Short-chain fatty acid-producing bacterial strains attenuate experimental ulcerative colitis by promoting M2 macrophage polarization via JAK/STAT3/FOXO3 axis inactivation.

BACKGROUND: Patients with inflammatory bowel disease (IBD), dysbiosis, and immunosuppression who receive fecal microbiota transplantation (FMT) from healthy donors are at an increased risk of developing bacteremia. This study investigates the efficacy of a mixture of seven short-chain fatty acid (SCFA)-producing bacterial strains (7-mix), the resulting culture supernatant mixture (mix-sup), and FMT for treating experimental ulcerative colitis (UC) and evaluates underlying mechanisms. METHODS: Utilizing culturomics, we isolated and cultured SCFA-producing bacteria from the stool of healthy donors. We used a mouse model of acute UC induced by dextran sulfate sodium (DSS) to assess the effects of 7-mix, mix-sup, and FMT on intestinal inflammation and barrier function, microbial abundance and diversity, and gut macrophage polarization by flow cytometry, immunohistochemistry, 16S rRNA gene sequencing, and transwell assays. RESULTS: The abundance of several SCFA-producing bacterial taxa decreased in patients with UC. Seven-mix and mix-sup suppressed the inflammatory response and enhanced intestinal mucosal barrier function in the mouse model of UC to an extent similar to or superior to that of FMT. Moreover, 7-mix and mix-sup increased the abundance of SCFA-producing bacteria and SCFA concentrations in colitic mice. The effects of these interventions on the inflammatory response and gut barrier function were mediated by JAK/STAT3/FOXO3 axis inactivation in macrophages by inducing M2 macrophage polarization in vivo and in vitro. CONCLUSIONS: Our approach provides new opportunities to rationally harness live gut probiotic strains and metabolites to reduce intestinal inflammation, restore gut microbial composition, and expedite the development of safe and effective treatments for IBD.

Pretreatment with an antibiotics cocktail enhances the protective effect of probiotics by regulating SCFA metabolism and Th1/Th2/Th17 cell immune responses.

BACKGROUND: Probiotics are a potentially effective therapy for inflammatory bowel disease (IBD); IBD is linked to impaired gut microbiota and intestinal immunity. However, the utilization of an antibiotic cocktail (Abx) prior to the probiotic intervention remains controversial. This study aims to identify the effect of Abx pretreatment from dextran sulfate sodium (DSS)-induced colitis and to evaluate whether Abx pretreatment has an enhanced effect on the protection of Clostridium butyricum Miyairi588 (CBM) from colitis. RESULTS: The inflammation, dysbiosis, and dysfunction of gut microbiota as well as T cell response were both enhanced by Abx pretreatment. Additionally, CBM significantly alleviated the DSS-induced colitis and impaired gut epithelial barrier, and Abx pretreatment could enhance these protective effects. Furthermore, CBM increased the benefit bacteria abundance and short-chain fatty acids (SCFAs) level with Abx pretreatment. CBM intervention after Abx pretreatment regulated the imbalance of cytokines and transcription factors, which corresponded to lower infiltration of Th1 and Th17 cells, and increased Th2 cells. CONCLUSIONS: Abx pretreatment reinforced the function of CBM in ameliorating inflammation and barrier damage by increasing beneficial taxa, eliminating pathogens, and inducing a protective Th2 cell response. This study reveals a link between Abx pretreatment, microbiota, and immune response changes in colitis, which provides a reference for the further application of Abx pretreatment before microbiota-based intervention.

Rapamycin extenuates experimental colitis by modulating the gut microbiota.

