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Purpose: Brain dysfunction is a significant complication of sepsis, commonly referred to as sepsis-associated encephalopathy (SAE). Alterations in gut microbiota during sepsis may contribute to development of SAE through the gut-brain axis. This study investigated effects of fecal transplantation from healthy or endotoxemic individuals on gut microbiota and brain function in a rat model of LPS-associated encephalopathy.

Methods: Following LPS induction, rats received daily oral gavage of fecal microbiota transplants for 3 days. Sensory and motor functions were assessed daily throughout the 7-day study period after LPS exposure. On day 7 post-LPS, the study examined gut microbiota structure and composition, serum and fecal short-chain fatty acids (SCFAs) levels, ileal villus length, intestinal permeability, neuronal and glial ultrastructure, cytokine concentrations (pro-inflammatory and anti-inflammatory), and mitochondrial bioenergetics.

Results: Administration of healthy donor feces preserved gut microbial structure and composition, maintained ileal villus length, and improved intestinal permeability following LPS treatment. Additionally, it increased SCFA levels, reduced pro-inflammatory cytokines, enhanced anti-inflammatory cytokine release, and restored sensitivity to mechanical and thermal stimuli, as well as motor function. Rats treated with healthy donor feces also exhibited reduced neuronal necrosis and a decreased density of mitochondria in cortical astrocytes. Notably, mitochondrial metabolism in LPS-treated rats returned to near-normal levels following treatment with healthy donor feces. In contrast, administration of endotoxemic donor feces exacerbated these effects in LPS-treated rats.

Conclusion: Ameliorating gut dysbiosis prevents mitochondrial dysfunction in astrocytes by promoting SCFA production and enhancing anti-inflammatory cytokine release. This process preserves neuronal integrity and mitigates the severity of encephalopathy.

Sepsis, a dysregulated host response to infection, remains a growing global health concern, particularly in older adults. While much attention focuses on acute survival, an increasing number of sepsis survivors experience persistent neurological complications, including impairments in memory, attention, and executive function. In severe cases, these may manifest as sepsis-associated delirium or progress to long-term cognitive impairment and dementia. The mechanisms driving these outcomes are complex and incompletely understood, partly due to limited baseline cognitive data and significant variability among older adults. A central feature of sepsis-induced brain dysfunction is sustained neuroinflammation, which bridges peripheral immune activation and central nervous system injury. Mounting evidence implicates macrophages, including circulating monocytes and brain-resident microglia, as key regulators of this neuroimmune axis. Inflammatory conditions during sepsis often drive macrophage polarization toward a pro-inflammatory M1 phenotype, leading to the release of cytokines and reactive oxygen species that exacerbate blood-brain barrier disruption and neuronal injury. Conversely, impaired transition to the M2 phenotype hinders inflammation resolution and tissue repair. Critically, this interaction is bidirectional, where neuroinflammatory signals from activated microglia can influence peripheral macrophage behavior, creating a self-reinforcing inflammatory loop that may prolong central nervous system damage. This process is especially concerning in older adults who may have preexisting immune vulnerabilities and varying baseline cognitive status, which presents unique challenges for therapeutic targeting. This review highlights the central and dynamic role of macrophage polarization in sepsis-associated cognitive decline. Understanding how systemic and neuroinflammatory pathways converge through macrophage signaling may reveal new therapeutic targets to mitigate long-term neurological complications in sepsis survivors. Graphical abstract-Sepsis alters the abundance and polarization of macrophage subpopulations, contributing to both short- and long-term cognitive impairment. In the acute phase, these changes may manifest as sepsis-associated delirium (SAD), while in the long term, sustained immune dysregulation and neuroinflammation may contribute to persistent cognitive deficits, including memory loss and executive dysfunction.

Background: Patients undergoing cardiac surgery with cardiopulmonary bypass (CSCPB) are at substantial postoperative risk, which may be influenced by alterations in gut microbiota and metabolites. The roles of these biological changes in postoperative outcomes remain inadequately explored.

