Gut microbiota-derived succinate aggravates acute lung injury after intestinal ischaemia/reperfusion in mice.

INTRODUCTION: Acute lung injury (ALI) is a major cause of morbidity and mortality after intestinal ischaemia/reperfusion (I/R). The gut microbiota and its metabolic byproducts act as important modulators of the gut-lung axis. This study aimed to define the role of succinate, a key microbiota metabolite, in intestinal I/R-induced ALI progression. METHODS: Gut and lung microbiota of mice subjected to intestinal I/R were analysed using 16S rRNA gene sequencing. Succinate level alterations were measured in germ-free mice or conventional mice treated with antibiotics. Succinate-induced alveolar macrophage polarisation and its effects on alveolar epithelial apoptosis were evaluated in succinate receptor 1 (Sucnr1)-deficient mice and in murine alveolar macrophages transfected with Sucnr1-short interfering RNA. Succinate levels were measured in patients undergoing cardiopulmonary bypass, including intestinal I/R. RESULTS: Succinate accumulated in lungs after intestinal I/R, and this was associated with an imbalance of succinate-producing and succinate-consuming bacteria in the gut, but not the lungs. Succinate accumulation was absent in germ-free mice and was reversed by gut microbiota depletion with antibiotics, indicating that the gut microbiota is a source of lung succinate. Moreover, succinate promoted alveolar macrophage polarisation, alveolar epithelial apoptosis and lung injury during intestinal I/R. Conversely, knockdown of Sucnr1 or blockage of SUCNR1 in vitro and in vivo reversed the effects of succinate by modulating the phosphoinositide 3-kinase-AKT/hypoxia-inducible factor-1α pathway. Plasma succinate levels significantly correlated with intestinal I/R-related lung injury after cardiopulmonary bypass. CONCLUSION: Gut microbiota-derived succinate exacerbates intestinal I/R-induced ALI through SUCNR1-dependent alveolar macrophage polarisation, identifying succinate as a novel target for gut-derived ALI in critically ill patients.

Gut microbiota dysbiosis is associated with sepsis-induced cardiomyopathy in patients: A case-control study.

BACKGROUND: Myocardial injury is a major complication of sepsis and a key factor affecting prognosis. Therefore, early and accurate diagnosis and timely management of sepsis-induced cardiomyopathy (SICM) are of great significance for the prevention and treatment of sepsis. The gut microbiota has been shown to be closely associated with sepsis or myocardial injury, but the association between the gut microbiota and SICM is not fully understood. This study aimed to explore the link between gut microbiota composition and SICM. METHODS: A case-control and single-center study of clinical features and gut microbiota profiles by Metagenome and Virome was conducted in SICM patients (n = 15) and sepsis-uninduced cardiomyopathy patients (SNICM, n = 16). RESULTS: Compared with SNICM patients, SICM patients showed significant myocardial injury and higher 28-day mortality, SOFA scores, lactate levels, and infection levels on admission. Meanwhile, differences in the composition of gut bacteria, archaea, fungi, and viruses were analyzed between the two groups. Differential gut bacteria or viruses were found to have a good predictive effect on SICM. Furthermore, gut bacteria and viruses that differed between the two groups were strongly related. The abundance of Cronobacter and Cronobacter phage was higher in the SICM group than in the SNICM group, and the receiver operating characteristic curve showed that Cronobacter and Cronobacter phage both had a good predictive effect on SICM. CONCLUSIONS: SICM patients may have specific gut microbiota signatures, and Cronobacter and Cronobacter phages have a good ability to identify and diagnose SICM.

Preoperative fasting confers protection against intestinal ischaemia/reperfusion injury by modulating gut microbiota and their metabolites in a mouse model.