BACKGROUND AND AIM: Autophagy and gut microbiota correlates closely with the inflammatory bowel disease. Herein, we aimed to study the roles of rapamycin on the gut microbiota in inflammatory bowel disease. METHODS: Acute colitis was induced with dextran sodium sulfate (DSS) and 2,4,6-trinitrobenzenesulfonic acid solution in mice. Mice were administered with rapamycin or hydroxychloroquine. Weight loss, disease activity index scores, histopathological score, serum inflammatory cytokines, intestinal permeability, and colonic autophagy-related proteins were detected. Cecal content was also preserved in liquid nitrogen and subsequently analyzed following the 16S DNA sequencing. The antibiotic cocktail-induced microbiome depletion was performed to further investigate the relationship between autophagy activation and gut microbiota. RESULTS: Compared with the control group, the colonic autophagy-related proteins of P62, mTOR, and p-mTOR increased significantly, while the levels of LC3B and ATG16L1 decreased (all P < 0.05) in the model group. After rapamycin intervention, the colonic pathology of mice improved, while the disease activity index score decreased substantially; the colon length increased, and the expression of IL-6 and TNF-α decreased. Following hydroxychloroquine treatment, some indicators suggested aggravation of colitis. Principal coordinates analysis showed that the DSS group was located on a separate branch from the rapamycin group but was closer to the hydroxychloroquine group. Compared with the DSS group, the rapamycin group was associated with higher abundances of f_Lactobacillaceae (P = 0.0151), f_Deferribacteraceae (P = 0.0290), g_Lactobacillus (P = 0.0151), g_Mucispirillum (P = 0.0137), s_Lactobacillus_reuteri (P = 0.0028), and s_Clostridium_sp_Culture_Jar-13 (P = 0.0082) and a lower abundance of s_Bacteroides_sartorii (P = 0.0180). Linear discriminant analysis effect size showed that rapamycin increased the abundances of Lactobacillus-reuteri, Prevotellaceae, Paraprevotella, Christensenella and Streptococcus and decreased those of Peptostreptococcaceae and Romboutsia Bacteroides-sartorii. Besides, the improvement effect of autophagy activation on colitis disappears following gut microbiome depletion. CONCLUSION: The therapeutic effects of rapamycin on extenuating experimental colitis may be related to the gut microbiota.

Infiltration of a Unique CD8+CD274+ Cell Subgroup in Hepatocellular Carcinoma is Associated with Poor Clinical Outcomes.

Introduction: Immune checkpoint (IC) inhibitor-related immunotherapies have attracted considerable attention in hepatocellular carcinoma (HCC). High IC expression and high tumor infiltrating lymphocyte levels are the current indicators of sensitivity to IC inhibitors. Thus, it is imperative to apply precision medicine strategies for patient selection. Methods: Six independent HCC cohorts were used for analysis at the single-cell and tissue levels. Multiplex immunofluorescence and immunochemistry staining assays were used to validate our results. A series of methodologies were used for immune-related evaluations. Results: Herein, we uncovered a unique CD8+CD274+ cell subpopulation that is associated with tumor progression and poor survival in HCC at the single-cell level. We assessed this subset at the tissue level and found that the prognostic significance of CD274 is dependent on CD8A expression in HCC. Subsequently, we identified a unique high-risk subpopulation that showed high CD8A expression coupled with intense CD274 expression in multiple HCC cohorts. CD8AHighCD274High* subgroup was correlated with malignant indexes and remained an independent prognostic factor when considering the influence of these indexes. Molecular characteristic analyses showed that the CD8AHighCD274High* subgroup harbored more mutations, had higher immune response activity and presented enrichment of cancer-related biological processes. Moreover, this high-risk subpopulation in HCC was characterized by high immune cell infiltration, low tumor purity, and enrichment of cancer-related signatures. Finally, cases with this phenotype demonstrated higher immunomodulator and IC levels and greater sensitivity to IC inhibitors. Conclusion: Our findings illustrate that some HCC patients may have a poor prognosis despite high CD8+ T-cell infiltration. These patients would probably benefit from IC inhibitor-based combination treatment.

Pattern recognition receptors in the development of nonalcoholic fatty liver disease and progression to hepatocellular carcinoma: An emerging therapeutic strategy.

