Gut microbiome and frailty: insight from genetic correlation and mendelian randomization.

Observational studies have shown that the gut microbiome is associated with frailty. However, whether these associations underlie causal effects remains unknown. Thus, this study aimed to assess the genetic correlation and causal relationships between the genetically predicted gut microbiome and frailty using linkage disequilibrium score regression (LDSC) and Mendelian Randomization (MR). Summary statistics for the gut microbiome were obtained from a genome-wide association study (GWAS) meta-analysis of the MiBioGen consortium (N = 18,340). Summary statistics for frailty were obtained from a GWAS meta-analysis, including the UK Biobank and TwinGene (N = 175,226). We used LDSC and MR analyses to estimate the genetic correlation and causality between the genetically predicted gut microbiome and frailty. Our findings indicate a suggestive genetic correlation between Christensenellaceae R-7 and frailty. Moreover, we found evidence for suggestive causal effects of twelve genus-level gut microbes on frailty using at least two MR methods. There was no evidence of horizontal pleiotropy or heterogeneity in the MR analysis. This study provides suggestive evidence for a potential genetic correlation and causal association between several genetically predicted gut microbes and frailty. More population-based observational studies and animal experiments are required to clarify this association and the underlying mechanisms.

Fuzheng Nizeng Decoction regulated ferroptosis and endoplasmic reticulum stress in the treatment of gastric precancerous lesions: A mechanistic study based on metabolomics coupled with transcriptomics.

Background: Fuzheng Nizeng Decoction (FZNZ) has a history of decades in gastric precancerous lesions (GPL) treatment, which has shown clear clinical efficacy. Blocking GPL is a key measure to reduce the incidence of gastric cancer (GC). Therefore, we aim to investigate the mechanism of FZNZ-induced ferroptosis and endoplasmic reticulum (ER) in MNNG-induced gastric precancerous lesion (MC) cells, which has been rarely studied in Traditional Chinese Medicine (TCM). Methods: First, CCK8 and lactate dehydrogenase assays were conducted to study the potential effect of FZNZ on MC cells. Second, combined transcriptomic and metabolomic analysis were used to explore the effect and mechanism of FZNZ. Functionally, the occurrence of ferroptosis was assessed by transmission electron microscopy morphological observation and measurement of ferrous iron levels, lipid peroxidation, and glutathione levels. Finally, the expression levels of mRNAs or proteins related to ferroptosis and ER stress were determined by qPCR or western blot assays, respectively. Results: FZNZ inhibited MC cells viability and induced cell death. By metabolomics coupled with transcriptomics analysis, we found that the mechanism of FZNZ treatment induced ferroptosis and was related to glutathione metabolism and ER stress. We then, for the first time, found that FZNZ induced ferroptosis, which contributed to an increase in intracellular ferrous iron, reactive oxygen species, and malondialdehyde and a decrease in glutathione. Meanwhile, the protein level of glutathione peroxidase 4 (GPX4) was decreased. The mRNA levels of ATF3/CHOP/CHAC1, which are related to ferroptosis and ER stress, were also upregulated. Conclusion: Our results elaborate that FZNZ could induce ferroptosis and ER stress in MC cells, and reduce GPX4/GSH. ATF3/CHOP/CHAC1 may play a crosstalk role, which provides a new molecular mechanism for the treatment of GPL.

Are neurodegenerative diseases associated with an increased risk of inflammatory bowel disease? A two-sample Mendelian randomization study.

Background: Several studies have shown that neurodegenerative diseases (e.g., Parkinson's disease [PD] and Alzheimer's disease [AD]) are associated with inflammatory bowel disease (IBD), but the causality and direction of their associations remain unclear. Mendelian randomization (MR) studies have explored the causal effects of IBD on PD and AD. However, only a few studies examined this reverse association. Thus, this study aimed to explore whether there are causal associations of genetically predicted PD and AD with IBD, using a two-sample MR study. Methods: Summary statistics for IBD, ulcerative colitis (UC), and Crohn's disease (CD) were derived from a genome-wide association study (GWAS) meta-analysis, which included the International IBD Genetics Consortium and the UK IBD Genetics Consortium (n=59,957). Genetic variants associated with the largest meta-analysis of GWAS of PD (n=1,474,097) and AD (n=455,258) were used as instrumental variables. We used multiple methods, including inverse variance weighted (IVW), weighted median (WM), MR-Egger regression, weighted mode, and Robust Adjusted Profile Score (RAPS) methods, to estimate the effects of genetically predicted PD and AD on IBD. To confirm the validity of the analysis, we also evaluated the pleiotropic effects, heterogeneity, and leave-one-out sensitivity analysis that drive causal associations. Results: The results of the IVW method, WM, and RAPS showed that genetically predicted PD was significantly associated with an increased risk of UC (odds ratio [OR]IVW=1.068, OR WM=1.107, OR RAPS=1.069, all P<0.05). Additionally, we found that there were significant associations of genetically predicted PD with CD (OR IVW=1.064, OR RAPS=1.065, all P<0.05) and IBD (OR IVW=1.062, OR RAPS=1.063, all P<0.05) using the IVW method and RAPS. However, there was no significant causal evidence of genetically predicted AD in IBD, UC, or CD among all MR methods. In all MR analyses, there were no horizontal pleiotropy (all P>0.05), or statistical heterogeneity. The sensitivity analysis results of the leave-one-out sensitivity analysis showed that the causal effect estimations of genetically predicted PD and AD on IBD were robust. Conclusions: Our MR study corroborated a causal association between genetically predicted PD and IBD but did not support a causal effect of genetically predicted AD on IBD. More animal experiments or population-based observational studies are required to clarify the underlying mechanisms of PD and IBD.