BACKGROUND: Intestinal ischaemia/reperfusion (I/R) injury is a grave surgical event with high morbidity and mortality. Preoperative fasting might confer protection against intestinal I/R injury by altering the composition of gut microbiota and their respective metabolites. METHODS: An intestinal I/R mouse model was established and subjected to preoperative fasting for 24 h or fed ad libitum. Intestinal I/R injury was assessed using histological examination and survival analysis. Faecal samples were collected for 16S rDNA sequencing and metabolomic analysis. Faecal transplantation of fasted and non-fasted mice and humans was conducted to evaluate the effects of gut microbiota on intestinal I/R. Murine small intestinal cells wecre subjected to oxygen and glucose deprivation/reoxygenation as an in vitro I/R model. RESULTS: Preoperative fasting protected against intestinal I/R injury and improved survival in mice (P<0.001). In addition, 16S rDNA sequencing revealed that preoperative fasting increased the diversity and restructured the composition of the gut microbiota after intestinal I/R. Mice that received microbiota from fasted mice and humans showed less intestinal damage than those that received microbiota from fed subjects. Metabolomic analysis showed that the profiles of gut microbial metabolites differed between fasted and fed groups. Specifically, the concentration of petroselinic acid was significantly higher in the fasted group (P=0.009). Treatment of intestinal I/R mice with petroselinic acid alleviated intestinal injury in vivo and decreased cell apoptosis by mediating AMP-activated protein kinase-mammalian target of rapamycin-P70S6K signaling in vitro. CONCLUSIONS: Preoperative fasting protected against intestinal I/R injury by modulating gut microbiota and petroselinic acid, suggesting a novel therapeutic strategy.

Predictive and Preventive Potential of Preoperative Gut Microbiota in Chronic Postoperative Pain in Breast Cancer Survivors.

BACKGROUND: Evidence suggests a potential relationship between gut microbiota and chronic postoperative pain (CPP). This study aimed to explore the predictive and preventive potential of preoperative gut microbiota in CPP in breast cancer survivors. METHODS: In the clinical experiments, we designed a nested case-control study to compared preoperative gut microbiota of breast cancer survivors with and without CPP using 16s rRNA sequencing. The primary outcome was clinically meaningful pain in or around the operative area 3 months after surgery. Logistic prediction models based on previously identified risk factors for CPP in breast cancer survivors were tested with and without differential bacteria to evaluate the model's potential for improvement with the addition of gut microbiota information. In the animal experiments, preoperative fecal microbiota was transplanted from patients with and without CPP to mice, and a spared nerve injury (SNI) model was used to mimic neuropathic pain in CPP. Mechanical hyperalgesia and the expression of markers of spinal microglia and peroxisome proliferator-activated receptor-γ (PPAR-γ) were assessed. RESULTS: Sixty-six CPP patients and 66 matched controls were analyzed. Preoperative gut microbiota composition was significantly different in the 2 groups at phylus, family, and genera levels. The discrimination of the clinical prediction model (determined by area under the receiver operating characteristic curve) improved by 0.039 and 0.099 after the involvement of differential gut microbiota at the family and genus levels, respectively. After fecal microbiota transplantation (FMT), "CPP microbiota" recipient mice exhibited significantly increased mechanical hyperalgesia and decreased expression of Ppar-γ and arginase-1 (Arg-1) in the spinal cord. CONCLUSIONS: Preoperative gut microbiota has the potential to predict and prevent the development of CPP and plays a causal role in its development via the PPAR-γ-microglia pathway in the spinal cord. Thus, it could be targeted to develop a prevention strategy for CPP in breast cancer survivors.

Interleukin-10 expands transit-amplifying cells while depleting Lgr5+ stem cells via inhibition of Wnt and notch signaling.

Epithelial regeneration is essential for homeostasis and mucosal barrier repair. In this study, we aimed to define the effect of IL-10 on mucosal healing. Intestinal stem cells (ISCs) cultures and mice were treated with recombinant mice IL-10 (rmIL-10). The level of cell proliferation, differentiation, death and related signaling pathways for self-renewal of ISCs were measured in vitro and in vivo. It was uncovered that rmIL-10 increased the size and death, but reduced the total number of organoids. In addition, rmIL-10 depleted Lgr5+ ISCs and reduced epithelial proliferation, but enhanced the differentiation of epithelial cells and expanded numbers of transit-amplifying (TA) cells. These changes are related to the decrease of Wnt and Notch signals in vivo and in vitro. Meanwhile, increased expression of Paneth cells and decreased expression of enteroendocrine cells and goblet cells were induced by rmIL-10. Thus, our data indicate that IL-10 reduces the survival of Lgr5+ ISCs and proliferation of epithelial cells by inhibiting Notch and Wnt signaling, but promotes enhanced the differentiation of epithelial cells and expanded numbers of TA cells. Therefore, IL-10 acts as an anti-inflammatory factor, but may damage intestinal mucosa repair and maybe a potential target for the treatment of intestinal injury.

Correction to: L-Fucose ameliorates high-fat diet-induced obesity and hepatic steatosis in mice.

