS: These data suggest that the urban environment, including the drinking water supply system, increases the likelihood of healthy children in urban areas harbouring more potentially pathogenic Salmonella organisms in their gut than found in rural healthy children.

Insights Into the Emergence of Paroxysmal Nocturnal Hemoglobinuria.

Paroxysmal Nocturnal Hemoglobinuria (PNH) is a disease as simple as it is complex. PNH patients develop somatic loss-of-function mutations in phosphatidylinositol N-acetylglucosaminyltransferase subunit A gene (PIGA), required for the biosynthesis of glycosylphosphatidylinositol (GPI) anchors. Ubiquitous in eukaryotes, GPI anchors are a group of conserved glycolipid molecules responsible for attaching nearly 150 distinct proteins to the surface of cell membranes. The loss of two GPI-anchored surface proteins, CD55 and CD59, from red blood cells causes unregulated complement activation and hemolysis in classical PNH disease. In PNH patients, PIGA-mutant, GPI (-) hematopoietic cells clonally expand to make up a large portion of patients' blood production, yet mechanisms leading to clonal expansion of GPI (-) cells remain enigmatic. Historical models of PNH in mice and the more recent PNH model in rhesus macaques showed that GPI (-) cells reconstitute near-normal hematopoiesis but have no intrinsic growth advantage and do not clonally expand over time. Landmark studies identified several potential mechanisms which can promote PNH clonal expansion. However, to what extent these contribute to PNH cell selection in patients continues to be a matter of active debate. Recent advancements in disease models and immunologic technologies, together with the growing understanding of autoimmune marrow failure, offer new opportunities to evaluate the mechanisms of clonal expansion in PNH. Here, we critically review published data on PNH cell biology and clonal expansion and highlight limitations and opportunities to further our understanding of the emergence of PNH clones.