Revealing the novel effect of Jinghua Weikang capsule against the antibiotic resistance of Helicobacter pylori.

Background: Helicobacter pylori (H. pylori) infects half of the human population globally. Eradication rates with triple or quadruple therapy have decreased owing to the increasing rate of antibiotic resistance. Jinghua Weikang capsule (JWC) is the first and most popular Chinese patent medicine approved by the state for the treatment of gastritis and peptic ulcers caused by H. pylori infection in China. Previous studies have found that JWC has a certain bactericidal effect on drug-resistant H. pylori and its major component, Chenopodium ambrosioides L. inhibits biofilm formation, but the mechanism remains unclear. This study focused on drug-resistant H. pylori and explored whether JWC could reverse drug resistance and its related mechanisms. Method: The agar plate dilution method, E-test method, and killing kinetics assay were used to evaluate the bactericidal effect of JWC on antibiotic-resistant H. pylori and its effect on antibiotic resistance. Sanger sequencing was used to detect mutations in drug resistance genes. The crystal violet method, scanning electron microscopy, and confocal laser scanning microscopy were used to evaluate the effects of JWC on biofilms. qPCR was performed to evaluate the effect of JWC on the expression of efflux pump-related genes. qPCR and immunofluorescence were used to evaluate the effects of JWC on H. pylori adhesion. Results: JWC showed considerable antibacterial activity against drug-resistant H. pylori strains, with minimum inhibitory concentration (MIC) values ranging from 64 to 1,024 µg/ml. The MIC of metronidazole (MTZ) against H. pylori 26,695-16R decreased from 64 to 6 µg/ml after treatment with 1/2 MIC of JWC. The resistance of H. pylori 26,695-16R to MTZ was reversed by JWC, and its effect was better than that of PaßN and CCCP. H. pylori 26,695-16R is a moderate biofilm-forming strain, and JWC (16-64 µg/ml) can inhibit the formation of biofilms in H. pylori 26,695-16R. JWC reduced the expression of HP0605-HP0607 (hefABC), HP0971-HP0969 (hefDEF), HP1327-HP1329 (hefGHI), and HP1489-HP1487. JWC reduced the adhesion of H. pylori to GES-1 cells and the expression of adhesives NapA, SabA, and BabA. Conclusion: The reversal of MTZ resistance by JWC may be achieved through the adhesin/efflux pump-biofilm pathway.

Application of a semi-automatic, intensive follow-up for improving efficacy and adherence of Helicobacter pylori eradication therapy: A randomized controlled trial.

A complete understanding and good adherence are crucial for successful Helicobacter pylori eradication. Proper frequency of reminders might be helpful to both doctors and patients to maintain adherence during treatment. The study was to evaluate the influence of an intensive follow-up system based on a clinical database on H. pylori eradication therapy. A total of 196 eligible patients were equally and randomly divided into an intensive follow-up group and a control group. Both groups were administered bismuth-containing quadruple therapy for 14 days. Patients in the intensive follow-up group were informed of pre-treatment, including the duration and potential adverse events. Subsequently, they received telephone follow-ups on days 3 and 14 and 3 days before the urea breath test (UBT). The time points were automatically reminded by a follow-up system in the established clinical database. The control group was only informed of pre-treatment information. UBT was performed 4 weeks after treatment in both groups to assess the presence of H. pylori. The eradication rate, patient compliance, and adverse events were calculated and compared. The H. pylori eradication rates of the intensive follow-up and control groups were 94.7% (90/95, 95% CI: 90%-99%) and 92.9% (78/84, 95% CI: 87%-98%), respectively, by PP analysis (p = 0.601), and 91.8% (90/98, 95% CI: 86%-97%) and 81.6% (80/98, 95% CI: 74%-89%) by ITT analysis (p = 0.035). Adverse events occurred in 9 intensive follow-up group patients and 12 in the control group. Adherence was 96.9% (95/98) in the intensive follow-up group and 85.7% (84/98) in the control group. Semi-automatic intensive follow-up contributed to a higher eradication rate and adherence to H. pylori treatment.