An amendment to this paper has been published and can be accessed via the original article.

Intestinal Microbiota Mediates the Susceptibility to Polymicrobial Sepsis-Induced Liver Injury by Granisetron Generation in Mice.

Sepsis-induced liver injury is recognized as a key problem in intensive care units. The gut microbiota has been touted as an important mediator of liver disease development; however, the precise roles of gut microbiota in regulating sepsis-induced liver injury are unknown. Here, we aimed to investigate the role of the gut microbiota in sepsis-induced liver injury and the underlying mechanism. Cecal ligation and puncture (CLP) was used to induce polymicrobial sepsis and related liver injury. Fecal microbiota transplantation (FMT) was used to validate the roles of gut microbiota in these pathologies. Metabolomics analysis was performed to characterize the metabolic profile differences between sepsis-resistant (Res; survived to 7 days after CLP) and sepsis-sensitive (Sen; moribund before or approximately 24 hours after CLP) mice. Mice gavaged with feces from Sen mice displayed more-severe liver damage than did mice gavaged with feces from Res mice. The gut microbial metabolic profile between Sen and Res mice was different. In particular, the microbiota from Res mice generated more granisetron, a 5-hydroxytryptamine 3 (5-HT3 ) receptor antagonist, than the microbiota from Sen mice. Granisetron protected mice against CLP-induced death and liver injury. Moreover, proinflammatory cytokine expression by macrophages after lipopolysaccharide (LPS) challenge was markedly reduced in the presence of granisetron. Both treatment with granisetron and genetic knockdown of the 5-HT3A receptor in cells suppressed nuclear factor kappa B (NF-кB) transactivation and phosphorylated p38 (p-p38) accumulation in macrophages. Gut microbial granisetron levels showed a significantly negative correlation with plasma alanine aminotransferase (ALT)/aspartate aminotransferase (AST) levels in septic patients. Conclusion: Our study indicated that gut microbiota plays a key role in the sensitization of sepsis-induced liver injury and associates granisetron as a hepatoprotective compound during sepsis development.

Intestinal iNKT cells migrate to liver and contribute to hepatocyte apoptosis during alcoholic liver disease.

We investigated the migration of intestinal immune cells to the liver and their contribution to alcoholic liver disease. In mice fed ethanol, we found that an increased number of invariant natural killer T (iNKT) cells, which respond to the antigen presented by CD1d, migrated from mesenteric lymph nodes to the liver. iNKT cells react to lipid antigens, so we studied their activities in mice with intestinal epithelial cell-specific deletion of Pparg (PpargΔIEC) as a model for altering intestinal lipidomic profiles. Levels of CD1d increased in intestines of ethanol-fed PpargΔIEC mice, and in cell-tracking experiments, more iNKT cells migrated to the liver, compared with mice without disruption of Pparg. Livers of PpargΔIEC mice had increased markers of apoptosis and liver injury after ethanol feeding. iNKT cells isolated from livers of ethanol-fed PpargΔIEC mice induced apoptosis of cultured hepatocytes. An inhibitor of iNKT cells reduced ethanol-induced liver injury in PpargΔIEC mice. Duodenal tissues from patients with alcohol-use disorder have been found to have increased levels of CD1d compared with tissues from patients without alcohol overuse. Ethanol use, therefore, activates iNKT cells in the intestine to migrate to liver, where they-along with the resident hepatic iNKT cells-contribute to hepatocyte death and injury. NEW & NOTEWORTHY In this article, we studied migration of intestinal immune cells into the liver in response to ethanol-induced liver disease. We found that chronic ethanol feeding induces expression of CD1d by enterocytes, which activate invariant natural killer T (iNKT) cells in mesenteric lymph nodes; activation is further increased with loss of peroxisome proliferator-activated receptor gamma gene and altered lipid profiles. The activated iNKT cells migrate into the liver, where they promote hepatocyte apoptosis. Patients with alcohol use disorder have increased expression of CD1d in the small intestine. Strategies to block these processes might be developed to treat alcoholic liver disease.

Light exposure influences the diurnal oscillation of gut microbiota in mice.