Nonalcoholic fatty liver disease (NAFLD) is characterized by excessive lipid accumulation and has become the leading chronic liver disease worldwide. NAFLD is viewed as the hepatic manifestation of metabolic syndrome, ranging from simple steatosis and nonalcoholic steatohepatitis (NASH) to advanced fibrosis, eventually leading to cirrhosis and hepatocellular carcinoma (HCC). The pathogenesis of NAFLD progression is still not clear. Pattern recognition receptor (PRR)-mediated innate immune responses play a critical role in the initiation of NAFLD and the progression of NAFLD-related HCC. Toll-like receptors (TLRs) and the cyclic GMP-AMP (cGAMP) synthase (cGAS) are the two major PRRs in hepatocytes and resident innate immune cells in the liver. Increasing evidence indicates that the overactivation of TLRs and the cGAS signaling pathways may contribute to the development of liver disorders, including NAFLD progression. However, induction of PRRs is critical for the release of type I interferons (IFN-I) and the maturation of dendritic cells (DCs), which prime systemic antitumor immunity in HCC therapy. In this review, we will summarize the emerging evidence regarding the molecular mechanisms of TLRs and cGAS in the development of NAFLD and HCC. The dysfunction of PRR-mediated innate immune response is a critical determinant of NAFLD pathology; targeting and selectively inhibiting TLRs and cGAS signaling provides therapeutic potential for treating NALF-associated diseases in humans.

Nucleolar protein treacle ribosome biogenesis factor 1 maintains gastric cancer cell proliferation by regulating R-loop associated DNA replication stress.

BACKGROUND AND AIM: Gastric cancer (GC) is a common malignant neoplasm in the gastrointestinal tract, accounting for high mortality globally. Treacle ribosome biogenesis factor 1 (TCOF1) is a nucleolar protein, which has been reported to be implicated in the pathogenesis of Treacher Collins syndrome and the development of several types of human cancer. However, the role of TCOF1 in GC is not known. METHODS: Immunohistochemistry was carried out to determine TCOF1 expression in GC tissues. Immunofluorescence, co-IP, and DNA fiber assays were conducted to investigate the function of TCOF1 in GC-derived BGC-823 and SGC-7901 cell lines. RESULTS: TCOF1 expression was aberrantly increased in GC tissues compared with adjacent normal tissues. In addition, we found that TCOF1 left the nucleolus and localized to R-loops (DNA/RNA hybrids) during S phase in GC cells. Furthermore, TCOF1 interacted with DDX5 and suppressed R-loop levels. Knockdown of TCOF1 led to increased nucleoplasmic R-loops specifically during S phase, which restrained DNA replication and cell proliferation. Overexpression of R-loop eraser RNaseH1 rescued the DNA synthesis defects and decreased DNA damage caused by TCOF1 depletion. CONCLUSION: These findings demonstrate a novel role of TCOF1 in maintaining GC cell proliferation by alleviating R-loop associated DNA replication stress.

Worldwide research on extraction and recovery of cobalt through bibliometric analysis: a review.

Cobalt is a strategic and critical mineral whose demand is expected to grow rapidly. This study aims to provide a comprehensive summary of cobalt extraction and recovery research from 2012 to 2021 in the form of bibliometric analysis. The work was based on the Science Citation Index Expanded (Web of Science) and carried out using the InCites of Clarivate for bibliometric data analysis and the software VOSviewer for science mapping. By analyzing a dataset of 4967 publications, the most influential journals, countries, authors, institutions, and publications were identified, and the keyword co-occurrence networks were mapped. The China mainland produced the most publications, while the USA had the highest average number of citations per publication and the UK was the most collaborative with other countries. The keyword analysis shows that the research hotspots gradually shifted over time from early means and methods for determination of cobalt in solution to recovery of cobalt from spent lithium batteries, smelting slag, copper-cobalt ore, etc. The research will be focused on further improvement and optimization of the separation, extraction, and recovery processes of cobalt from spent batteries in recent and future years, and three approaches were promoted to facilitate economization and industrialization of the processes in this field.

Nociceptor neurons direct goblet cells via a CGRP-RAMP1 axis to drive mucus production and gut barrier protection.

Neuroepithelial crosstalk is critical for gut physiology. However, the mechanisms by which sensory neurons communicate with epithelial cells to mediate gut barrier protection at homeostasis and during inflammation are not well understood. Here, we find that Nav1.8+CGRP+ nociceptor neurons are juxtaposed with and signal to intestinal goblet cells to drive mucus secretion and gut protection. Nociceptor ablation led to decreased mucus thickness and dysbiosis, while chemogenetic nociceptor activation or capsaicin treatment induced mucus growth. Mouse and human goblet cells expressed Ramp1, receptor for the neuropeptide CGRP. Nociceptors signal via the CGRP-Ramp1 pathway to induce rapid goblet cell emptying and mucus secretion. Notably, commensal microbes activated nociceptors to control homeostatic CGRP release. In the absence of nociceptors or epithelial Ramp1, mice showed increased epithelial stress and susceptibility to colitis. Conversely, CGRP administration protected nociceptor-ablated mice against colitis. Our findings demonstrate a neuron-goblet cell axis that orchestrates gut mucosal barrier protection.

