Effects of microbiome-based interventions on neurodegenerative diseases: a systematic review and meta-analysis.

Neurodegenerative diseases (NDDs) are characterized by neuronal damage and progressive loss of neuron function. Microbiome-based interventions, such as dietary interventions, biotics, and fecal microbiome transplant, have been proposed as a novel approach to managing symptoms and modulating disease progression. Emerging clinical trials have investigated the efficacy of interventions modulating the GM in alleviating or reversing disease progression, yet no comprehensive synthesis have been done. A systematic review of the literature was therefore conducted to investigate the efficacy of microbiome-modulating methods. The search yielded 4051 articles, with 15 clinical trials included. The overall risk of bias was moderate in most studies. Most microbiome-modulating interventions changed the GM composition. Despite inconsistent changes in GM composition, the meta-analysis showed that microbiome-modulating interventions improved disease burden (SMD, - 0.57; 95% CI - 0.93 to - 0.21; I2 = 42%; P = 0.002) with a qualitative trend of improvement in constipation. However, current studies have high methodological heterogeneity and small sample sizes, requiring more well-designed and controlled studies to elucidate the complex linkage between microbiome, microbiome-modulating interventions, and NDDs.

Post-traumatic stress, depression, and anxiety during the 2021 Myanmar conflict: a nationwide population-based survey.

Background: The UN warns that Myanmar faces the 'triple crises' of mass conflict, uncontrolled COVID-19, and economic collapse. Therefore, we aimed to assess the population mental health burden, healthcare needs, and the associated risk factors in Myanmar. Methods: We established a nationwide random sample and recruited 1038 adults via random digit dialling from July 3-Aug 9, 2021, during the ongoing conflict since Feb 1, 2021, and surge in SARS-CoV-2 infections. Probable post-traumatic stress disorder (PTSD) was assessed using the PTSD Checklist-Civilian Version. Probable depression and anxiety were assessed using the Patient Health Questionnaire-2 and the Generalized Anxiety Disorder-2. We calculated population attributable fractions for probable mental disorders using multivariable logistic regression models. Based on the mental health burden and healthcare-seeking patterns, we projected the need for mental health services. Findings: During the 'triple crises', a third of adults in Myanmar (34.9%, 95% CI 32.0-37.7) reported a probable mental disorder. Prevalence of probable PTSD, depression, and anxiety were 8.1% (6.6-9.7), 14.3% (12.0-16.6), and 22.2% (19.7-24.7), respectively. We estimated that up to 79.9% (43.8-97.9) of probable PTSD was attributable to political stress. This corresponds to 2.1 million (1.1-3.2 million) fewer adults with probable PTSD if political stress was removed from the population. The mental health burden could translate into roughly 5.9 million adults seeking mental health services. Interpretation: The mental health burden in Myanmar is substantial, and population mental health might only be restored when the three crises have ended. An accelerated peace process is critical to protecting Myanmar's population mental health. Funding: This research was supported the Research Grants Council of the Hong Kong Special Administrative Region, China (Project No. HKU 17606122) and the Michele Tansella Award.

Virological response to nucleos(t)ide analogues treatment in chronic hepatitis B patients is associated with Bacteroides-dominant gut microbiome.

