Gut symbionts alleviate MASH through a secondary bile acid biosynthetic pathway.

The gut microbiota has been found to play an important role in the progression of metabolic dysfunction-associated steatohepatitis (MASH), but the mechanisms have not been established. Here, by developing a click-chemistry-based enrichment strategy, we identified several microbial-derived bile acids, including the previously uncharacterized 3-succinylated cholic acid (3-sucCA), which is negatively correlated with liver damage in patients with liver-tissue-biopsy-proven metabolic dysfunction-associated fatty liver disease (MAFLD). By screening human bacterial isolates, we identified Bacteroides uniformis strains as effective producers of 3-sucCA both in vitro and in vivo. By activity-based protein purification and identification, we identified an enzyme annotated as ß-lactamase in B. uniformis responsible for 3-sucCA biosynthesis. Furthermore, we found that 3-sucCA is a lumen-restricted metabolite and alleviates MASH by promoting the growth of Akkermansia muciniphila. Together, our data offer new insights into the gut microbiota-liver axis that may be leveraged to augment the management of MASH.

Evaluation of compost quality and the environmental effects of semipermeable membrane composting with poultry manure using sawdust or mushroom residue as the bulking agent.

Herein, the effects of different bulking agents (sawdust and mushroom residue), on compost quality and the environmental benefits of semipermeable film composting with poultry manure were investigated. The results show that composting with sawdust as the bulking agent resulted in greater efficiency and more cost benefits than composting with mushroom residue, and the cost of sawdust for treating an equal volume of manure was only 1/6 of that of mushroom residue. Additionally, lignin degradation and potential carbon emission reduction in the sawdust group were better than those in the mushroom residue group, and the lignin degradation efficiency of the bottom sample in the sawdust group was 48.57 %. Coupling between lignin degradation and potential carbon emission reduction was also closer in sawdust piles than in mushroom residue piles, and sawdust is more environmentally friendly. The abundance of key functional genes was higher at the bottom of each pile relative to the top and middle. Limnochordaceae, Lactobacillus and Enterococcus were the core microorganisms involved in coupling between lignin degradation and potential carbon emission reduction, and the coupled relationship was influenced by electric conductivity, ammonia nitrogen and total nitrogen in the compost piles. This study provides important data for supporting bulking agent selection in semipermeable film composting and for improving the composting process. The results have high value for compost production and process application.

Transfer and Retention Effects of a Motor Program in Children With Autism Spectrum Disorders.

The current study examined the acquisition, retention, and transfer effects of a motor program. Children with autism spectrum disorder participated in a 9-week program that targeted 13 fundamental motor skills based upon the Test of Gross Motor Development-3. Assessments were conducted before and after the program, as well as at 2-month follow-up. Significant improvements were found on not only the trained fundamental motor skills (acquisition) but also the untrained tasks on balance (transfer). The follow-up tests revealed continuous improvement on the trained locomotor skills (retention), as well as the untrained skills on balance (retention + transfer). These findings highlight the importance of continuous support and long-term participation on motor practices.

Is there a relationship between plasma, cytokine concentrations, and the subsequent risk of postpartum hemorrhage?