Altered Pattern of Immunoglobulin A-Targeted Microbiota in Inflammatory Bowel Disease After Fecal Transplantation.

Adaptive immune response to the gut microbiota is one of the main drivers of inflammatory bowel disease (IBD). Under inflammatory conditions, immunoglobulin (Ig)-targeted bacteria are altered. However, changes in Ig-targeted bacteria in Asian patients with IBD with ulcerative colitis (UC) remain unclear. Furthermore, changes in IgA-targeted bacteria in patients with UC treated with fecal microbiota transplantation (FMT) are unclear. Here, we analyzed fecal samples of patients with IBD and patients with UC before and after FMT by flow cytometry. We found that the percentage of IgA/G-coated bacteria can be used to assess the severity of IBD. Besides oral pharyngeal bacteria such as Streptococcus, we hypothesized that Megamonas, Acinetobacter, and, especially, Staphylococcus might play an important role in IBD pathogenesis. Moreover, we evaluated the influence of FMT on IgA-coated bacteria in patients with UC. We found that IgA-bacterial interactions were re-established in human FMT recipients and resembled those in the healthy fecal donors. Additionally, the IgA targeting was not influenced by delivery methods: gastroscopy spraying and colonic transendoscopic enteral tubing (TET). Then, we established an acute dextran sulfate sodium (DSS)-induced mouse model to explore whether FMT intervention would impact IgA/G memory B cell in the intestine. We found that after FMT, both IgA/G memory B cell and the percentage of IgA/G-targeted bacteria were restored to normal levels in DSS mice.

Characterization of short-chain fatty acids in patients with ulcerative colitis: a meta-analysis.

BACKGROUND: Studies investigating the changes in short-chain fatty acids (SCFAs) in patients with ulcerative colitis (UC) have yielded inconsistent results. We performed a meta-analysis of studies that investigated the alterations in different SCFAs among UC patients to assess their role in the development of UC. METHODS: Three databases were searched for relevant studies published as of April 2021. Results are presented as standardized mean difference (SMD) with 95% confidence interval (95% CI). RESULTS: Eleven studies were included in the meta-analysis. Compared to healthy subjects, UC patients had significantly lower concentrations of total SCFAs (SMD = - 0.88, 95%CI - 1.44, - 0.33; P < 0.001), acetate (SMD = - 0.54, 95% CI - 0.91, - 0.17; P = 0.004), propionate, (SMD = - 0.37, 95% CI - 0.66, - 0.07; P = 0.016), and valerate (SMD = - 0.91, 95% CI - 1.45, - 0.38; P < 0.001). On subgroup analysis based on disease status, patients with active UC had reduced concentrations of acetate (SMD = - 1.83, 95% CI - 3.32, - 0.35; P = 0.015), propionate (SMD = - 2.51, 95% CI - 4.41, - 0.61; P = 0.009), and valerate (SMD = - 0.91, 95% CI - 1.45, - 0.38; P < 0.001), while UC patients in remission had similar concentrations with healthy subjects. Patients with active UC had lower butyrate level (SMD = - 2.09, 95% CI - 3.56, - 0.62; P = 0.005) while UC patients in remission had higher butyrate level (SMD = 0.71, 95% CI 0.33, 1.10; P < 0.001) compared with healthy subjects. CONCLUSION: UC patients had significantly decreased concentrations of total SCFAs, acetate, propionate, and valerate compared with healthy subjects. In addition, inconsistent changes of certain special SCFAs were observed in UC patients with different disease status.

Effectiveness and Safety of Tofacitinib for Ulcerative Colitis: Systematic Review and Meta-analysis.