The gut microbiota exhibit diurnal compositional and functional oscillations that influence the host homeostasis. However, the upstream factors that affect the microbial oscillations remain elusive. Here, we focused on the potential impact of light exposure, the main factor that affects the host circadian oscillation, on the diurnal oscillations of intestinal microflora to explore the upstream factor that governs the fluctuations of the gut microbes. The gut microbiota of the mice that were underwent regular light/dark (LD) cycles exhibited a robust rhythm at both compositional and functional level, in all parts of the intestine. Comparably, constant darkness (Dark-Dark, DD) led to the loss of the rhythmic oscillations in almost all parts of the intestine. Additionally, the abundance of Clostridia in DD conditions was dramatically enhanced in the small intestine. Our data indicated light exposure is the upstream factor that governs the regular diurnal fluctuations of gut microbiota in vivo.

L-Fucose ameliorates high-fat diet-induced obesity and hepatic steatosis in mice.

BACKGROUND: L-Fucose (Fuc), a six-deoxy hexose monosaccharide, is present endogenously in humans and animals and has a wide range of biological functions. In the present study, we aimed to examine the effect of Fuc on obesity and hepatic steatosis in mice fed a high-fat diet (HFD). METHODS: C57BL/6 mice were fed a normal chow (NC) or HFD for 18 weeks to induce obesity and fatty liver. Fuc was administered intragastrically from the 8th week to the end of the experiment (18 weeks). RESULTS: Metagenomic analysis showed that HFD altered the genomic profile of gut microbiota in the mice; specifically, expression of alpha-L-fucosidase, the gene responsible for Fuc generation, was markedly reduced in the HFD group compared with that in the NC group. Fuc treatment decreased body weight gain, fat accumulation, and hepatic triglyceride elevation in HFD-fed mice. In addition, Fuc decreased the levels of endotoxin-producing bacteria of the Desulfovibrionaceae family and restored HFD-induced enteric dysbiosis at both compositional and functional levels. CONCLUSION: Our findings suggest that Fuc might be a novel strategy to treat HFD-induced obesity and fatty liver.

Gut microbe-derived milnacipran enhances tolerance to gut ischemia/reperfusion injury.

There are significant differences in the susceptibility of populations to intestinal ischemia/reperfusion (I/R), but the underlying mechanisms remain elusive. Here, we show that mice exhibit significant differences in susceptibility to I/R-induced enterogenic sepsis. Notably, the milnacipran (MC) content in the enterogenic-sepsis-tolerant mice is significantly higher. We also reveal that the pre-operative fecal MC content in cardiopulmonary bypass patients, including those with intestinal I/R injury, is associated with susceptibility to post-operative gastrointestinal injury. We reveal that MC attenuates mouse I/R injury in wild-type mice but not in intestinal epithelial aryl hydrocarbon receptor (AHR) gene conditional knockout mice (AHRflox/flox) or IL-22 gene deletion mice (IL-22-/-). Collectively, our results suggest that gut microbiota affects susceptibility to I/R-induced enterogenic sepsis and that gut microbiota-derived MC plays a pivotal role in tolerance to intestinal I/R in an AHR/ILC3/IL-22 signaling-dependent manner, revealing the pathological mechanism, potential prevention and treatment drugs, and treatment strategies for intestinal I/R.

Exosomal circEZH2_005, an intestinal injury biomarker, alleviates intestinal ischemia/reperfusion injury by mediating Gprc5a signaling.

Intestinal ischemia/reperfusion (I/R) injury is a severe clinical condition without optimal diagnostic markers nor clear molecular etiological insights. Plasma exosomal circular RNAs (circRNAs) are valuable biomarkers and therapeutic targets for various diseases, but their role in intestinal I/R injury remains unknown. Here we screen the expression profile of circRNAs in intestinal tissue exosomes collected from intestinal I/R mice and identify circEZH2_005 as a significantly downregulated exosomal circRNA. In parallel, circEZH2_005 is also reduced in the plasma of clinical cardiac surgery patients who developed postoperative intestinal I/R injury. Exosomal circEZH2_005 displays a significant diagnostic value for intestinal injury induced by I/R. Mechanistically, circEZH2_005 is highly expressed in intestinal crypt cells. CircEZH2_005 upregulation promotes the proliferation of Lgr5+ stem cells by direct interaction with hnRNPA1, and enhanced Gprc5a stability, thereby alleviating I/R-induced intestinal mucosal damage. Hence, exosomal circEZH2_005 may serve as a biomarker for intestinal I/R injury and targeting the circEZH2_005/hnRNPA1/Gprc5a axis may be a potential therapeutic strategy for intestinal I/R injury.

Association Between Gut Dysbiosis and Sepsis-Induced Myocardial Dysfunction in Patients With Sepsis or Septic Shock.