BACKGROUND: Postpartum hemorrhage remains the leading cause of maternal mortality. However, there is an insufficient understanding of atonic postpartum hemorrhage. Uterine atony is the most common cause of postpartum hemorrhage. Although an association between myometrium inflammatory cytokines and atonic postpartum hemorrhage has been demonstrated preliminarily, it is not clinically useful in predicting postpartum hemorrhage. Plasma is more readily available, and the assessment of its inflammatory status is more relevant to biological markers of postpartum hemorrhage and might explain the pathophysiology of atonic postpartum hemorrhage. OBJECTIVE: Our objective was to examine changes in maternal plasma cytokines in women with atonic postpartum hemorrhage. STUDY DESIGN: This was a retrospective longitudinal case-control study of pregnant women with singleton gestations at term undergoing vaginal delivery. Cases were women with atonic postpartum hemorrhage, and 1:1 propensity-score matching was used to match the control group. Maternal plasma was collected in the first trimester, early third trimester, and late third trimester, and multiplex Luminex assay was used to determine the cytokine concentrations. Multivariate logistic regressions were used to determine the association between maternal cytokines at different stages of pregnancy and atonic postpartum hemorrhage. RESULTS: A total of 36 pregnant women met the clinical diagnostic criteria for atonic postpartum hemorrhage, and 36 patients without postpartum hemorrhage were matched as the control group. Concentrations were lower for most cytokines in the atonic postpartum hemorrhage group in the first and early third trimester. However, in the late third trimester, higher plasma concentrations of basic fibroblast growth factor, interleukin-1 alpha, interleukin-1 beta, interleukin-1 receptor antagonist, interleukin-2 receptor alpha, interleukin-16, interleukin-18, macrophage colony stimulating factor, macrophage inflammatory protein-1 alpha, beta-nerve growth factor, tumor necrosis factor-related apoptosis-induced ligand, and stem cell factor were significantly associated with increased risk of atonic postpartum hemorrhage. Multiple testing correction showed that basic fibroblast growth factor (P<.001; fold change [FC]=1.16), macrophage inflammatory protein-1 alpha (P<.001; FC=1.15), and stem cell factor (P=.001; FC=1.25) had the most significant difference (P<.001). The prediction model of atonic postpartum hemorrhage constructed by these significantly changed cytokines had a high predictive efficiency (area under the curve, 0.84; sensitivity, 0.78; specificity, 0.83; +likelihood ratio, 4.66; -likelihood ratio, 0.27). CONCLUSION: Higher concentrations of maternal plasma cytokines in the late third trimester are associated with high risk of subsequent atonic postpartum hemorrhage. These indicators may be potential biomarkers for predicting atonic postpartum hemorrhage.

Does Symptom Severity Moderate the Relationship Between Body Mass Index and Motor Competence in Children With Autism Spectrum Disorders? An Exploratory Study.

To date, there has been little research considering both autism spectrum disorder (ASD) symptom severity and motor impairment simultaneously when investigating their associations with obesity. This study was designed to identify the moderating role of symptom severity in the relationship between motor competence and overweight/obesity for children with ASD. Seventy-eight children with a clinical diagnosis were recruited from a large autism rehabilitation center in Wuhan, China. Chi-square, partial correlation, and moderation regression analyses revealed that the prevalence of overweight and obesity was similar regardless of symptom severity. Balance was the only motor skill that correlated with body mass index. Furthermore, symptom severity significantly moderated the correlation. Children with low autism severity might be more likely to demonstrate the relationship between balance and body mass index than those with high autism severity. Combating obesity by enhancing motor competence should cautiously consider personal and environment factors such as individual severity of ASD.

Loss of myeloid-specific lamin A/C drives lung metastasis through Gfi-1 and C/EBPε-mediated granulocytic differentiation.

The immune-suppressive tumor microenvironment promotes metastatic spread and outgrowth. One of the major contributors is tumor-associated myeloid cells. However, the molecular mechanisms regulating their differentiation and function are not well understood. Here we report lamin A/C, a nuclear lamina protein associated with chromatin remodeling, was one of the critical regulators in cellular reprogramming of tumor-associated myeloid cells. Using myeloid-specific lamin A/C knockout mice and triple-negative breast cancer (TNBC) mouse models, we discovered that the loss of lamin A/C drives CD11b+ Ly6G+ granulocytic lineage differentiation, alters the production of inflammatory chemokines, decreases host antitumor immunity, and increases metastasis. The underlying mechanisms involve an increased H3K4me3 leading to the upregulation of transcription factors (TFs) Gfi-1 and C/EBPε. Decreased lamin A/C and increased Gfi-1 and C/EBPε were also found in the granulocytic subset in the peripheral blood of human cancer patients. Our data provide a mechanistic understanding of myeloid lineage differentiation and function in the immune-suppressive microenvironment in TNBC metastasis.

