Effects of Lactobacillus-fermented low-protein diets on the growth performance, nitrogen excretion, fecal microbiota and metabolomic profiles of finishing pigs.

This study investigated the effects of Lactobacillus-fermented low-protein diet on the growth performance, nitrogen balance, fecal microbiota, and metabolomic profiles of finishing pigs. A total of 90 finishing pigs were assigned to one of three dietary treatments including a normal protein diet (CON) as well as two experimental diets in which a low-protein diet supplemented with 0 (LP) or 1% Lactobacillus-fermented low-protein feed (FLP). In comparison with CON, the LP and FLP significantly increased average daily gain (P = 0.044), significantly decreased feed to gain ratio (P = 0.021), fecal nitrogen (P < 0.01), urine nitrogen (P < 0.01), and total nitrogen (P < 0.01), respectively. The LP group exhibited increased abundances of unclassified_f_Selenomonadaceae, Coprococcus, Faecalibacterium, and Butyricicoccus, while the abundances of Verrucomicrobiae, Verrucomicrobiales, Akkermansiaceae, and Akkermansia were enriched in the FLP group. Low-protein diet-induced metabolic changes were enriched in sesquiterpenoid and triterpenoid biosynthesis and Lactobacillus-fermented low-protein feed-induced metabolic changes were enriched in phenylpropanoid biosynthesis and arginine biosynthesis. Overall, low-protein diet and Lactobacillus-fermented low-protein diet improved the growth performance and reduce nitrogen excretion, possibly via altering the fecal microbiota and metabolites in the finishing pigs. The present study provides novel ideas regarding the application of the low-protein diet and Lactobacillus-fermented low-protein diet in swine production.

Model informed drug development: HSK21542 PBPK model supporting dose decisions in specific populations.

HKS21542, a highly selective activator of peripheral kappa opioid receptor agonists, plays a critical role in antinociception and itch inhibition during clinical development. Due to its indication population and elimination characteristics, it is imperative to evaluate the potential HSK21542 systemic exposure in individuals with renal impairment, hepatic impairment, the elderly, and the geriatric population. Here, a physiologically-based pharmacokinetic (PBPK) model for HSK21542 was developed based on in vitro metabolism and transport characteristics and in vivo elimination mechanism. Meanwhile, the potential systemic exposure of HSK21542 in specific populations was evaluated. The predicted results indicated increased systemic exposure in patients with renal impairment, hepatic impairment and in the elderly. Compared to the healthy volunteers aged 20-60 years, the AUC0-24h increased by 52 %-71 % in population with moderate to severe renal impairment, by 46 %-77 % in those with mild to severe hepatic impairment, and by 45 %-85 % in the elderly population aged 65-95-years. Conversely, the pediatric population demonstrated a potential decrease in systemic exposure, ranging from 20 % to 37 % in patients aged 0-17 years due to the physiological characteristics. Combined with the predicted results and the exposure-response relationship observed for HSK21542 and its analog (CR845), dosage regimens were designed for the target population with renal and hepatic impairment, supporting the successfully conducted trials (CTR20201702 and CTR20211940). Moreover, the observed exposure of HSK21542 in the elderly closely matched the predicted results within the same age group. Additionally, based on the predicted results, potential reductions in systemic exposure in pediatric patients should be carefully considered to avoid potential treatment failure in future clinical trials.

Pharmacokinetics and exposure-safety relationship of ciprofol for sedation in mechanically ventilated patients in the intensive care unit.