Clinical Symptoms and Outcomes of Severe Pneumonia Caused by Chlamydia psittaci in Southwest China.

Here, we aimed to retrospectively analyze the clinical characteristics of 27 patients with severe pneumonia caused by Chlamydia psittaci between January 2019 and April 2021 in southwest China. To this end, we collected data on the exposure history, clinical symptoms, laboratory examination, imaging characteristics, evolution, etiology, treatment, and outcomes to suggest a better diagnosis and prevention system. Our results showed that a metagenomic next-generation sequencing test could provide early diagnosis. All patients were sensitive to quinolones and tetracyclines, and the recovery rate was relatively high. Overall, all patients were in critical condition with moderate to severe acute respiratory distress syndrome and shock. In conclusion, early diagnosis of pneumonia caused by C. psittaci depends on effective molecular testing, and most patients recover after treatment.

Efficacy and Safety of Chinese Herbal Medicine Xiao Yao San in Functional Gastrointestinal Disorders: A meta-Analysis and Trial Sequential Analysis of Randomized Controlled Trials.

Background and Aims: Functional gastrointestinal disorders are now named disorders of gut-brain interaction (DGBI) according to the Rome IV criteria, characterized by the interaction of gastrointestinal symptoms and dysregulation of central nervous systems. Xiao-Yao-San (XYS) is effective in the treatment of gastrointestinal symptoms in China, especially in patients with concurrent mood disorders. A meta-analysis was designed to evaluate the efficacy and safety of Xiao-Yao-San for FGIDs. Methods: We searched randomized controlled trials in seven databases from their inception till November 22, 2021. Pooled analysis included therapeutic efficacy, symptom score, Self-Rating Anxiety Scale (SAS) score, Self-Rating Depression Scale (SDS) score, and the recurrence rate. Conventional meta-analysis with random-effects model or fixed-effects model and trial sequential analysis (TSA) were performed. Results: A total of 48 RCTs were eligible for inclusion (n = 4,403). Meta-analysis results showed that XYS could improve the effective rate of FGIDs compared with western drugs [RR = 1.23; (95%CI, 1.19-1.27); p < 0.00001], and XYS combined with western medicine could also improve the effective rate [RR = 1.26; (95%CI, 1.21-1.33); p < 0.00001]. In addition, XYS could reduce the symptom score [SMD = -1.07; (95%CI -1.42, -0.72); Z = 6.03; p < 0.00001], SAS score [MD = -6.24; (95%CI -7.48, -4.99); Z = 9.81; p < 0.00001] and SDS score [MD = -6.70; (95%CI -8.18, -5.21); Z = 8.83; p < 0.00001] of FGIDs patients, and reduce the recurrence rate [MD = -6.70; (95%CI -8.18, -5.21); Z = 8.83; p < 0.00001]. XYS was safe in most cases and no serious adverse events were observed in any of the included trials. TAS showed adequate "information size" for the primary outcome, and further confirmed the efficacy of XYS in the treatment of FGIDs. Conclusion: XYS could improve symptoms and reduce recurrence rates in FGIDs patients, and XYS may be a potential candidate for the treatment of FGIDs. However, due to the limited quality of current studies, more long-term, randomized, double-blinded clinical trials are needed in future studies. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=284308, identifier CRD42021284308.