Intermedin Restores Hyperhomocysteinemia-induced Macrophage Polarization and Improves Insulin Resistance in Mice.

Hyperhomocysteinemia (HHcy) is a condition characterized by an abnormally high level of homocysteine, an inflammatory factor. This condition has been suggested to promote insulin resistance. To date, the underlying molecular mechanism remains largely unknown, and identifying novel therapeutic targets for HHcy-induced insulin resistance is of high priority. It is well known that intermedin (IMD), a calcitonin family peptide, exerts potent anti-inflammatory effects. In this study, the effects of IMD on HHcy-induced insulin resistance were investigated. Glucose tolerance and insulin tolerance tests were performed on mice treated with IMD by minipump implantation (318 ng/kg/h for 4 weeks) or adipocyte-specific IMD overexpression mice (Adipo-IMD transgenic mice). The expression of genes and proteins related to M1/M2 macrophages and endoplasmic reticulum stress (ERS) was evaluated in adipose tissues or cells. The expression of IMD was identified to be lower in the plasma and adipose tissues of HHcy mice. In both IMD treatment by minipump implantation and Adipo-IMD transgenic mice, IMD reversed HHcy-induced insulin resistance, as revealed by glucose tolerance and insulin tolerance tests. Further mechanistic study revealed that IMD reversed the Hcy-elevated ratio of M1/M2 macrophages by inhibiting AMP-activated protein kinase activity. Adipo-IMD transgenic mice displayed reduced ERS and lower inflammation in adipose tissues with HHcy. Soluble factors from Hcy-treated macrophages induced adipocyte ERS, which was reversed by IMD treatment. These findings revealed that IMD treatment restores the M1/M2 balance, inhibits chronic inflammation in adipose tissues, and improves systemic insulin sensitivity of HHcy mice.

Macrophage inflammasome mediates hyperhomocysteinemia-aggravated abdominal aortic aneurysm.

Abdominal aortic aneurysm (AAA) is a serious vascular disease with high mortality. Our previous study suggested that hyperhomocysteinemia (HHcy) exaggerates the occurrence of AAA. Here, we investigated whether macrophage inflammasome is involved in HHcy-aggravated AAA formation. Two independent HHcy-aggravated AAA models, perivascular calcium phosphate-treated C57BL/6 mice and angiotensin II (Ang II)-infused apolipoprotein E-deficient (ApoE(-/-)) mice were used. NLPR3, caspase 1, and interleukin-1ß (IL-1ß) levels were higher in aneurysmal lesions of both HHcy models compared to controls, preferentially in macrophages. Similarly, macrophage inflammasome activation was observed in vitro. Folic acid administration reversed the HHcy-accelerated AAA, with ameliorated activation of inflammasome in the tunica adventitia. Lentiviral silencing of NLRP3 significantly ameliorated HHcy-aggravated AAA formation. We observed increased mitochondrial production of reactive oxygen species (ROS) and energy switch from oxidative phosphorylation to glycolysis with excess Hcy in macrophages. Blocking mitochondrial ROS production in macrophages abolished inflammasome activation. Our study highlights the potential importance of macrophage inflammasome in the pathogenesis and development of HHcy-aggravated AAA.

Cadm1 is a metastasis susceptibility gene that suppresses metastasis by modifying tumor interaction with the cell-mediated immunity.