BACKGROUND: Gut dysbiosis is present in chronic hepatitis B virus (HBV) infection. In this study, we integrated microbiome and metabolome analysis to investigate the role of gut microbiome in virological response to nucleos(t)ide analogues (NAs) treatment. METHODS: Chronic HBV patients were prospectively recruited for steatosis and fibrosis assessments via liver elastography, with full-length 16S sequencing performed to identify the compositional gut microbiota differences. Fasting plasma bile acids were quantified by liquid chromatography-tandem mass spectrometry. FINDINGS: All patients (n = 110) were characterized into three distinct microbial clusters by their dominant genus: c-Bacteroides, c-Blautia, and c-Prevotella. Patients with c-Bacteroides had a higher plasma ursodeoxycholic acids (UDCA) level and an increase in 7-alpha-hydroxysteroid dehydrogenase (secondary bile acid biotransformation) than other clusters. In NAs-treated patients (n = 84), c-Bacteroides was associated with higher odds of plasma HBV-DNA undetectability when compared with non-c-Bacteroides clusters (OR 3.49, 95% CI 1.43-8.96, p = 0.01). c-Blautia was positively associated with advanced fibrosis (OR 2.74, 95% CI 1.09-7.31, p = 0.04). No such associations were found in treatment-naïve patients. Increased Escherichia coli relative abundance (0.21% vs. 0.03%, p = 0.035) was found in on-treatment patients (median treatment duration 98.1 months) with advanced fibrosis despite HBV DNA undetectability. An enrichment in l-tryptophan biosynthesis was observed in patients with advanced fibrosis, which exhibited a positive correlation with Escherichia coli. INTERPRETATION: Collectively, unique bacterial signatures, including c-Bacteroides and c-Blautia, were associated with virological undetectability and fibrosis evolution during NAs therapy in chronic HBV, setting up intriguing possibilities in optimizing HBV treatment. FUNDING: This study was supported by the Guangdong Natural Science Fund (2019A1515012003).

Gut virome in inflammatory bowel disease and beyond.

OBJECTIVE: The gut virome is a dense community of viruses inhabiting the gastrointestinal tract and an integral part of the microbiota. The virome coexists with the other components of the microbiota and with the host in a dynamic equilibrium, serving as a key contributor to the maintenance of intestinal homeostasis and functions. However, this equilibrium can be interrupted in certain pathological states, including inflammatory bowel disease, causing dysbiosis that may participate in disease pathogenesis. Nevertheless, whether virome dysbiosis is a causal or bystander event requires further clarification. DESIGN: This review seeks to summarise the latest advancements in the study of the gut virome, highlighting its cross-talk with the mucosal microenvironment. It explores how cutting-edge technologies may build upon current knowledge to advance research in this field. An overview of virome transplantation in diseased gastrointestinal tracts is provided along with insights into the development of innovative virome-based therapeutics to improve clinical management. RESULTS: Gut virome dysbiosis, primarily driven by the expansion of Caudovirales, has been shown to impact intestinal immunity and barrier functions, influencing overall intestinal homeostasis. Although emerging innovative technologies still need further implementation, they display the unprecedented potential to better characterise virome composition and delineate its role in intestinal diseases. CONCLUSIONS: The field of gut virome is progressively expanding, thanks to the advancements of sequencing technologies and bioinformatic pipelines. These have contributed to a better understanding of how virome dysbiosis is linked to intestinal disease pathogenesis and how the modulation of virome composition may help the clinical intervention to ameliorate gut disease management.

Combing fecal microbial community data to identify consistent obesity-specific microbial signatures and shared metabolic pathways.

Obesity is associated with altered gut microbiome composition but data across different populations remain inconsistent. We meta-analyzed publicly available 16S-rRNA sequence datasets from 18 different studies and identified differentially abundant taxa and functional pathways of the obese gut microbiome. Most differentially abundant genera (Odoribacter, Oscillospira, Akkermansia, Alistipes, and Bacteroides) were depleted in obesity, indicating a deficiency of commensal microbes in the obese gut microbiome. From microbiome functional pathways, elevated lipid biosynthesis and depleted carbohydrate and protein degradation suggested metabolic adaptation to high-fat, low-carbohydrate, and low-protein diets in obese individuals. Machine learning models trained on the 18 studies were modest in predicting obesity with a median AUC of 0.608 using 10-fold cross-validation. The median AUC increased to 0.771 when models were trained in eight studies designed for investigating obesity-microbiome association. By meta-analyzing obesity-associated microbiota signatures, we identified obesity-associated depleted taxa that may be exploited to mitigate obesity and related metabolic diseases.

Ecological change of the gut microbiota during pregnancy and progression to dyslipidemia.