Ciprofol (HSK3486) is a newly developed, highly selective γ-aminobutyric acid-A (GABAA) receptor potentiator that is recently approved for a new indication of sedation for patients in the intensive care unit (ICU) in China. This analysis aimed to characterize the population pharmacokinetics (PopPKs) of ciprofol and evaluate the relationship of exposure with hypotension in mechanically ventilated patients in the ICU. A total of 462 subjects with 3918 concentration measurements from two clinical trials of mechanically ventilated patients in the ICU, four clinical trials of elective surgical patients, and six clinical trials of healthy subjects were used in the PopPK analysis. Exposure-safety relationship for hypotension was evaluated based on the data gathered from 112 subjects in two clinical trials of mechanically ventilated patients in the ICU. Ciprofol pharmacokinetics (PKs) was adequately described by a three-compartment linear disposition model with first-order elimination. Body weight, age, sex, blood sampling site (vein vs. arterial), study design (long-term infusion vs. short-term infusion), and patient population (ICU vs. non-ICU) were identified as statistically significant covariates on the PKs of ciprofol. Within the exposure range of the mechanically ventilated ICU patient population, no meaningful association was observed between ciprofol exposure and the incidence of hypotension. These results support the dosing regimen currently used in mechanically ventilated patients in the ICU.

Maternal Malic Acid May Ameliorate Oxidative Stress and Inflammation in Sows through Modulating Gut Microbiota and Host Metabolic Profiles during Late Pregnancy.

Sows suffer oxidative stress and inflammation induced by metabolic burden during late pregnancy, which negatively regulates reproductive and lactating performances. We previously found that L-malic acid (MA) alleviated oxidative stress and inflammation and improved reproductive performances in sows. However, the mechanism underlying the MA's positive effects remains unexplored. Here, twenty Large White × Landrace sows with similar parity were randomly divided into two groups and fed with a basal diet or a diet supplemented with 2% L-malic acid complex from day 85 of gestation to delivery. The gut microbiome, fecal short-chain fatty acids, and untargeted serum metabolome were determined. Results showed that Firmicutes, Bacteroidota, and Spirochaetota were the top abundant phyla identified in late pregnancy for sows. Maternal MA supplementation modulated the composition but not the richness and diversity of gut microbiota during late pregnancy. Correlation analysis between gut microbiota and antioxidant capacity (or inflammation indicators) revealed that unclassified_f_Ruminococcaceae, unclassified_f_Lachnospiraceae, UCG-002, norank_f_norank_o_RF3, and Lactobacillus might play a role in anti-oxidation, and Lachnospiraceae_XPB1014_group, Lachnospiraceae_NK4A136_group, UCG-002, unclassified_f_Ruminococcaceae, Candidatus_Soleaferrea, norank_f_UCG-010, norank_f_norank_o_RF39, and unclassified_f_Lachnospiraceae might be involved in the anti-inflammatory effect. The improved antioxidant and inflammation status induced by MA might be independent of short chain fatty acid changes. In addition, untargeted metabolomics analysis exhibited different metabolic landscapes of sows in the MA group from in the control group and revealed the contribution of modified amino acid and lipid metabolism to the improved antioxidant capacity and inflammation status. Notably, correlation results of gut microbiota and serum metabolites, as well as serum metabolites and antioxidant capacity (or inflammation indicators), demonstrated that differential metabolism was highly related to the fecal microorganisms and antioxidant or inflammation indicators. Collectively, these data demonstrated that a maternal dietary supply of MA can ameliorate oxidative stress and inflammation in sows through modulating gut microbiota and host metabolic profiles during late pregnancy.

Parity changed fecal microbiota of sows and its correlation with milk long-chain fatty acid profiles.

The goal of this study was to characterize the fecal microbiota profiles of gestating sows, along with the fecal microbiota and milk fatty acid contents of lactating sows and their correlations with reproductive performance at different parities. The results showed that the microbiota of third parity gestating sows contained a greater abundance of Prevotella compared to the other two parity groups, while lactating sows exhibiting higher reproductive performance at fifth parity exhibited a greater abundance of Lactobacillus species. The lactating sows with higher reproductive performance also exhibited higher total monounsaturated fatty acid (MUFA) and higher total polyunsaturated fatty acid (PUFA) levels relative to sows with lower reproductive performance at all three analyzed parities, especially sows at fifth parity produced the lowest total saturated fatty acid (SFA) levels, and showed the highest C18:1n9c and C18:2n6c concentrations. In correlational analyses, the abundance of Oligella, Lactobacillus, and Corynebacterium was highly positively correlated with C18:1n9c, C18:2n6c, and C20:4n6. Overall, these results provide a rational basis for efforts to improve sow reproductive performance through the provision of precisely regulated nutrition. KEY POINTS: • Clear differences in the fecal microbiota were evident between sows of different parities. • Lactating sows with high reproductive performance showed distinct milk fatty acid profiles.