Metastasis is a complex process utilizing both tumor-cell-autonomous properties and host-derived factors, including cellular immunity. We have previously shown that germline polymorphisms can modify tumor cell metastatic capabilities through cell-autonomous mechanisms. However, how metastasis susceptibility genes interact with the tumor stroma is incompletely understood. Here, we employ a complex genetic screen to identify Cadm1 as a novel modifier of metastasis. We demonstrate that Cadm1 can specifically suppress metastasis without affecting primary tumor growth. Unexpectedly, Cadm1 did not alter tumor-cell-autonomous properties such as proliferation or invasion, but required the host's adaptive immune system to affect metastasis. The metastasis-suppressing effect of Cadm1 was lost in mice lacking T cell-mediated immunity, which was partially phenocopied by depleting CD8(+) T cells in immune-competent mice. Our data show a novel function for Cadm1 in suppressing metastasis by sensitizing tumor cells to immune surveillance mechanisms, and this is the first report of a heritable metastasis susceptibility gene engaging tumor non-autonomous factors.

Hyperhomocysteinemia promotes insulin resistance by inducing endoplasmic reticulum stress in adipose tissue.

Type 2 diabetes is a chronic inflammatory metabolic disease, the key point being insulin resistance. Endoplasmic reticulum (ER) stress plays a critical role in the pathogenesis of type 2 diabetes. Previously, we found that hyperhomocysteinemia (HHcy) induced insulin resistance in adipose tissue. Here, we hypothesized that HHcy induces ER stress, which in turn promotes insulin resistance. In the present study, the direct effect of Hcy on adipose ER stress was investigated by the use of primary rat adipocytes in vitro and mice with HHcy in vivo. The mechanism and the effect of G protein-coupled receptor 120 (GPR120) were also investigated. We found that phosphorylation or expression of variant ER stress markers was elevated in adipose tissue of HHcy mice. HHcy activated c-Jun N-terminal kinase (JNK), the downstream signal of ER stress in adipose tissue, and activated JNK participated in insulin resistance by inhibiting Akt activation. Furthermore, JNK activated c-Jun and p65, which in turn triggered the transcription of proinflammatory cytokines. Both in vivo and in vitro assays revealed that Hcy-promoted macrophage infiltration aggravated ER stress in adipose tissue. Chemical chaperones PBA and TUDCA could reverse Hcy-induced inflammation and restore insulin-stimulated glucose uptake and Akt activation. Activation of GPR120 reversed Hcy-induced JNK activation and prevented inflammation but not ER stress. Therefore, HHcy inhibited insulin sensitivity in adipose tissue by inducing ER stress, activating JNK to promote proinflammatory cytokine production and facilitating macrophage infiltration. These findings reveal a new mechanism of HHcy in the pathogenesis of insulin resistance.

A comparative study on fundamental movement skills among children with autism spectrum disorder and typically developing children aged 7-10.

Background: Autism Spectrum Disorder (ASD) is a neurodevelopmental condition with unique differences in social interaction, communication, and a spectrum of behavioral characteristics. In the past, motor disturbance in individuals with ASD has not been considered a significant core deficit due to the predominant focus on sociability and communication issues. However, recent studies indicate that motor deficits are indeed associated with the fundamental symptoms of ASD. As there is limited research on the motor behavior of children with ASD, particularly in China, the objective of this study is to investigate the development of fundamental movement skills (FMS) in children with ASD and compare them to typically developing children. Method: The study recruited 108 children with ASD (87 boys, 21 girls) aged 7-10 years from two special education rehabilitation centers in Wuhan, China. For comparison, a control group of 108 typically developing children, matched by age and gender, was randomly selected from three local primary schools. FMS were assessed using the Movement Assessment Battery for Children - Second Edition (MABC-2), which evaluates manual dexterity, aiming and catching, as well as static and dynamic balance. Group differences on MABC-2 percentile scores were analyzed using descriptive statistics and Mann-Whitney U test. Effect sizes were also calculated for practical significance. Results: Findings from the study showed that a significant majority, around 80%, of children with ASD either displayed motor challenges or were at risk of developing such delays. When comparing to their typically developing peers, children with ASD scored notably lower in areas of manual dexterity, ball skills, and both static and dynamic balance (with all these findings being statistically significant at p < 0.001). Interestingly, gender did not show a significant influence on these results (p > 0.05). Conclusion: In addition to addressing the other skill development areas outlined in the diagnostic manual for ASD, clinicians diagnosing and treating children with ASD should also assess the presence of motor skill development. For individuals with ASD who have co-existing motor difficulties, it is essential to offer evidence-based interventions tailored to their specific needs.