BACKGROUND: The objective of our systematic review and meta-analysis was to evaluate the effectiveness and safety of tofacitinib in the treatment of moderate-severe ulcerative colitis (UC). METHODS: We searched Medline, Embase, Web of Science, and Cochrane Central to identify articles and abstracts reporting efficacy or safety data on tofacitinib use in UC. Primary outcome assessed was remission. Secondary outcomes included clinical response, steroid free remission, and adverse events (AEs). RESULTS: A total of 26 studies were included. The rates of remission were 29.81% [95% confidence interval (CI): 22.37%-37.25%, I2 : 90%] at week 8, 32.27% (95% CI: 27.67%-36.88%, I2 : 42%) at 6 months and 38.03% (95% CI: 33.59%-42.48%, I2 : 0%) at 1-year. Clinical response rates were 59.41% (95% CI: 55.03%-63.94%, I2 : 61%) at week 8, 48.99% (95% CI: 36.92%-61.06%, I2 : 91%) at 6 months and 50.87% (95% CI: 42.16%-59.58%, I2 : 67%) at 1-year. Odds ratio of clinical response at week 8 in biologic naive versus biologic experienced patients was 1.59 (95% CI: 0.54-4.63). Pooled incidence rate for serious infections, major adverse cardiovascular events, and nonmelanotic squamous cell malignancies across all doses was 4.41 per 100-patient years (PYs) (95% CI: 2.32-8.38 per 100-PY, I2 : 78%), 0.91 per 100-PY (95% CI: 0.43-1.93 per 100-PY, I2 : 37%) and 0.91 per 100-PY (95% CI: 0.61-1.34 per 100-PY, I2 : 0%), respectively. Higher dose was associated with an increased frequency of AEs. CONCLUSIONS: While the overall efficacy and safety of tofacitinib in moderate-severe UC is consistent with clinical trial data, the dose dependent increase in AEs highlights the significance of early dose de-escalation. Rate of clinical response after tofacitinb induction was similar in biologic naive and biologic experienced patients.

Guideline Adherence of ß-blocker Initiating Dose and its Consequence in Hospitalized Patients With Heart Failure With Reduced Ejection Fraction.

Background: We aim to investigate the guideline adherence of ß-blocker (BB) initiating dose in Chinese hospitalized patients with heart failure with reduced ejection fraction (HFrEF) and whether the adherence affected the in-hospital outcomes. Methods: This was a retrospective study of patients hospitalized with HFrEF who had initiated BBs during their hospitalization. We defined adherence to clinical practice guidelines as initiating BB with standard dose and non-adherence to guidelines if otherwise, and examined the association between adherence to guidelines and in-hospital BB-related adverse events. Subgroup analyses based on sex, age, coronary heart disease, and hypertension were performed. Results: Among 1,104 patients with HFrEF initiating BBs during hospitalization (median length of hospitalization, 12 days), 304 (27.5%) patients received BB with non-adherent initiating dose. This non-adherence was related to a higher risk (hazard ratio [95% confidence interval]) of BB dose reduction or withdrawal (1.78 [1.42 to 2.22], P < 0.001), but not significantly associated with risks of profound bradycardia, hypotension, cardiogenic shock requiring intravenous inotropes, and severe bronchospasm requiring intravenous steroid during hospitalization. Conclusion: This study identified that over a fourth of patients had received BBs with an initiating dose that was not adherent to guidelines in Chinese hospitalized patients with HFrEF, and this non-adherence was associated with BB dose reduction or withdrawal during hospitalization.

Genome insights of Enterococcus raffinosus CX012922, isolated from the feces of a Crohn's disease patient.

BACKGROUND: Enterococcus raffinosus is one of the Enterococcus species that often cause nosocomial infections. To date, only one E. raffinosus genome has been completely assembled, and the genomic features have not been characterized. Here, we report the complete genome sequence of the strain CX012922, isolated from the feces of a Crohn's disease patient, and perform a comparative genome analysis to the relevant Enterococcus spp. strains in silico. RESULTS: De novo assembly of the sequencing reads of the strain CX012922 generated a circular genome of 2.83 Mb and a circular megaplasmid of 0.98 Mb. Phylogenomic analysis revealed that the strain CX012922 belonged to the E. raffinosus species. By comparative genome analysis, we found that some strains previously identified as E. raffinosus or E. gilvus should be reclassified as novel species. Genome islands (GIs), virulence factors, and antibiotic genes were found in both the genome and the megaplasmid, although pathogenic genes were mainly encoded in the genome. A large proportion of the genes encoded in the megaplasmid were involved in substrate utilization, such as raffinose metabolism. Giant megaplasmids (~1 Mb) equipped with toxin-antitoxin (TA) systems generally formed symbiosis relationships with the genome of E. raffinosus strains. CONCLUSIONS: Enterococcus spp. have a higher species-level diversity than is currently appreciated. The pathogenicity of E. raffinosus is mainly determined by the genome-encoded virulence factors, while the megaplasmid broadens the gene function pool. The symbiosis between the genome and the megaplasmids endows E. raffinosus with large genomic sizes as well as versatile gene functions, especially for their colonization, adaptation, virulence, and pathogenesis in the human gut.