Insights into the mechanism of L-malic acid on drip loss of chicken meat under commercial conditions.

BACKGROUND: A deterioration in the meat quality of broilers has attracted much more attention in recent years. L-malic acid (MA) is evidenced to decrease meat drip loss in broilers, but the underlying molecular mechanisms are still unclear. It's also not sure whether the outputs obtained under experimental conditions can be obtained in a commercial condition. Here, we investigated the effects and mechanisms of dietary MA supplementation on chicken meat drip loss at large-scale rearing. RESULTS: Results showed that the growth performance and drip loss were improved by MA supplementation. Meat metabolome revealed that L-2-aminoadipic acid, ß-aminoisobutyric acid, eicosapentaenoic acid, and nicotinamide, as well as amino acid metabolism pathways connected to the improvements of meat quality by MA addition. The transcriptome analysis further indicated that the effect of MA on drip loss was also related to the proper immune response, evidenced by the enhanced B cell receptor signaling pathway, NF-κB signaling pathway, TNF signaling pathway, and IL-17 signaling pathway. CONCLUSIONS: We provided evidence that MA decreased chicken meat drip loss under commercial conditions. Metabolome and transcriptome revealed a comprehensive understanding of the underlying mechanisms. Together, MA could be used as a promising dietary supplement for enhancing the water-holding capacity of chicken meat.

Retinoic acid enhances ovarian steroidogenesis by regulating granulosa cell proliferation and MESP2/STAR/CYP11A1 pathway.

INTRODUCTION: Ovarian steroidogenesis not only affects the embryonic development and pregnancy outcome, but also associates with many diseases in mammals and women. Exploring the nutrients and mechanisms influencing ovarian steroidogenesis is critical to maintaining the optimal reproductive performance, as well as guaranteeing body health. OBJECTIVES: This research aimed to explore the effect of retinol metabolism on ovarian steroidogenesis and the underlying mechanisms. METHODS: Comparative transcriptomic analysis of ovaries from normal and low reproductive performance sows were performed to identify the main causes leading to low fertility. The metabolites regulating steroid hormones synthesis were investigated in ovarian granulosa cells. Gene interference, overexpression, dual-luciferase reporter assays, chromatin immunoprecipitation and transcriptome analysis were further conducted to explore the underlying mechanisms of Aldh1a1 mediating ovarian steroidogenesis. RESULTS: Transcriptome analysis of ovaries from normal and low reproductive performance sows showed the significant differences in both retinol metabolism and steroid hormones synthesis, indicating retinol metabolism probably influenced steroid hormones synthesis. The related metabolite retinoic acid was furtherly proven a highly active and potent substance strengthening estrogen and progesterone synthesis in ovarian granulosa cells. For the first time, we revealed that retinoic acid synthesis in porcine and human ovarian granulosa cells was dominated by Aldh1a1, and required the assistance of Aldh1a2. Importantly, we demonstrated that Aldh1a1 enhanced the proliferation of ovarian granulosa cells by activating PI3K-Akt-hedgehog signaling pathways. In addition, Aldh1a1 regulated the expression of transcription factor MESP2, which targeted the transcription of Star and Cyp11a1 through binding to corresponding promoter regions. CONCLUSION: Our data identified Aldh1a1 modulates ovarian steroidogenesis through enhancing granulosa cell proliferation and MESP2/STAR/CYP11A1 pathway. These findings provide valuable clues for improving ovarian health in mammals.