Interlukin-22 improves ovarian function in polycystic ovary syndrome independent of metabolic regulation: a mouse-based experimental study.

BACKGROUND: Polycystic ovary syndrome (PCOS) is a reproductive endocrine disorder with multiple metabolic abnormalities. Most PCOS patients have concomitant metabolic syndromes such as insulin resistance and obesity, which often lead to the development of type II diabetes and cardiovascular disease with serious consequences. Current treatment of PCOS with symptomatic treatments such as hormone replacement, which has many side effects. Research on its origin and pathogenesis is urgently needed. Although improving the metabolic status of the body can alleviate reproductive function in some patients, there is still a subset of patients with metabolically normal PCOS that lacks therapeutic tools to address ovarian etiology. METHODS: The effect of IL-22 on PCOS ovarian function was verified in a non-metabolic PCOS mouse model induced by dehydroepiandrosterone (DHEA) and rosiglitazone, as well as granulosa cell -specific STAT3 knockout (Fshrcre+Stat3f/f) mice (10 groups totally and n = 5 per group). Mice were maintained under controlled temperature and lighting conditions with free access to food and water in a specific pathogen-free (SPF) facility. Secondary follicles separated from Fshrcre+Stat3f/f mice were cultured in vitro with DHEA to mimic the hyperandrogenic environment in PCOS ovaries (4 groups and n = 7 per group) and then were treated with IL-22 to investigate the specific role of IL-22 on ovarian function. RESULTS: We developed a non-metabolic mice model with rosiglitazone superimposed on DHEA. This model has normal metabolic function as evidenced by normal glucose tolerance without insulin resistance and PCOS-like ovarian function as evidenced by irregular estrous cycle, polycystic ovarian morphology (PCOM), abnormalities in sex hormone level. Supplementation with IL-22 improved these ovarian functions in non-metabolic PCOS mice. Application of DHEA in an in vitro follicular culture system to simulate PCOS follicular developmental block and ovulation impairment. Follicles from Fshrcre+Stat3f/f did not show improvement in POCS follicle development with the addition of IL-22. In DHEA-induced PCOS mice, selective ablation of STAT3 in granulosa cells significantly reversed the ameliorative effect of IL-22 on ovarian function. CONCLUSION: IL-22 can improve non-metabolic PCOS mice ovarian function. Granulosa cells deficient in STAT3 reverses the role of IL-22 in alleviating ovary dysfunction in non-metabolic PCOS mice.

The Hydrophilic Metabolite UMP Alleviates Obesity Traits through a HIF2α-ACER2-Ceramide Signaling Axis.

Metabolic abnormalities contribute to the pathogenesis of obesity and its complications. Yet, the understanding of the interactions between critical metabolic pathways that underlie obesity remains to be improved, in part owing to the lack of comprehensive metabolomics studies that reconcile data from both hydrophilic and lipophilic metabolome analyses that can lead to the identification and characterization of key signaling networks. Here, the study conducts a comprehensive metabolomics analysis, surveying lipids and hydrophilic metabolites of the plasma and omental adipose tissue of obese individuals and the plasma and epididymal adipose tissue of mice. Through these approaches, it is found that a significant accumulation of ceramide due to inhibited sphingolipid catabolism, while a significant reduction in the levels of uridine monophosphate (UMP), is critical to pyrimidine biosynthesis. Further, it is found that UMP administration restores sphingolipid homeostasis and can reduce obesity in mice by reversing obesity-induced inhibition of adipocyte hypoxia inducible factor 2a (Hif2α) and its target gene alkaline ceramidase 2 (Acer2), so as to promote ceramide catabolism and alleviate its accumulation within cells. Using adipose tissue Hif2α-specific knockout mice, the study further demonstrates that the presence of UMP can alleviate obesity through a HIF2α-ACER2-ceramide pathway, which can be a new signaling axis for obesity improvement.