The composition of the gut microbiome was previously found to be associated with clinical responses to dyslipidemia, but there is limited consensus on the dynamic change of the gut microbiota during pregnancy and the specific microbiome characteristics linked to dyslipidemia in pregnant women. We collected fecal samples from 513 pregnant women at multiple time points during pregnancy in a prospective cohort. Taxonomic composition and functional annotations were determined by 16S rRNA amplicon sequencing and shotgun metagenomic sequencing. The predictive potential of gut microbiota on the risk of dyslipidemia was determined. The gut microbiome underwent dynamic changes during pregnancy, with significantly lower alpha diversity observed in dyslipidemic patients compared to their healthy counterparts. Several genera, including Bacteroides, Paraprevotella, Alistipes, Christensenellaceae R7 group, Clostridia UCG-014, and UCG-002 were negatively associated with lipid profiles and dyslipidemia. Further metagenomic analysis recognized a common set of pathways involved in gastrointestinal inflammation, where disease-specific microbes played an important role. Machine learning analysis confirmed the link between the microbiome and its progression to dyslipidemia, with a micro-averaged AUC of 0.824 (95% CI: 0.782-0.855) combined with blood biochemical data. Overall, the human gut microbiome, including Alistipes and Bacteroides, was associated with the lipid profile and maternal dyslipidemia during pregnancy by perturbing inflammatory functional pathways. Gut microbiota combined with blood biochemical data at the mid-pregnancy stage could predict the risk of dyslipidemia in late pregnancy. Therefore, the gut microbiota may represent a potential noninvasive diagnostic and therapeutic strategy for preventing dyslipidemia in pregnancy.

Effects of Gut Microbiome Modulation on Reducing Adverse Health Outcomes among Elderly and Diabetes Patients during the COVID-19 Pandemic: A Randomised, Double-Blind, Placebo-Controlled Trial (IMPACT Study).

Gut microbiota is believed to be a major determinant of health outcomes. We hypothesised that a novel oral microbiome formula (SIM01) can reduce the risk of adverse health outcomes in at-risk subjects during the coronavirus disease 2019 (COVID-19) pandemic. In this single-centre, double-blind, randomised, placebo-controlled trial, we recruited subjects aged ≥65 years or with type two diabetes mellitus. Eligible subjects were randomised in a 1:1 ratio to receive three months of SIM01 or placebo (vitamin C) within one week of the first COVID-19 vaccine dose. Both the researchers and participants were blinded to the groups allocated. The rate of adverse health outcomes was significantly lower in the SIM01 group than the placebo at one month (6 [2.9%] vs. 25 [12.6], p < 0.001) and three months (0 vs. 5 [3.1%], p = 0.025). At three months, more subjects who received SIM01 than the placebo reported better sleep quality (53 [41.4%] vs. 22 [19.3%], p < 0.001), improved skin condition (18 [14.1%] vs. 8 [7.0%], p = 0.043), and better mood (27 [21.2%] vs. 13 [11.4%], p = 0.043). Subjects who received SIM01 showed a significant increase in beneficial Bifidobacteria and butyrate-producing bacteria in faecal samples and strengthened the microbial ecology network. SIM01 reduced adverse health outcomes and restored gut dysbiosis in elderly and diabetes patients during the COVID-19 pandemic.

Antimicrobial Resistance Policy Protagonists and Processes-A Qualitative Study of Policy Advocacy and Implementation.

Antimicrobial resistance (AMR) fundamentally weakens societal foundations economically and in health care. The development of well-considered policies against AMR is important. However, in many places, AMR policy implementation remains elusive. This study aims to identify enablers and deterrents as well as processes and conditions in AMR policy advocacy. It also aims to identify AMR implementation conditions where AMR national policies are adopted and, to a certain extent, formulated and implemented. This study adopts qualitative research methodology and applies the Grounded Theory Framework to identify thematic findings from interviews conducted in China, Japan, Norway, the United Kingdom (UK), and the United States of America (US). It was identified that AMR policy protagonists are critical to filtering AMR issues and identifying policies "fit to prioritize" and "fit to implement". They have helped move policy prioritization needles in the UK and the US and engaged in diplomatic efforts in the UK. In these cases, no clientelism was considered. In the US, protagonists who talked to the right decision-makers in the right office at the right time both moved AMR issues from individuals to institutional agenda and from social norms to policy agenda. To conclude, there are three thematic policy conditions that are significant to AMR policy advocacy and implementation: committed personal championship, institutionalization of policies, and social norms facilitate AMR policy advocacy and implementation.