Population pharmacokinetic/pharmacodynamic modeling and exposure-response analysis of ciprofol in the induction and maintenance of general anesthesia in patients undergoing elective surgery: A prospective dose optimization study.

AIM: This study aimed to establish a population pharmacokinetic and pharmacodynamic (PK-PD) model to explore the optimal maintenance dose and appropriate starting time of maintenance dose after induction of ciprofol and investigate the efficacy and safety of ciprofol for general anesthesia induction and maintenance in patients undergoing elective surgery. METHOD: A total of 334 subjects with 3092 concentration measurements from nine clinical trials and 115 subjects with 5640 bispectral index (BIS) measurements from two clinical trials were used in the population PK-PD analysis. Exposure-response relationships for both efficacy endpoints (duration of anesthesia successful induction, time to recovery from anesthesia, time to respiratory recovery, and time from discontinuation to the 1st/3rd consecutive Aldrete score ≥ 9) and safety variables (hypotension, bradycardia, and injection site pain) were evaluated based on the data gathered from 115 subjects in two clinical trials. RESULT: Ciprofol pharmacokinetics (PK) were adequately described by a three-compartment model with first-order elimination from the central compartment and redistribution from the deep and shallow peripheral compartments. An inhibitory sigmoidal Emax model best described the relationship between ciprofol effect-site concentrations and BIS measurements. Body weight, age, sex, blood sampling site, and study type (short-term infusion vs long-term infusion) were identified as statistically significant covariates on the PK of ciprofol. No covariates were found to have a significant effect on the pharmacodynamic (PD) parameters. The PK-PD simulation results showed that the optimal maintenance dose was 0.8 mg/kg/h and the appropriate time to start the maintenance dose was 4-5 mins after the induction dose of ciprofol. Within the exposure range of this study, no meaningful correlations between ciprofol exposures and efficacy or safety endpoints were observed. CONCLUSION: A population PK-PD model was successfully developed to describe the ciprofol PK and BIS changes. Efficacy was consistent across the exposure range with a well-tolerated safety profile indicating no maintenance dose adjustment is required for patients undergoing elective surgery.

CFHTF2 Is Needed for Vegetative Growth, Conidial Morphogenesis and the Osmotic Stress Response in the Tea Plant Anthracnose (Colletotrichum fructicola).

Tea is an important cash crop worldwide, and its nutritional value has led to its high economic benefits. Tea anthracnose is a common disease of tea plants that seriously affects food safety and yield and has a far-reaching impact on the sustainable development of the tea industry. In this study, phenotypic analysis and pathogenicity analysis were performed on knockout and complement strains of HTF2-the transcriptional regulator of tea anthracnose homeobox-and the pathogenic mechanism of these strains was explored via RNA-seq. The MoHox1 gene sequence of the rice blast fungus was indexed, and the anthracnose genome was searched for CfHTF2. Evolutionary analysis recently reported the affinity of HTF2 for C. fructicola and C. higginsianum. The loss of CfHTF2 slowed the vegetative growth and spore-producing capacity of C. fructicola and weakened its resistance and pathogenesis to adverse conditions. The transcriptome sequencing of wild-type N425 and CfHTF2 deletion mutants was performed, and a total of 3144 differentially expressed genes (DEGs) were obtained, 1594 of which were upregulated and 1550 of which were downregulated. GO and KEGG enrichment analyses of DEGs mainly focused on signaling pathways such as the biosynthesis of secondary metabolites. In conclusion, this study lays a foundation for further study of the pathogenic mechanism of tea anthracnose and provides a molecular basis for the analysis of the pathogenic molecular mechanism of CfHTF2.

Lactobacillus-driven feed fermentation regulates microbiota metabolism and reduces odor emission from the feces of pigs.