Selection strategy of dextran sulfate sodium-induced acute or chronic colitis mouse models based on gut microbial profile.

BACKGROUND: Dextran sulfate sodium (DSS) replicates ulcerative colitis (UC)-like colitis in murine models. However, the microbial characteristics of DSS-triggered colitis require further clarification. To analyze the changes in gut microbiota associated with DSS-induced acute and chronic colitis. METHODS: Acute colitis was induced in mice by administering 3% DSS for 1 week in the drinking water, and chronic colitis was induced by supplementing drinking water with 2.5% DSS every other week for 5 weeks. Control groups received the same drinking water without DSS supplementation. The histopathological score and length of the colons, and disease activity index (DAI) were evaluated to confirm the presence of experimental colitis. Intestinal microbiota was profiled by 16S rDNA sequencing of cecal content. RESULTS: Mice with both acute and chronic DSS-triggered colitis had significantly higher DAI and colon histopathological scores in contrast to the control groups (P < 0.0001, P < 0.0001), and the colon was remarkably shortened (P < 0.0001, P < 0.0001). The gut microbiota α-diversity was partly downregulated in both acute and chronic colitis groups in contrast to their respective control groups (Pielou index P = 0.0022, P = 0.0649; Shannon index P = 0.0022, P = 0.0931). The reduction in the Pielou and Shannon indices were more obvious in mice with acute colitis (P = 0.0022, P = 0.0043). The relative abundance of Bacteroides and Turicibacter was increased (all P < 0.05), while that of Lachnospiraceae, Ruminococcaceae, Ruminiclostridium, Rikenella, Alistipes, Alloprevotella, and Butyricicoccus was significantly decreased after acute DSS induction (all P < 0.05). The relative abundance of Bacteroides, Akkermansia, Helicobacter, Parabacteroides, Erysipelatoclostridium, Turicibacter and Romboutsia was also markedly increased (all P < 0.05), and that of Lachnospiraceae_NK4A136_group, Alistipes, Enterorhabdus, Prevotellaceae_UCG-001, Butyricicoccus, Ruminiclostridium_6, Muribaculum, Ruminococcaceae_NK4A214_group, Family_XIII_UCG-001 and Flavonifractor was significantly decreased after chronic DSS induction (all P < 0.05). CONCLUSION: DSS-induced acute and chronic colitis demonstrated similar symptoms and histopathological changes. The changes in the gut microbiota of the acute colitis model were closer to that observed in UC. The acute colitis model had greater abundance of SCFAs-producing bacteria and lower α-diversity compared to the chronic colitis model.

Deficiencies in Planning Interventional Trial Registration of COVID-19 in China.

Background: The coronavirus disease 2019 (COVID-19) pandemic has affected the world since late 2019. The efforts to control the spread of the virus need to be supported by credible evidence. Therefore, we analyzed the rationality of the timeline and geographic distribution of COVID-19 trial registration in mainland China. Methods: We searched the Chinese Clinical Trial Registry (ChiCTR, http://www.chictr.org.cn/) and International Clinical Trials Registry Platform (ICTRP, https://www.who.int/ictrp/en/) using keywords including novel coronavirus, coronavirus pneumonia, 2019-nCoV, COVID-19, and SARS-COV-2 from 1 December 2019 to 27 April 2020 and included interventional randomized and non-randomized trials including patients with confirmed cases of COVID-19 in mainland China. The registered trials were reviewed, and data were independently extracted by two reviewers based on the inclusion criteria. Results: A total of 263 registered interventional trials were included in the study. We defined the sample size index (SI) as the total number of patients needed by the trials divided by the total number of patients diagnosed with COVID-19. A total of 84,341 patients had been diagnosed with COVID-19 in China as of 26 April 2020, and the included trials had a combined sample size of 31,156 patients (SI: 0.37). After control of the COVID-19 epidemic was achieved in China (February 18, 2020), the SI was 1.54, suggesting that the number of patients needed by the trials was greater than the number of newly diagnosed patients. The SIs in 8 out of 26 provinces in mainland China were >1. Conclusions: Our results suggested a clear over registration of COVID-19 trials in China, especially after control of the pandemic was achieved, preventing the generation of high-quality evidence.