Objective: Sepsis-induced myocardial dysfunction (SIMD) seriously affects the evolution and prognosis of the sepsis patient. The gut microbiota has been confirmed to play an important role in sepsis or cardiovascular diseases, but the changes and roles of the gut microbiota in SIMD have not been reported yet. This study aims to assess the compositions of the gut microbiota in sepsis or septic patients with or without myocardial injury and to find the relationship between the gut microbiota and SIMD. Methods: The prospective, observational, and 1:1 matched case-control study was conducted to observe gut microbiota profiles from patients with SIMD (n = 18) and matched non-SIMD (NSIMD) patients (n = 18) by 16S rRNA gene sequencing. Then the relationship between the relative abundance of microbial taxa and clinical indicators and clinical outcomes related to SIMD was analyzed. The receiver operating characteristic (ROC) curves were used to evaluate the predictive efficiencies of the varied gut microbiota to SIMD. Results: SIMD was associated with poor outcomes in sepsis patients. The beta-diversity of the gut microbiota was significantly different between the SIMD patients and NSIMD subjects. The gut microbiota profiles in different levels significantly differed between the two groups. Additionally, the abundance of some microbes (Klebsiella variicola, Enterobacteriaceae, and Bacteroides vulgatus) was correlated with clinical indicators and clinical outcomes. Notably, ROC analysis indicated that K. variicola may be a potential biomarker of SIMD. Conclusion: Our study indicates that SIMD patients may have a particular gut microbiota signature and that the gut microbiota might be a potential diagnostic marker for evaluating the risk of developing SIMD.

The role of intestinal microbiota and its metabolites in intestinal and extraintestinal organ injury induced by intestinal ischemia reperfusion injury.

Intestinal ischemia/reperfusion (I/R) is a common pathophysiological process in clinical severe patients, and the effect of intestinal I/R injury on the patient's systemic pathophysiological state is far greater than that of primary intestinal injury. In recent years, more and more evidence has shown that intestinal microbiota and its metabolites play an important role in the occurrence, development, diagnosis and treatment of intestinal I/R injury. Intestinal microbiota is regulated by host genes, immune response, diet, drugs and other factors. The metabolism and immune potential of intestinal microbiota determine its important significance in host health and diseases. Therefore, targeting the intestinal microbiota and its metabolites may be an effective therapy for the treatment of intestinal I/R injury and intestinal I/R-induced extraintestinal organ injury. This review focuses on the role of intestinal microbiota and its metabolites in intestinal I/R injury and intestinal I/R-induced extraintestinal organ injury, and summarizes the latest progress in regulating intestinal microbiota to treat intestinal I/R injury and intestinal I/R-induced extraintestinal organ injury.

Use of dexmedetomidine to alleviate intestinal ischemia-reperfusion injury via intestinal microbiota modulation in mice.

Background: Intestinal ischemia-reperfusion (I/R) injury is a serious condition with unacceptable mortality rates. Our previous study revealed a protective effect of dexmedetomidine (DEX) on intestinal I/R injury, but its underlying mechanism remains unclear. Gut microbiota imbalance is associated with the progression of I/R injury. We hypothesized that DEX would attenuate intestinal I/R injury via modulating gut microbiota. Methods: An I/R injury model was established in C57BL/6 mice in the presence or absence of DEX preconditioning. Some mice were treated with antibiotics to deplete intestinal bacteria. Fecal microbiota transplantation (FMT) was performed by transplanting the feces of DEX-pretreated mice into a new batch of I/R mice. We analyzed the expression of Bacteroidetes and Firmicutes in feces, survival rate, and inflammatory cytokines. Results: DEX reversed I/R-induced bacterial abnormalities by increasing the ratio of Firmicutes to Bacteroidetes [DEX + I/R 3.02±0.36 vs. normal saline (NS) + I/R 0.82±0.15; 95% CI: 0.80-3.60; P<0.05] and was accompanied by increased 72-hour survival (0.40±0.16 vs. 0.10±0.09; P<0.05). The protective effect of DEX did not significantly differ from that of DEX + antibiotics. Furthermore, the bacteria of the DEX-pretreated mice decreased the release of inflammatory factors. Conclusions: This study revealed that DEX can alleviate intestinal I/R injury through a microbiota-related mechanism, providing a potential avenue for the management of intestinal I/R injury.