The microbial metabolite agmatine acts as an FXR agonist to promote polycystic ovary syndrome in female mice.

Polycystic ovary syndrome (PCOS), an endocrine disorder afflicting 6-20% of women of reproductive age globally, has been linked to alterations in the gut microbiome. We previously showed that in PCOS, elevation of Bacteroides vulgatus in the gut microbiome was associated with altered bile acid metabolism. Here we show that B. vulgatus also induces a PCOS-like phenotype in female mice via an alternate mechanism independent of bile acids. We find that B. vulgatus contributes to PCOS-like symptoms through its metabolite agmatine, which is derived from arginine by arginine decarboxylase. Mechanistically, agmatine activates the farnesoid X receptor (FXR) pathway to subsequently inhibit glucagon-like peptide-1 (GLP-1) secretion by L cells, which leads to insulin resistance and ovarian dysfunction. Critically, the GLP-1 receptor agonist liraglutide and the arginine decarboxylase inhibitor difluoromethylarginine ameliorate ovarian dysfunction in a PCOS-like mouse model. These findings reveal that agmatine-FXR-GLP-1 signalling contributes to ovarian dysfunction, presenting a potential therapeutic target for PCOS management.

Candida albicans accelerates atherosclerosis by activating intestinal hypoxia-inducible factor2α signaling.

The gut microbiota is closely linked to atherosclerosis. However, the role of intestinal fungi, essential members of the complex microbial community, in atherosclerosis is poorly understood. Herein, we show that gut fungi dysbiosis is implicated in patients with dyslipidemia, characterized by higher levels of Candida albicans (C. albicans), which are positively correlated with plasma total cholesterol and low-density lipoprotein-cholesterol (LDL-C) levels. Furthermore, C. albicans colonization aggravates atherosclerosis progression in a mouse model of the disease. Through gain- and loss-of-function studies, we show that an intestinal hypoxia-inducible factor 2α (HIF-2α)-ceramide pathway mediates the effect of C. albicans. Mechanistically, formyl-methionine, a metabolite of C. albicans, activates intestinal HIF-2α signaling, which drives increased ceramide synthesis to accelerate atherosclerosis. Administration of the HIF-2α selective antagonist PT2385 alleviates atherosclerosis in mice by reducing ceramide levels. Our findings identify a role for intestinal fungi in atherosclerosis progression and highlight the intestinal HIF-2α-ceramide pathway as a target for atherosclerosis treatment.

Sphingosine d18:1 promotes nonalcoholic steatohepatitis by inhibiting macrophage HIF-2α.

Non-alcoholic steatohepatitis (NASH) is a severe type of the non-alcoholic fatty liver disease (NAFLD). NASH is a growing global health concern due to its increasing morbidity, lack of well-defined biomarkers and lack of clinically effective treatments. Using metabolomic analysis, the most significantly changed active lipid sphingosine d18:1 [So(d18:1)] is selected from NASH patients. So(d18:1) inhibits macrophage HIF-2α as a direct inhibitor and promotes the inflammatory factors secretion. Male macrophage-specific HIF-2α knockout and overexpression mice verified the protective effect of HIF-2α on NASH progression. Importantly, the HIF-2α stabilizer FG-4592 alleviates liver inflammation and fibrosis in NASH, which indicated that macrophage HIF-2α is a potential drug target for NASH treatment. Overall, this study confirms that So(d18:1) promotes NASH and clarifies that So(d18:1) inhibits the transcriptional activity of HIF-2α in liver macrophages by suppressing the interaction of HIF-2α with ARNT, suggesting that macrophage HIF-2α may be a potential target for the treatment of NASH.

TGF-beta and immune cells: an important regulatory axis in the tumor microenvironment and progression.