Methods: We collected 54 preoperative samples and 33 postoperative samples from 60 CSCPB patients. Metagenomic and metabolomic sequencing were performed to identify the gut microbiota and serum and fecal metabolites. We examined the dynamic pattern of these microbiota and metabolites, as well as their associations with the postoperative risks. Additionally, we developed a predictive model for postoperative risk based on preoperative microbiome and metabolome data.

Results: We revealed significant alterations of gut microbiota ( P = 0.012), serum metabolites ( P = 3.50 e-10 ), and fecal metabolites ( P = 0.0081) in patients following CSCPB, among which lysophosphatidylcholines (LPCs) exhibited notable changes. Particularly, we identified a potential regulatory function of the microbiota on LPC metabolism, which further influences the postoperative risk. The predictive model for intensive care unit stay duration achieved a mean absolute error of 1.27 days and an R² of 0.63, suggesting its utility in assessing postoperative risk. Also, our study provides a valuable resource (catalogue GM3C) for further investigation into potential medical targets in CSCPB patients, comprising more than 2,000 metagenome-assembled genomes and 3 million unigenes.

Conclusions: Our study reveals that the gut microbiome and LPC-centered metabolism form a functional network influencing postoperative risk in CSCPB patients. These findings underscore the role of gut-derived signals in modulating noninfectious inflammatory responses and host imbalance, offering a multiomics framework for decoding systemic complications beyond classical sepsis paradigms.

Trial registration: ClinicalTrials.gov (NCT04032938). Registered 25 July 2019, https://clinicaltrials.gov/study/NCT04032938#study-record-dates .

Objective: Polytrauma (PT) and hemorrhagic shock (HS) can result in multiple organ dysfunction syndrome, with the intestine playing a critical role as a remote trauma organ due to disruption of the gut-blood barrier and associated fluid imbalances. At the molecular level, the role of both tight junction proteins, which maintain barrier sealing, and aquaporins (AQPs), which regulate water transport, remains not fully understood in the context of trauma.

Hypothesis: We hypothesize that remote intestinal injury results in altered expression patterns of key AQPs (AQP1 and AQP3) and tight junction proteins in the small and large intestine following PT and HS.

Methods: A long-term porcine model of PT with or without HS was employed, incorporating guideline-driven intensive care management. Animals were assigned to three experimental groups and corresponding samples analyzed: Sham (n = 9), PT alone (n = 8), and PT with HS (n = 5). Inflammatory mediators, intestinal damage markers, and antimicrobial peptides were assessed in blood samples during the time course after trauma. At 72 hours after injury, ileum and colon tissues were harvested for gene expression analyses of tight junction molecules and AQPs (AQP1 and AQP3).

Results: PT and HS caused a significant elevation in the antimicrobial peptides calprotectin and β-defensin. The analysis of tight junction protein expression revealed an unaffected intestinal expression profile of claudin-1 and occludin following experimental PT or PT + HS. In the colon, there was a significant reduction in the expression profile of tight junction protein-1 after PT, and a reduction in the expression of the sodium/bicarbonate cotransporter after both PT and PT + HS. In the ileum, there was a striking loss of 80% AQP1 expression in the PT and PT + HS group and a 54% decrease in AQP3 in the PT + HS group. However, these changes were not seen in the colon.

Conclusion: The PT and HS-driven reduction of key AQPs in the ileum may contribute to persistent gut-blood barrier dysfunction and could offer therapeutic targets to restore the intestinal fluid homeostasis following PT and HS.

Background: Patients with chronic kidney disease (CKD), particularly those undergoing hemodialysis, are highly susceptible to bacterial infections, which often progress to sepsis. Although the liver plays a crucial role in the host defense against sepsis, the precise mechanisms by which CKD alters systemic host defense, particularly the effects on liver immunity including Kupffer cells, remain elusive.

Methods: We developed a mouse CKD model by administering a diet containing 0.2% adenine for 4 weeks. The mice were then intravenously challenged with Escherichia coli. Mouse survival rate and liver macrophage functions were examined.