Efficacy and Safety of Modified Dual Therapy as the First-line Regimen for the Treatment of Helicobacter pylori Infection: A Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: In an era of antibiotic resistance, modified dual therapy has been paid much attention because of simple drug composition and low resistance of amoxicillin. However, its eradication rate as a first-line regimen remains controversial. This study is to evaluate the efficacy and safety of modified dual therapy for the initial treatment of Helicobacter pylori (H. pylori) infection compared with mainstream first-line therapies. METHODS: PubMed, the Cochrane Library, and Embase were searched for randomized clinical trials evaluating the efficacy and safety of modified dual therapy as the initial treatment for H. pylori eradication compared with guideline-recommended first-line therapies. A meta-analysis was conducted using Review Manager 5.3 and dichotomous data were estimated by the risk ratio (RR) with the 95% confidence interval (CI). We also performed subgroup analysis according to control groups and studies with antibiotic susceptibility tests. RESULTS: Eight studies including 1672 patients with H. pylori infection met the selection criteria and were assessed. The meta-analysis demonstrated that modified dual therapy achieved similar efficacy [85.83% vs. 86.77%, RR 0.99 (95% CI, 0.95-1.03), intention-to-treat analysis; 89.53% vs. 90.45%, RR 0.99 (95% CI, 0.96-1.02), per-protocol analysis] and compliance [95.77% vs. 95.56%, RR 1.00 (95% CI, 0.98-1.02)] compared with recommended first-line regimens. In addition, there were no significant differences in comparing the eradication rate of modified dual therapy with clarithromycin triple therapy, bismuth quadruple therapy, and concomitant therapy, respectively. Subgroup analysis based on the studies with antibiotic susceptibility tests also confirmed a similar efficacy. However, modified dual therapy showed fewer adverse effects [8.70% vs. 22.38%, RR 0.39 (95% CI, 0.28-0.54)], with a significant difference (P<0.00001). CONCLUSION: Modified dual therapy achieved equal efficacy and compliance compared with recommended first-line regimens for H. pylori infection, and generally modified dual therapy showed fewer side effects.

Innovative Perspectives of Integrated Chinese Medicine on H. pylori.

Helicobacter pylori (H. pylori) treatment requires the development of more effective therapies, mainly owing to the challenges posed by the bacterial resistance to antibiotics. In China, critically high infection and antibiotic resistance rates have limited the application of classic H. pylori eradication therapies. Consequently, researchers are attempting to find new solutions by drawing from traditional medicine. This article reviews basic scientific and clinical progress in the use of integrated Chinese and Western medicine (IM) to treat H. pylori; describes the conflicting results between in vivo and in vitro studies in this regard; discusses the observed clinical effects of IM, with emphasis on traditional patent medicines; and proposes a role for IM in both the diagnosis and treatment of H. pylori, including the use of tongue manifestation as an early diagnostic method and capitalizing on IM's direct and indirect methods for enhancing antibiotic effect.

The Antibacterial Activity of Mass Galla Chinesis et Camelliae Fermentata on Helicobacter pylori Infection.

Mass Galla chinesis et camelliae Fermentata (Chinese gall leaven, CGL) was investigated for activities against Helicobacter pylori (H. pylori) both in vitro and in vivo. The agar dilution method and time-kill curves, as in vitro assays and an in vivo study using a Kunming mice model, were performed. CGL demonstrated a strong anti-Helicobacter pylori activity in vitro with the minimal inhibitory concentrations (MICs) against multiple H. pylori strains of 0.5~8 mg/ml and the decreasing trend time-kill curves when increasing CGL concentrations. H. pylori eradication rates in vivo were evaluated based on rapid urease test (RUT) and histopathologic criteria. Results revealed that the eradication rates in the CGL groups were 40% (4/10) in the high dosage group, 33% (4/11) in the medium dosage group, and 18% (2/11) in the low dosage group, with the difference between the high dosage and H. pylori control groups being significant (P = 0.035). The H. pylori colonization scores could be reduced partly by CGL. These in vivo results demonstrated that CGL in a rationally high dosage might be the most effective.

Jinghua Weikang capsule protects against Helicobacter pylori-induced inflammatory responses via the nuclear factor-kappa B signaling pathway.

OBJECTIVE: To investigate the inhibitory effect of Jinghua Weikang capsule (JWC) on gastric inflammation induced by Helicobacter pylori (H. pylori) via the nuclear factor-kappa B (NF-¦ÊB) signaling pathway in Kunming mice. METHODS: We investigated the anti-inflammation potential of JWC extract in vivo in a H. pylori-induced gastritis mouse model. The expression of inflammation-related molecules was evaluated by Western blotting, and the concentrations of in vivo inflammatory markers were measured by enzyme-linked immunosorbent assay. Inflammatory cell infiltration was evaluated by histopathological examination, and mRNA levels of related genes were evaluated by quantitative reverse transcription polymerase chain reaction. RESULTS: JWC had a dose-dependent protective effect against H. pylori-induced gastritis by protecting gastric epithelial cells and inhibiting inflammatory cell infiltration. Mechanistically, JWC decreased the protein levels of phosphorylated I¦ÊB¦Á and NF-¦ÊB p65, mRNA levels of NF-¦ÊB pathway molecules, and plasma levels of tumor necrosis factor-¦Á and interleukin 1 beta. CONCLUSION: An important finding of our study is that JWC attenuated gastrointestinal inflammation and ulceration and exerted a protective effect against gastric injury via inhibition of inflammation reactions and regulating the canonical NF-κB signaling pathway in vivo.