Cross-Talk Between Butyric Acid and Gut Microbiota in Ulcerative Colitis Following Fecal Microbiota Transplantation.

Fecal microbiota transplantation (FMT) can inhibit the progression of ulcerative colitis (UC). However, how FMT modulates the gut microbiota and which biomarker is valuable for evaluating the efficacy of FMT have not been clarified. This study aimed to determine the changes in the gut microbiota and their relationship with butyric acid following FMT for UC. Fecal microbiota (FM) was isolated from healthy individuals or mice and transplanted into 12 UC patients or colitis mice induced by dextran sulfate sodium (DSS). Their clinical colitis severities were monitored. Their gut microbiota were analyzed by 16S sequencing and bioinformatics. The levels of fecal short-chain fatty acids (SCFAs) from five UC patients with recurrent symptoms after FMT and individual mice were quantified by liquid chromatography-mass spectrometry (LC-MS). The impact of butyric acid on the abundance and diversity of the gut microbiota was tested in vitro. The effect of the combination of butyric acid-producing bacterium and FMT on the clinical responses of 45 UC patients was retrospectively analyzed. Compared with that in the controls, the FMT significantly increased the abundance of butyric acid-producing bacteria and fecal butyric acid levels in UC patients. The FMT significantly increased the α-diversity, changed gut microbial structure, and elevated fecal butyric acid levels in colitis mice. Anaerobic culture with butyrate significantly increased the α-diversity of the gut microbiota from colitis mice and changed their structure. FMT combination with Clostridium butyricum-containing probiotics significantly prolonged the UC remission in the clinic. Therefore, fecal butyric acid level may be a biomarker for evaluating the efficacy of FMT for UC, and addition of butyrate-producing bacteria may prolong the therapeutic effect of FMT on UC by changing the gut microbiota.

Alterations in Gut Microbial Communities Across Anatomical Locations in Inflammatory Bowel Diseases.

We previously discovered that gut microbiota can serve as universal microbial biomarkers for diagnosis, disease activity assessment, and predicting the response to infliximab treatment for inflammatory bowel diseases (IBD). Much still remains unknown about the relationship between alterations in gut microbiota and IBD affected bowel region, in particular in the case of ulcerative colitis (UC) and colonic Crohn's disease (cCD) without endoscopic and biopsy data. In the current study gut microbiota from a population in China was found to be distinct from that of the Western world [Human Microbiome Project (HMP) data]. Furthermore, both gut microbiota greatly differed from microbiota of other anatomical locations (oral, skin, airway, and vagina), with higher alpha-diversity (Chinese gut > HMP gut > oral microbiome > airway microbiome > skin microbiome > vaginal microbiome), and marked differences in microbiome composition. In patients with IBD in China, UC was characterized by the presence of Gardnerella, while cCD was characterized by the presence of Fusobacterium. Moreover, gut microbiota, such as Gardnerella and Fusobacterium, may be potential biomarkers for identifying UC from cCD. Together, this study revealed crucial differences in microbial communities across anatomical locations, and demonstrated that there was an important association between IBD affected bowel region and gut microbiota.

Extracellular vesicles of Fusobacterium nucleatum compromise intestinal barrier through targeting RIPK1-mediated cell death pathway.