Results: CKD mice had significantly higher mortality after E. coli challenge as compared to control mice, which was accompanied by marked elevations of serum tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-12 p70, and IL-18, a significant decrease in serum interferon-gamma levels, and significantly higher bacterial counts in the blood and liver 24 hours after the challenge. CKD mice also displayed an increased number of liver monocyte-derived macrophages and enhanced intracellular TNF-α production in response to bacterial challenge compared to control mice. In contrast, although the number of Kupffer cells remained unchanged, their bactericidal activity, assessed by pHrodo-labeled E. coli, was significantly reduced in CKD mice. Adoptive transfer of Kupffer cells from control mice to CKD mice significantly increased the survival rate of CKD mice after E. coli challenge.

Conclusions: CKD increases susceptibility to E. coli infection in mice, potentially by reducing the antibacterial function of Kupffer cells while increasing the abundance of liver monocyte-derived macrophages and their TNF-α production.

Objectives: Determining the endpoint of resuscitation in septic shock is essential to enhance effectiveness, prevent over-resuscitation, and improve outcomes. We designed this study to investigate whether sublingual microcirculation monitoring can serve as an effective marker for assessing the efficacy of resuscitation therapy in septic shock.

Methods: A total of 72 septic shock patients were included in our final analysis, excluding those with heart function impairments, including sepsis-induced cardiomyopathy. Sublingual microcirculation parameters were measured at two time points: before resuscitation and 6 hours postresuscitation. Additionally, the values of macrocirculatory parameters, blood gas analysis variables, and organ prognosis indicators were collected at multiple time points before and after resuscitation. Spearman correlation analysis was performed to assess the correlations among these variables. Furthermore, the receiver operating characteristic curve analysis method was employed to evaluate the predictive performance of sublingual microcirculation parameters and other relevant factors for patient prognosis. Finally, we determined the optimal threshold of proportion of perfused vessel (PPV) 6h by anchoring it to three key aspects: tissue oxygenation (Lac 24h ), organ dysfunction progression (△APACHE II 3d and △SOFA 3d ), and long-term outcomes (adverse prognosis and 28-day mortality).

Results: Sublingual microcirculation variables postresuscitation showed no significant correlation with conventional circulation variables. PPV 6h had the highest predictive efficacy for 28-day prognosis, better than PcvO2 6h , the best predictor among conventional variables. The optimal PPV 6h threshold (68.6%) was determined using three key criteria mentioned above. Patients meeting this threshold after resuscitation showed improved microcirculation (lower lactate levels and faster clearance), reduced organ dysfunction (lower APACHE II and SOFA scores, less need for continuous renal replacement therapy), and better long-term outcomes (fewer vasoactive drugs, 28-day lower mortality).

Conclusions: Our study highlights the potential utility of sublingual microcirculation as an adjunctive tool for reflecting the effectiveness of resuscitation therapy and proposes that the PPV 6h >68.6% may serve as a target for early goal-directed therapy in future studies.

Sepsis-induced acute lung injury (ALI) leads to high mortality. NOP2/Sun RNA methyltransferase family member 7 (NSUN7) is a methyltransferase of 5-methylcytosine (m5C) modification that is highly expressed in sepsis. However, whether NSUN7 affects ALI progression remains largely unknown. This study aimed to investigate the role of NSUN7 in sepsis-induced ALI and its underlying molecular mechanism. A sepsis mouse model was established by cecal ligation puncture, and lung epithelial cells (MLE-12) were exposed to lipopolysaccharide (LPS) to establish an in vitro model. Cell pyroptosis, NSUN7-mediated m5C methylation of tumor necrosis factor receptor-associated factor 6 (TRAF6), and lung pathology and inflammation were analyzed. The results showed that NSUN7 expression was enhanced in the lungs of septic mice and LPS-induced MLE-12 cells. Silencing of NSUN7 suppressed LPS-induced pyroptosis, which was reversed by TRAF6. Additionally, knockdown of NSUN7 decreased TRAF6 expression, reduced TRAF6 m5C levels, and shortened TRAF6 half-life. Moreover, silencing of NSUN7 attenuated lung injury in sepsis mice and decreased proinflammatory factor levels. In conclusion, NSUN7 promotes pyroptosis of lung epithelial cells in sepsis-induced ALI by stabilizing TRAF6 in a m5C-dependent manner. These findings suggest that NSUN7 may be a promising therapeutic target for sepsis-induced ALI.