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In this study, we investigated whether L-theanine (LTA) ameliorates adverse pregnancy outcomes in high-fat diet (HFD)-induced gestational obesity mice. Gestational obese mice models received HFD and fecal microbiota transplantation (FMT) from pregnant obese women, followed by LTA treatment. Gut microbiota DNA from six obese and six normal pregnant women was analyzed. Also assessed were lipid profiles, inflammatory factors, gut permeability, FXR/FGF15 expression, pup weight, and placental function. Alpha- and beta-diversity analyses showed reduced gut microbial diversity in the obese pregnant women. Postpartum hemorrhage, cholesterol, and triglycerides inversely correlated with Weissella , while BMI was positively associated with Escherichia-Shigella . Neonatal weight correlated positively with Subdoligranulum and negatively with Megamonas . Fasting glucose was significantly positively associated with Bacteroides vulgatus , whereas neonatal body weight inversely correlated with Eubacterium ramulus . In gestational obesity mice, LTA administration reduced weight gain, visceral/gonadal adiposity, metabolic markers (fasting glucose/insulin/cholesterol), gut barrier dysfunction (TNF-α, IL-6, IL-8, Claudin-2), and linked to FXR/FGF15 pathway alterations. Furthermore, LTA intervention suppressed MCP-1, IL-1β, F4/80 and hepatic lipid metabolism regulators (CD36, SREBP1c, SCD1, GLUT4, Cyp7a1, IRS-1), while also mitigating placental tissue junction zone abnormalities and pup weight. To sum up, LTA-mediated attenuation of adverse pregnancy outcomes associates with FXR/FGF15 pathway alterations, concomitant with restoration of metabolic homeostasis and inflammation suppression.

Immunoglobulin A (IgA) nephropathy (IgAN) is characterized by the deposition of IgA1 in the glomerular mesangium, which induces secondary glomerular and tubulointerstitial inflammation and subsequently leads to podocyte apoptosis and fibrosis. This condition often progresses to end-stage renal disease and lacks effective targeted treatment. Our study aimed to explore the role of M2 macrophage-mediated Ubiquitin C-terminal hydrolase L1 (UCHL1) expression in podocytes and its potential impact on the progression of IgAN. This study established an IgAN cellular model by exposing podocytes to aggregated IgA1 (aIgA1)-treated glomerular mesangial cells supernatants and assessed the impact of M2 macrophage polarization on UCHL1 expression and podocyte apoptosis. Additionally, we utilized siRNA technology and overexpression constructs to investigate the direct effects of UCHL1 modulation on podocyte apoptosis. The supernatant from aIgA1-treated glomerular mesangial cells significantly induced apoptosis in podocytes. Based on this, M2 macrophage polarization was induced using interleukin (IL)-4. The results showed that M2 macrophages (CD163 + ) effectively alleviated podocyte apoptosis by reducing the secretion of inflammatory cytokines IL-6, tumor necrosis factor (TNF)-α, and IL-1β, as well as downregulating the expression of apoptosis-related proteins. Notably, M2 macrophages (CD163 + ) inhibited the expression of UCHL1 in podocytes. Blockade of UCHL1 promoted podocyte proliferation, reduced apoptosis, and downregulated the protein expression of the fibrotic markers vascular endothelial growth factor and collagen type IV. Overexpression of UCHL1 reversed the protective effects of M2 macrophages on podocyte apoptosis. M2 macrophage (CD163 + )-mediated UCHL1 downregulation in podocytes presents a potential therapeutic approach for IgAN by alleviating apoptosis.