Microbial factors that mediate microbes-host interaction in ulcerative colitis (UC), a chronic disease seriously affecting human health, are not fully known. The emerging oncobacterium Fusobacterium nucleatum (Fn) secretes extracellular vesicles carrying several types of harmful molecules in the intestine which can alter microbes-host interaction, especially the epithelial homeostasis in UC. However, the mechanism is not yet clear. Previously, we isolated EVs by the ultracentrifugation of Fn culture media and characterized them as the potent inducer of pro-inflammatory cytokines. Here, we examined the mechanism in detail. We found that in macrophage/Caco-2 co-cultures, FnEVs significantly promoted epithelial barrier loss and oxidative stress damage, which are related to epithelial necroptosis caused by the activation of receptor-interacting protein kinase 1 (RIPK1) and receptor-interacting protein kinase 3 (RIPK3). Furthermore, FnEVs promoted the migration of RIPK1 and RIPK3 into necrosome in Caco2 cells. Notably, these effects were reversed by TNF-α neutralizing antibody or Necrostatin-1 (Nec-1), a RIPK1 inhibitor. This suggested that FADD-RIPK1-caspase-3 signaling is involved in the process. Moreover, the observed effects were verified in the murine colitis model treated with FnEVs or by adoptive transfer of FnEVs-trained macrophages. In conclusion, we propose that RIPK1-mediated epithelial cell death promotes FnEVs-induced gut barrier disruption in UC and the findings can be used as the basis to further investigate this disease.

Population diversity of cardiovascular outcome trials and real-world patients with diabetes in a Chinese tertiary hospital.

BACKGROUND: Recent cardiovascular outcome trials (CVOTs) changed the therapeutic strategy of guidelines for type 2 diabetes. We compared the characteristics of patients from real-world hospital settings with those of participants in recent pragmatic randomized trials. METHODS: This electronic medical record (EMR)-based retrospective observational study investigated the data of patients with diabetes from inpatient and outpatient settings in West China Hospital of Sichuan University from January 1, 2011, to June 30, 2019. We identified patients meeting the inclusion criteria of a pragmatic randomized trial (EMPA-REG OUTCOME) based on EMRs and compared their baseline characteristics with those of the trial participants. The cutoff for the clinical significance of each characteristic was set as its minimal clinically important difference based on expert consultation. RESULTS: We included 48,257 inpatients and 36,857 outpatients with diabetes and found that 8389 (17.4%) inpatients and 2646 (7.2%) outpatients met the inclusion criteria for the EMPA-REG OUTCOME trial. Compared with the trial population, the real-world inpatients meeting the eligibility criteria of the EMPA-REG OUTCOME had similar age, blood pressure, and lipid profiles but comprised of fewer males, metformin users, anti-hypertensive drug users, and aspirin users, and had a lower body mass index. The group of outpatients meeting the eligibility criteria had fewer males, similar age, fewer metformin users, fewer insulin users, fewer anti-hypertensive drug users, and fewer aspirin users compared with the trial population. CONCLUSIONS: The trial population in EMPA-REG OUTCOME represents only a small portion of patients with diabetes from the inpatient and outpatient departments of a Chinese tertiary medical center. Evidence localization in different clinical settings and validation are essential to enabling extrapolation of the results from CVOTs in patients with diabetes to Chinese clinical practice.

Intestinal mucosal microbiota composition of patients with acquired immune deficiency syndrome in Guangzhou, China.

Acquired immune deficiency syndrome, caused by the human immunodeficiency virus (HIV), has been associated with intestinal dysbiosis, which includes an increase in the number of mucosa-associated pathobionts. In the present study, the intestinal mucosal microbiota patterns of HIV-infected patients were compared with those of healthy individuals in a population from Guangzhou, China. The gut microbiota of intestinal mucosal samples from 12 patients with HIV (transmission routes included sex and intravenous drug abuse) was compared with that of 12 healthy age- and sex-matched controls. Gut microbial communities were profiled via sequencing of the bacterial 16S ribosomal RNA genes. Dysbiosis in HIV-infected individuals was characterized by decreased α-diversity, decreased levels of Firmicutes and increased levels of Proteobacteria. Furthermore, low mean counts of Lachnoclostridium, Roseburia, Thauera, Dorea and Roseburia inulinivorans, and high mean counts of Halomonas and Shewanella bacteria, were indicated to be HIV-associated mucosal bacterial alterations. The relative abundance of Fusobacterium and Lachnoclostridium was significantly decreased, while that of Halomonas and Shewanella was significantly increased in patients with sexually transmitted HIV-infection compared with healthy controls. Alterations of the gut microbiota during HIV infection were also indicated to be associated with the route of HIV transmission. Certain bacteria may be potential biomarkers for HIV infection in patients from Guangzhou, China.