A Retrospective Study of Antimicrobial Resistant Bacteria Associated with Feline and Canine Urinary Tract Infection in Hong Kong SAR, China-A Case Study on Implication of First-Line Antibiotics Use.

Urinary tract infection (UTI) is a common clinical diagnosis for which empirical antibiotics are used in veterinary medicine. For veterinarians, the description of canine and feline antibiograms can help with making prudent use decisions and guideline formulation. For public health officers and epidemiologists, a urinary antibiogram overview helps track and trend antimicrobial resistance (AMR). There is currently a knowledge gap in AMR prevalence associated with urinary tract infection in feline and canine patients and the resistance percentage of these microbes against some of the over-the-counter antibiotics available to local pet owners. This study has two aims. First, it aims to investigate the frequency of the bacteria and bacterial-resistance pattern in urine samples obtained from feline and canine patients. Second, it aims to determine the resistance of Escherichia coli (E. coli), the most frequently isolated bacteria, to first-line antibiotics. Results: We identified the five most-frequently isolated bacterial species and determined these isolates' antibiotic sensitivity and resistance. The most-frequently isolated bacteria in feline and canine patients was Escherichia coli (E. coli). E. coli was identified, on average, in 37.2% of canine and 46.5% of feline urine samples. Among feline urinary samples, Enterococcus (14.7%) and Staphylococcus (14.5%) spp. were isolated more frequently, followed by Pseudomonas (4.8%) and Klebsiella (5.2%) spp. (). In canine samples, Proteus (17.9%) and Staphylococcus (13.2%) spp. were isolated more frequently, followed by Enterococcus (10.0%) and Klebsiella (8.59%) spp. Among these isolates, 40 to 70% of Staphylococcus spp. bacterial isolates from feline and canine patients were resistant to amoxicillin and ampicillin. During the three-year study period, among canine patients, 10 to 20% of Staphylococcus spp. bacterial isolates were resistance to fluoroquinolones, other quinolones, and third-generation cephalosporins. Among feline patients, 10% of Staphylococcus spp., 15 to 20% of E. coli, 50 to 60% of Klebsiella spp., and 90% of Pseudomonas spp. were resistant to cefovecin, a commonly used antibiotic.

Cysteine protected cells from H2O2-induced damage and promoted long-chain fatty acids synthesis in vivo to improve γ-aminobutyric acid production in Levilactobacillus brevis.

Levilactobacillus brevis NPS-QW-145 isolated from kimchi is deficient in glutamate dehydrogenase-encoding gene (gdhA) to form glutamate, hence it required exogenous supplementation of glutamate/monosodium glutamate (MSG) for decarboxylation reaction to produce γ-aminobutyric acid (GABA). However, GABA conversion rate from MSG was relatively low. The individual effect of 20 amino acids on regulating GABA biosynthesis was investigated. Cysteine was selected to significantly improve GABA production from MSG. It was found that Lb. brevis was capable of producing H2O2, cysteine protected Lb. brevis against H2O2-induced oxidative damage to increase cell viability for the enhancement of GABA production. Moreover, cysteine promoted glucose consumption to produce acetyl-CoA for synthesizing long-chain fatty acids to significantly up-regulate GABA biosynthesis. These findings deciphered antioxidative capability of cysteine in Lb. brevis 145 and provided a theoretical basis for fatty acids synthesis-mediated GABA synthesis in Lb. brevis 145, and possibly in other lactic acid bacteria.

Unpacking multi-level governance of antimicrobial resistance policies: the case of Guangdong, China.