IMPORTANCE: Our present study showed that dietary supplementation with feed fermented by Lactobacillus could promote the growth performance of pigs, regulate the microbiota, and inhibit the growth of harmful bacteria. It could prevent the accumulation of toxic substances and reduce odor emission from pig feces, thereby reducing environmental pollution. In addition, one key triumph of the present study was the isolation of Weissella cibaria ZWC030, and the strain could inhibit the production of skatole in vitro in our present results.

Geriatric syndromes, chronic inflammation, and advances in the management of frailty: A review with new insights.

As people age, geriatric syndromes characterized by frailty significantly impact both clinical practice and public health. Aging weakens people's immune functions, leading to chronic low-grade inflammation that ultimately contributes to the development of frailty. Effectively managing geriatric syndromes and frailty can help alleviate the economic burden of an aging population. This review delves into the intricate relationship among aging, infection-induced inflammation, chronic inflammation, and frailty. In addition, it analyzes various approaches and interventions to address frailty, such as smart rehabilitation programs and stem-cell treatments, offering promising solutions in this new era. Given the importance of this topic, further research into the mechanisms of frailty is crucial. Equally essential is the devising of relevant measures to delay its onset and the formulation of comprehensive clinical, research, and public health strategies to enhance the quality of life for elderly individuals.

Immunomodulatory Effects of Microcin C7 in Cyclophosphamide-Induced Immunosuppressed Mice.

Microcin C7 (McC) as a viable immunomodulator peptide can be a potential solution for pathogenic microbial infection in the post-antibiotic era and has gained substantial attention. This study was designed to evaluate the immunomodulatory activity of Microcin C7 in a cyclophosphamide (CTX)-induced immunodeficient mouse model. We show that Microcin C7 treatment significantly alleviated the CTX-caused body weight loss, improved the feed and water consumption to improve the state of the mice, and elevated the absolute number and proportion of peripheral blood lymphocytes as well as the level of hemoglobulin. We further aim to characterize the phenotypes of the immune function and intestinal health profiles. The results demonstrate that Microcin C7 treatment increased serum levels of immunoglobulin A (IgA), IgG, interleukin 6, and hemolysin, promoted splenic lymphocyte proliferation induced by concanavalin A and LPS, and enhanced the phagocytosis of peritoneal macrophages immunized by sheep red blood cells. Additionally, Microcin C7 treatment decreased levels of diamine oxidase and d-lactate, ameliorated CTX-induced intestinal morphological damage, and increased the levels of zonula occluden 1, occludin, claudin-1, mucin 2, and secretary IgA in the jejunum and colon. Moreover, Microcin C7 administration is sufficient to reverse CTX-induced intestinal microbiota dysbiosis by increasing the number of Lactobacillus and Bifidobacterium, decreasing the number of Escherichia coli in colonic contents. Collectively, our results demonstrate that Microcin C7 may have protective and immunomodulatory functions and could be a potential candidate used in animal feed, functional foods, and immunological regimens..

IL-6 translation is a therapeutic target of human cytokine release syndrome.

Chimeric antigen receptor (CAR) T therapies have achieved remarkable success for treating hematologic malignancies, yet are often accompanied by severe cytokine release syndrome (CRS). Here, an accidental clinical observation raised the possibility that metoprolol, an FDA-approved ß1 adrenergic receptor blocker widely used for cardiovascular conditions, may alleviate CAR T-induced CRS. Metoprolol effectively blocked IL-6 production in human monocytes through unexpected mechanisms of action of targeting IL-6 protein translation but not IL6 mRNA expression. Mechanistically, metoprolol diminished IL-6 protein synthesis via attenuating eEF2K-eEF2 axis-regulated translation elongation. Furthermore, an investigator-initiated phase I/II clinical trial demonstrated a favorable safety profile of metoprolol in CRS management and showed that metoprolol significantly alleviated CAR T-induced CRS without compromising CAR T efficacy. These results repurposed metoprolol, a WHO essential drug, as a potential therapeutic for CRS and implicated IL-6 translation as a mechanistic target of metoprolol, opening venues for protein translation-oriented drug developments for human inflammatory diseases.