Transforming growth factor beta (TGF-beta) plays an important role in tumor initiation and progression, functioning as both a suppressor and a promoter. The mechanisms underlying this dual role of TGF-beta remain unclear. TGF-beta exerts systemic immune suppression and inhibits host immunosurveillance. Neutralizing TGF-beta enhances CD8+ T-cell- and NK-cell-mediated anti-tumor immune responses. It also increases neutrophil-attracting chemokines resulting in recruitment and activation of neutrophils with an antitumor phenotype. In addition to its systemic effects, TGF-beta regulates infiltration of inflammatory/immune cells and cancer-associated fibroblasts in the tumor microenvironment causing direct changes in tumor cells. Understanding TGF-beta regulation at the interface of tumor and host immunity should provide insights into developing effective TGF-beta antagonists and biomarkers for patient selection and efficacy of TGF-beta antagonist treatment.

[Identification and expression of cytochrome C in tumor-bearing mice model with neuroblastoma].

OBJECTIVE: To screen, identify and verify the serum specific protein of neuroblastoma in a tumor-bearing murine model and speculate about the source of cytochrome C. METHODS: NB cells (KP-N-NS) were inoculated subcutaneously into nude mice. And the sera samples of tumor-bearing mice (observation group, n = 14) and controls (control group, n = 25) were collected at 4 weeks to screen for and identify differentially expressed proteins. The method of surface-enhanced laser desorption-ionization time-of-flight mass spectrometry (SELDI-TOF-MS) was employed to screen the serum specific protein of neuroblastoma between two groups. Then serum protein targets were purified by high-performance liquid chromatography (HPLC) and identified by LC-MS/MS (LTQ). RESULTS: By comparing protein peaks among two sera groups, we identified the peak (11 609) showing significant differential expression between two groups. The expression of peak (11 609) was 3338.4 ± 1410.9 in observation group and 59.8 ± 40.7 in control group. This peak was identified as murine cytochrome C. CONCLUSION: Cytochrome C is a serum specific protein for neuroblastoma tumor and it comes from the apoptosis of non-tumor cells.

IL-21R-STAT3 signalling initiates a differentiation program in uterine tissue-resident NK cells to support pregnancy.

Tissue-resident Natural Killer (trNK) cells are crucial components of local immunity that activate rapidly upon infection. However, under steady state conditions, their responses are tightly controlled to prevent unwanted tissue damage. The mechanisms governing their differentiation and activation are not fully understood. Here, we characterise uterine trNK cells longitudinally during pregnancy by single cell RNA sequencing and find that the combined expression pattern of 4-1BB and CD55 defines their three distinct stages of differentiation in mice. Mechanistically, an IL-21R-STAT3 axis is essential for initiating the trNK cell differentiation. The fully differentiated trNK cells demonstrate enhanced functionality, which is necessary for remodelling spiral arteries in the decidua. We identify an apoptotic program that is specific to the terminal differentiation stage, which may preclude tissue damage by these highly activated trNK cells. In summary, uterine trNK cells become intensely active and effective during pregnancy, but tightly controlled via a differentiation program that also limits potential harm, suggesting an intricate mechanism for harnessing trNK cells in maintaining pregnancy.

Microbial-host-isozyme analyses reveal microbial DPP4 as a potential antidiabetic target.

A mechanistic understanding of how microbial proteins affect the host could yield deeper insights into gut microbiota-host cross-talk. We developed an enzyme activity-screening platform to investigate how gut microbiota-derived enzymes might influence host physiology. We discovered that dipeptidyl peptidase 4 (DPP4) is expressed by specific bacterial taxa of the microbiota. Microbial DPP4 was able to decrease the active glucagon like peptide-1 (GLP-1) and disrupt glucose metabolism in mice with a leaky gut. Furthermore, the current drugs targeting human DPP4, including sitagliptin, had little effect on microbial DPP4. Using high-throughput screening, we identified daurisoline-d4 (Dau-d4) as a selective microbial DPP4 inhibitor that improves glucose tolerance in diabetic mice.