Against the backdrop of universal healthcare coverage and pre-existing policies on antimicrobial use, China has adopted a state-governed, multi-level, top-down policy governance approach around an antimicrobial resistance (AMR) national action plan (NAP). The Plan relies on tightening control over antimicrobial prescription and use in human and animal sectors. At the same time, medical doctors and veterinarians operate in an environment of high rates of infectious diseases, multi-drug resistance and poor livestock husbandry. In exploring the way that policy responsibilities are distributed, this study aims to describe how Guangdong as a province adopts national AMR policies in a tightly controlled public policy system and an economy with high disparity. We draw on an analysis of 225 AMR-relevant Chinese policy documents at the national and sub-national levels. We adopt a multi-level governance perspective and apply a temporal sequence framework to identify and analyse documents. To identify policy detail, we conducted keyword analysis using the Consolidated Framework for Implementation Research (CFIR) on policies that conserve antimicrobials. We also identify pre-existing medical and public policies associated with AMR. Our findings highlight the emphasis and policies around antimicrobial use regulation to address AMR in China.

Use of Sewage Surveillance for COVID-19: A Large-Scale Evidence-Based Program in Hong Kong.

BACKGROUND: Sewage surveillance, by detecting SARS-CoV-2 virus circulation at the community level, has the potential to supplement individual surveillance for COVID-19. However, to date, there have been no reports about the large-scale implementation and validation of sewage surveillance for public health action. OBJECTIVE: Here, we developed a standardized approach for SARS-CoV-2 detection in sewage and applied it prospectively to supplement public health interventions. METHODS: We analyzed 1,169 sewage samples collected at 492 sites from December 2020 to March 2021. Forty-seven of 492 sites tested positive, 44 (94%) of them had traceable sources of viral signals in the corresponding sewershed, either from previously unsuspected but subsequently confirmed patients or recently convalescent patients or from both patient groups. RESULTS: Sewage surveillance had a sensitivity of 54%, a specificity of 95%, a positive predictive value of 53%, and a negative predictive value of 95% for identifying a previously unsuspected patient within a sewershed. Sewage surveillance in Hong Kong provided a basis for the statutory public health action to detect silent COVID-19 transmission. DISCUSSION: Considering the epidemiological data together with the sewage testing results, compulsory testing was conducted for individual residents at 27 positive sewage sites and uncovered total of 62 previously unsuspected patients, demonstrating the value of sewage surveillance in uncovering previously unsuspected patients in the community. Our study suggests that sewage surveillance could be a powerful management tool for the control of COVID-19. https://doi.org/10.1289/EHP9966.

Evaluation of RT-qPCR Primer-Probe Sets to Inform Public Health Interventions Based on COVID-19 Sewage Tests.

Sewage surveillance is increasingly employed as a supplementary tool for COVID-19 control. Experiences learnt from large-scale trials could guide better interpretation of the sewage data for public health interventions. Here, we compared the performance of seven commonly used primer-probe sets in RT-qPCR and evaluated the usefulness in the sewage surveillance program in Hong Kong. All selected primer-probe sets reliably detected SARS-CoV-2 in pure water at 7 copies per µL. Sewage matrix did not influence RT-qPCR determination of SARS-CoV-2 concentrated from a small-volume sewage (30 mL) but introduced inhibitory impacts on a large-volume sewage (920 mL) with a ΔCt of 0.2-10.8. Diagnostic performance evaluation in finding COVID-19 cases showed that N1 was the best single primer-probe set, while the ORF1ab set is not recommended. Sewage surveillance using the N1 set for over 3200 samples effectively caught the outbreak trend and, importantly, had a 56% sensitivity and a 96% specificity in uncovering the signal sources from new cases and/or convalescent patients in the community. Our study paves the way for selecting detection primer-probe sets in wider applications in responding to the COVID-19 pandemic.

Upholding veterinary services as a pillar of one health in Myanmar.

Veterinary service is one of the pillars to restore One Health in Myanmar. In the immediate future, international support provided to Myanmar can relieve food shortage and some humanitarian crises. In the long run, societal trauma from the military coup and violence, infrastructure breakdown, and economic downturn complicated by the COVID-19 pandemic will make recovery of the nation harder. While the building blocks to achieve peace and humanitarianism are long and complicated, part of the interim solution is to restore Myanmar veterinary services. The restoration will ease food scarcity in the short-run, reduce sylvatic and zoonotic infection risks and re-capitalise societal infrastructure building in the long-run. Myanmar society cannot rebuild on its own-it needs international and national support to facilitate peace and humanitarianism.

The first case study of wastewater-based epidemiology of COVID-19 in Hong Kong.