Lactobacillus murinus alleviate intestinal ischemia/reperfusion injury through promoting the release of interleukin-10 from M2 macrophages via Toll-like receptor 2 signaling.

BACKGROUND: Intestinal ischemia/reperfusion (I/R) injury has high morbidity and mortality rates. Gut microbiota is a potential key factor affecting intestinal I/R injury. Populations exhibit different sensitivities to intestinal I/R injury; however, whether this interpopulation difference is related to variation in gut microbiota is unclear. Here, to elucidate the interaction between the gut microbiome and intestinal I/R injury, we performed 16S DNA sequencing on the preoperative feces of C57BL/6 mice and fecal microbiota transplantation (FMT) experiments in germ-free mice. The transwell co-culture system of small intestinal organoids extracted from control mice and macrophages extracted from control mice or Toll-like receptor 2 (TLR2)-deficient mice or interleukin-10 (IL-10)-deficient mice were established separately to explore the potential mechanism of reducing intestinal I/R injury. RESULTS: Intestinal I/R-sensitive (Sen) and intestinal I/R-resistant (Res) mice were first defined according to different survival outcomes of mice suffering from intestinal I/R. Fecal microbiota composition and diversity prior to intestinal ischemia differed between Sen and Res mice. The relative abundance of Lactobacillus murinus (L. murinus) at the species level was drastically higher in Res than that in Sen mice. Clinically, the abundance of L. murinus in preoperative feces of patients undergoing cardiopulmonary bypass surgery was closely related to the degree of intestinal I/R injury after surgery. Treatment with L. murinus significantly prevented intestinal I/R-induced intestinal injury and improved mouse survival, which depended on macrophages involvement. Further, in vitro experiments indicated that promoting the release of IL-10 from macrophages through TLR2 may be a potential mechanism for L. murinus to reduce intestinal I/R injury. CONCLUSION: The gut microbiome is involved in the postoperative outcome of intestinal I/R. Lactobacillus murinus alleviates mice intestinal I/R injury through macrophages, and promoting the release of IL-10 from macrophages through TLR2 may be a potential mechanism for L. murinus to reduce intestinal I/R injury. This study revealed a novel mechanism of intestinal I/R injury and a new therapeutic strategy for clinical practice. Video Abstract.

Gut microbiota-derived indole 3-propionic acid partially activates aryl hydrocarbon receptor to promote macrophage phagocytosis and attenuate septic injury.

Sepsis is associated with a high risk of death, and the crosstalk between gut microbiota and sepsis is gradually revealed. Indole 3-propionic acid (IPA) is a gut microbiota-derived metabolite that exerts immune regulation and organ protective effects. However, the role of IPA in sepsis is not clear. In this study, the role of IPA in sepsis-related survival, clinical scores, bacterial burden, and organ injury was assessed in a murine model of cecal ligation and puncture-induced polymicrobial sepsis. Aryl hydrocarbon receptor (AhR) highly specific inhibitor (CH223191) was used to observe the role of AhR in the protection of IPA against sepsis. The effects of IPA on bacterial phagocytosis by macrophages were investigated in vivo and vitro. The levels of IPA in feces were measured and analyzed in human sepsis patients and patient controls. First, we found that gut microbiota-derived IPA was associated with the survival of septic mice. Then, in animal model, IPA administration protected against sepsis-related mortality and alleviated sepsis-induced bacterial burden and organ injury, which was blunted by AhR inhibitor. Next, in vivo and vitro, IPA enhanced the macrophage phagocytosis through AhR. Depletion of macrophages reversed the protective effects of IPA on sepsis. Finally, on the day of ICU admission (day 0), septic patients had significantly lower IPA level in feces than patient controls. Also, septic patients with bacteremia had significantly lower IPA levels in feces compared with those with non-bacteremia. Furthermore, in septic patients, reduced IPA was associated with worse clinical outcomes, and IPA in feces had similar prediction ability of 28-day mortality with SOFA score, and increased the predictive ability of SOFA score. These findings indicate that gut microbiota-derived IPA can protect against sepsis through host control of infection by promoting macrophages phagocytosis and suggest that IPA may be a new strategy for sepsis treatment.

Propionate alleviates myocardial ischemia-reperfusion injury aggravated by Angiotensin II dependent on caveolin-1/ACE2 axis through GPR41.