Crystal structure of Tudor domain of TDRD3 in complex with a small molecule antagonist.

Tudor domain-containing protein 3 (TDRD3) is involved in regulating transcription and translation, promoting breast cancer progression, and modulating neurodevelopment and mental health, making it a promising therapeutic target for associated diseases. The Tudor domain of TDRD3 is essential for its biological functions, and targeting this domain with potent and selective chemical probes may modulate its engagement with chromatin and related functions. Here we reported a study of TDRD3 antagonist following on our earlier work on the development of the SMN antagonist, Compound 1, and demonstrated that TDRD3 can bind effectively to Compound 2, a triple-ring analog of Compound 1. Our structural analysis suggested that the triple-ring compound bound better to TDRD3 due to its smaller side chain at Y566 compared to W102 in SMN. We also revealed that adding a small hydrophobic group to the N-methyl site of Compound 1 can improve binding. These findings provide a path for identifying antagonists for single canonical Tudor domain-containing proteins such as TDRD3 and SMN.

Macitentan treatment of portopulmonary hypertension with hepatopulmonary syndrome: a case report and literature review.

Pulmonary arterial hypertension-targeted therapies in portopulmonary hypertension (PoPH) are scarce, let alone for patients with chronic liver failure (CLF) and hepatopulmonary syndrome (HPS). A 48-year male was admitted to the hospital because of cirrhosis for 18 years, systemic oedema, and chest distress after exercise for 1 week. He was diagnosed with CLF, PoPH, and HPS. After 7 weeks of macitentan treatment, the patient's activity tolerance, pulmonary artery systolic pressure, arterial partial pressure of oxygen (PaO2 ), cTNI, and NT-proBNP changes indicated gradual recovery, without hepatic safety concerns. This case indicated that administering macitentan in patients diagnosed as PoPH (with CLF and HPS) may be efficient and safe enough in a clinical setting.

Interaction of lactate/albumin and geriatric nutritional risk index on the all-cause mortality of elderly patients with critically ill heart failure: A cohort study.

BACKGROUND: Whether there is a multiplicative interaction of lactate/albumin (L/A) ratio and geriatric nutritional risk index (GNRI) on the mortality of critically ill elderly patients with heart failure (HF) remains unclear. HYPOTHESIS: To assess the interaction of L/A ratio and GNRI on the all-cause mortality in critically ill elderly patients with HF. METHODS: This was a retrospective cohort study and data were extracted from the Medical Information Mart for Intensive Care III (MIMIC-III) database. The endpoints were 28-day and 1-year all-cause mortality, and the independent variables were L/A ratio and GNRI. The multiplicative interaction of L/A ratio and GNRI on the mortality was examined using Cox proportional-hazards model. RESULTS: A total of 5627 patients were finally included. Results showed that patients with higher L/A ratio or GNRI ≤ 58 had higher risk of 28-day and 1-year all-cause mortality (all p < .01). We also found the significant multiplicative interaction effect between L/A ratio and GNRI score on the 28-day and 1-year all-cause mortality (both p < .05). The increased L/A ratio was associated with higher risk of 28-day and 1-year all-cause mortality in patients with GNRI ≤ 58 than those with GNRI > 58. CONCLUSIONS: There was a multiplicative interaction effect between L/A ratio and GNRI score on the mortality, and low GNRI score was associated with the increased risk of all-cause mortality with the increase of L/A ratio, suggesting the importance of nutrition-oriented intervention in critically ill elderly HF patients with high L/A ratio.

Separation and Analysis of Oxygen-Containing Compounds in a Shaanxi Middle/Low-Temperature Coal Tar.