Early detection and surveillance of severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) virus are key pre-requisites for the effective control of coronavirus disease (COVID-19). So far, sewage testing has been increasingly employed as an alternative surveillance tool for this disease. However, sampling site characteristics impact the testing results and should be addressed in the early use stage of this emerging tool. In this study, we implemented the sewage testing for SARS-CoV-2 virus across sampling sites with different sewage system characteristics. We first validated a testing method using "positive" samples from a hospital treating COVID-19 patients. This method was used to test 107 sewage samples collected during the third wave of the COVID-19 outbreak in Hong Kong (from June 8 to September 29, 2020), covering sampling sites associated with a COVID-19 hospital, public housing estates, and conventional sewage treatment facilities. The highest viral titer of 1975 copy/mL in sewage was observed in a sample collected from the isolation ward of the COVID-19 hospital. Sewage sampling at individual buildings detected the virus 2 days before the first cases were identified. Sequencing of the detected viral fragment confirmed an identical nucleotide sequence to that of the SARS-CoV-2 isolated from human samples. The virus was also detected in sewage treatment facilities, which serve populations of approximately 40,000 to more than one million people.

Characterization of respiratory microbial dysbiosis in hospitalized COVID-19 patients.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global pandemic of Coronavirus disease 2019 (COVID-19). However, the microbial composition of the respiratory tract and other infected tissues as well as their possible pathogenic contributions to varying degrees of disease severity in COVID-19 patients remain unclear. Between 27 January and 26 February 2020, serial clinical specimens (sputum, nasal and throat swab, anal swab and feces) were collected from a cohort of hospitalized COVID-19 patients, including 8 mildly and 15 severely ill patients in Guangdong province, China. Total RNA was extracted and ultra-deep metatranscriptomic sequencing was performed in combination with laboratory diagnostic assays. We identified distinct signatures of microbial dysbiosis among severely ill COVID-19 patients on broad spectrum antimicrobial therapy. Co-detection of other human respiratory viruses (including human alphaherpesvirus 1, rhinovirus B, and human orthopneumovirus) was demonstrated in 30.8% (4/13) of the severely ill patients, but not in any of the mildly affected patients. Notably, the predominant respiratory microbial taxa of severely ill patients were Burkholderia cepacia complex (BCC), Staphylococcus epidermidis, or Mycoplasma spp. (including M. hominis and M. orale). The presence of the former two bacterial taxa was also confirmed by clinical cultures of respiratory specimens (expectorated sputum or nasal secretions) in 23.1% (3/13) of the severe cases. Finally, a time-dependent, secondary infection of B. cenocepacia with expressions of multiple virulence genes was demonstrated in one severely ill patient, which might accelerate his disease deterioration and death occurring one month after ICU admission. Our findings point to SARS-CoV-2-related microbial dysbiosis and various antibiotic-resistant respiratory microbes/pathogens in hospitalized COVID-19 patients in relation to disease severity. Detection and tracking strategies are needed to prevent the spread of antimicrobial resistance, improve the treatment regimen and clinical outcomes of hospitalized, severely ill COVID-19 patients.

Multi-platform omics analysis reveals molecular signature for COVID-19 pathogenesis, prognosis and drug target discovery.

Disease progression prediction and therapeutic drug target discovery for Coronavirus disease 2019 (COVID-19) are particularly important, as there is still no effective strategy for severe COVID-19 patient treatment. Herein, we performed multi-platform omics analysis of serial plasma and urine samples collected from patients during the course of COVID-19. Integrative analyses of these omics data revealed several potential therapeutic targets, such as ANXA1 and CLEC3B. Molecular changes in plasma indicated dysregulation of macrophage and suppression of T cell functions in severe patients compared to those in non-severe patients. Further, we chose 25 important molecular signatures as potential biomarkers for the prediction of disease severity. The prediction power was validated using corresponding urine samples and plasma samples from new COVID-19 patient cohort, with AUC reached to 0.904 and 0.988, respectively. In conclusion, our omics data proposed not only potential therapeutic targets, but also biomarkers for understanding the pathogenesis of severe COVID-19.