Myocardial ischemia/reperfusion (I/R) injury is still a lack of effective therapeutic drugs, and its molecular mechanism is urgently needed. Studies have shown that the intestinal flora plays an important regulatory role in cardiovascular injury, but the specific mechanism has not been fully elucidated. In this study, we found that an increase in Ang II in plasma was accompanied by an increase in the levels of myocardial injury during myocardial reperfusion in patients with cardiopulmonary bypass. Furthermore, Ang II treatment enhanced mice myocardial I/R injury, which was reversed by caveolin-1 (CAV-1)-shRNA or strengthened by angiotensin-converting enzyme 2 (ACE2)-shRNA. The results showed that CAV-1 and ACE2 have protein interactions and inhibit each other's expression. In addition, propionate, a bacterial metabolite, inhibited the elevation of Ang II and myocardial injury, while GPR41-shRNA abolished the protective effects of propionate on myocardial I/R injury. Clinically, the propionate content in the patient's preoperative stool was related to Ang II levels and myocardial I/R injury levels during myocardial reperfusion. Taken together, propionate alleviates myocardial I/R injury aggravated by Ang II dependent on CAV-1/ACE2 axis through GPR41, which provides a new direction that diet to regulate the intestinal flora for treatment of myocardial I/R injury.

Screening and Identification of Key Genes, Pathways, and Drugs Associated with Neuropathic Pain in Dorsal Horn: Evidence from Bioinformatic Analysis.

PURPOSE: Neuropathic pain is a devastating complex condition occurring post-nervous system damage. Microglia in dorsal horn drives neuropathic pain as a kind of immune cell. We aimed to find potential differentially expressed genes (DEGs) and candidate pathways, which induced neuropathic pain, and to identify some new transcription factors and therapeutic drugs via bioinformatic analysis. METHODS: The microarray profile GSE60670 was downloaded and analyzed. DEGs were screened and analyzed through Gene Ontology (GO), pathway enrichment, and protein-to-protein interaction (PPI) network. Respectively, transcription factors (TFs) and potential therapeutic drugs for DEGs were predicted through NetworkAnalyst and DGIdb databases. At last, we chose top 10 DEGs for external validation. RESULTS: A total of 100 DEGs were identified. The results of pathway and GO analyses were closely related to malaria inflammatory pathway and inflammatory response. Three necessary PPI modules and 9 hub genes were identified in PPI analysis, and 277 DEG-TF pairs were found among 54 DEGs and 32 TF. Moreover, 22 candidate drugs were found to match 9 hub genes. External validation of 9 of the top 10 DEGs were consistent with bioinformatic analysis. CONCLUSION: This study provided comprehensive analyses for the functional gene sets and pathways related to neuropathic pain and promoted our understanding of the mechanism or therapy of neuropathic pain.

The gut microbiota metabolite capsiate promotes Gpx4 expression by activating TRPV1 to inhibit intestinal ischemia reperfusion-induced ferroptosis.

Ferroptosis, a new type of cell death has been found to aggravate intestinal ischemia/reperfusion (I/R) injury. However, little is known about the changes of gut microbiota and metabolites in intestinal I/R and the role of gut microbiota metabolites on ferroptosis-induced intestinal I/R injury. This study aimed to establish a mouse intestinal I/R model and ileum organoid hypoxia/reoxygenation (H/R) model to explore the changes of the gut microbiota and metabolites during intestinal I/R and protective ability of capsiate (CAT) against ferroptosis-dependent intestinal I/R injury. Intestinal I/R induced disturbance of gut microbiota and significant changes in metabolites. We found that CAT is a metabolite of the gut microbiota and that CAT levels in the preoperative stool of patients undergoing cardiopulmonary bypass were negatively correlated with intestinal I/R injury. Furthermore, CAT reduced ferroptosis-dependent intestinal I/R injury in vivo and in vitro. However, the protective effects of CAT against ferroptosis-dependent intestinal I/R injury were abolished by RSL3, an inhibitor of glutathione peroxidase 4 (Gpx4), which is a negative regulator of ferroptosis. We also found that the ability of CAT to promote Gpx4 expression and inhibit ferroptosis-dependent intestinal I/R injury was abrogated by JNJ-17203212, an antagonist of transient receptor potential cation channel subfamily V member 1 (TRPV1). This study suggests that the gut microbiota metabolite CAT enhances Gpx4 expression and inhibits ferroptosis by activating TRPV1 in intestinal I/R injury, providing a potential avenue for the management of intestinal I/R injury.