A middle/low-temperature coal tar (M/LTCT) was obtained from a low-temperature carbonization plant in Shaanxi, China. The M/LTCT was separated into light components and coal tar pitch through extraction. A series of alkanes, aromatic hydrocarbons, oxygen-containing arenes (OCAs), and nitrogen-containing arenes were fractionated from light components by medium-pressure preparative chromatography with gradient elution using petroleum ether and ethyl acetate. They were analyzed using a gas chromatography-mass spectrometer (GC-MS) and a Fourier transform infrared spectrometer. The OCAs were analyzed by a Fourier transform Orbitrap MS (quadrupole exactive Orbitrap mass spectrometer), and the molecular distribution of the O 1-O 6 species was studied. OCAs are mainly oxygen-containing aromatic compounds, including aromatic phenols, furans, alkoxy aromatic hydrocarbons, aromatic ethers, aromatic aldehydes, aromatic ketones, and aromatic acids. The position of the oxygen atom on the aromatic ring and the condensation form of the aromatic ring are studied.

Decitabine priming increases anti-PD-1 antitumor efficacy by promoting CD8+ progenitor exhausted T cell expansion in tumor models.

CD8+ exhausted T cells (Tex) are heterogeneous. PD-1 inhibitors reinvigorate progenitor Tex, which subsequently differentiate into irresponsive terminal Tex. The ability to maintain a capacity for durable proliferation of progenitor Tex is important, but the mechanism remains unclear. Here, we showed CD8+ progenitor Tex pretreated with decitabine, a low-dose DNA demethylating agent, had enhanced proliferation and effector function against tumors after anti-PD-1 treatment in vitro. Treatment with decitabine plus anti-PD-1 promoted the activation and expansion of tumor-infiltrated CD8+ progenitor Tex and efficiently suppressed tumor growth in multiple tumor models. Transcriptional and epigenetic profiling of tumor-infiltrated T cells demonstrated that the combination of decitabine plus anti-PD-1 markedly elevated the clonal expansion and cytolytic activity of progenitor Tex compared with anti-PD-1 monotherapy and restrained CD8+ T cell terminal differentiation. Strikingly, decitabine plus anti-PD-1 sustained the expression and activity of the AP-1 transcription factor JunD, which was reduced following PD-1 blockade therapy. Downregulation of JunD repressed T cell proliferation, and activation of JNK/AP-1 signaling in CD8+ T cells enhanced the antitumor capacity of PD-1 inhibitors. Together, epigenetic agents remodel CD8+ progenitor Tex populations and improve responsiveness to anti-PD-1 therapy.

Chenodeoxycholic Acid Improves Embryo Implantation and Metabolic Health through Modulating Gut Microbiota-Host Metabolites Interaction during Early Pregnancy.

Fetus loss in early pregnancy is of major concern to both humans and animals, and this issue is largely influenced by embryo implantation. Chenodeoxycholic acid (CDCA), a primary bile acid, contributes to metabolic improvements and protects against intrahepatic cholestasis of pregnancy. However, the effect of CDCA on embryo implantation during early pregnancy has not been investigated. The present study demonstrated that CDCA administration during early pregnancy improved embryo implantation in sows and rats, thereby improving the pregnancy outcomes of sows. CDCA significantly reduced inflammation, oxidative stress, and insulin resistance. The metabolomics analysis indicated significant differences in the fecal metabolome, especially regarding the level of secondary bile acids, between the control and CDCA-treated sows. CDCA also influenced the serum metabolite profiles in sows, and the serum L-Histidine level was significantly correlated with the abundance of 19 differential fecal metabolites. Importantly, L-Histidine administration improved embryo implantation and metabolic health in rats during early pregnancy. Moreover, CDCA administration during early pregnancy also led to long-term metabolic improvements in sows. Our data indicated that CDCA improved embryo implantation by alleviating inflammation and oxidative stress, improving insulin sensitivity, and modulating the interaction between the gut microbiota and host metabolites. Therefore, CDCA intervention is a potential therapeutic strategy regarding embryo loss during pregnancy.