The evaluation of fecal microbiota transplantation vs vancomycin in a Clostridioides difficile infection model.

Vancomycin is the preferred treatment for Clostridioides difficile infection (CDI) but has been associated with a high recurrence rate of CDI in treated patients. Fecal microbiota transplantation (FMT) has emerged as a remarkably successful treatment for recurrent CDI (rCDI). Herein, we present a mouse model of CDI to further define the changes in intestinal inflammation, flora, and metabolites following FMT versus vancomycin treatment and to find the potential therapy to restore colonization resistance. Both FMT and vancomycin treatment could ameliorate CDI-induced clinical features and intestinal tissue damage, with decrease in the levels of inflammatory mediators like IL-1ß, IL-6, TNF-α, G-CSF, and MCP-1 in the colon and plasma. Observing the fecal gut microbiome profile revealed that unlike vancomycin, FMT could replenish intestinal microbiota by augmenting the relative abundance of the phylum Bacteroidetes and eliminating the abundance of the phylum Proteobacteria. FMT also reduced the levels of several carbohydrates, such as raffinose and fructose-6-phosphate, and amino acids, including tryptophan and glutamyl-valine, in the gut metabolome, thus suppressing C. difficile germination and growth. Our results suggest that the FMT-induced reconstruction of a specific gut community structure and restoration of metabolites promote the recovery of colonization resistance in mice better than vancomycin, thus offering new insights for the prevention of rCDI. KEY POINTS: • Both FMT and vancomycin ameliorate CDI-induced inflammatory response. • FMT restores a specific community structure and gut metabolites. • Mice treated with FMT may promote the recovery of colonization resistance and has a better outcome.

A comparison of demographic, epidemiological and clinical characteristics of hospital influenza-related viral pneumonia patients.

BACKGROUND: Through the comparison of the demographic, epidemiological, and clinical characteristics of hospital human influenza (influenza A (H1N1) pdm09, H3N2, and B)-related and hospitalized avian-origin influenza A (H7N9)-related viral pneumonia patients, find the different between them. METHODS: A retrospective study was conducted in hospitalized influenza-related viral pneumonia patients. RESULTS: Human influenza A-related patients in the 35-49-year-old group were more than those with B pneumonia patients (p = 0.027), and relatively less in the ≥ 65-year-old group than B pneumonia patients (p = 0.079). The proportion of comorbid condition to human influenza A pneumonia was 58%, lower than B pneumonia and H7N9 pneumonia patients (78% vs. 77.8%; p = 0.013). The proportion of invasive mechanical ventilation (IMV), lymphocytopenia, elevated lactate dehydrogenase to hospitalized human influenza A-related viral pneumonia patients was higher than B pneumonia patients (p < 0.05), but lower than H7N9 pneumonia patients (p < 0.05). In the multivariate analysis, pulmonary consolidation (odds ratio (OR): 13.67; 95% confidence interval (CI) 1.54-121.12; p = 0.019) and positive bacterial culture (sputum) (OR: 7.71; 95% CI 2.48-24.03; p < 0.001) were independently associated with IMV, while shock (OR: 13.16; 95% CI 2.06-84.07; p = 0.006), white blood cell count > 10,000/mm3 (OR: 7.22; 95% CI 1.47-35.58; p = 0.015) and positive bacterial culture(blood or sputum) (OR: 6.27; 95% CI 1.36-28.85; p = 0.018) were independently associated with death in the three types hospitalized influenza-related viral pneumonia patients. CONCLUSIONS: Hospital influenza B-related viral pneumonia mainly affects the elderly and people with underlying diseases, while human influenza A pneumonia mainly affects the young adults; however, the mortality was similar. The hospitalized human influenza A-related viral pneumonia patients was severer than B pneumonia patients, but milder than H7N9 pneumonia patients. Pulmonary consolidation and positive bacterial culture (sputum) were independently associated with IMV, while shock, white blood cell count > 10,000/mm3, and positive bacterial culture (blood or sputum) were independently associated with death to three types hospitalized influenza-related viral pneumonia patients.

Alterations of the Gut Microbiota in Patients With Coronavirus Disease 2019 or H1N1 Influenza.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is an emerging serious global health problem. Gastrointestinal symptoms are common in COVID-19 patients, and severe acute respiratory syndrome coronavirus 2 RNA has been detected in stool specimens. However, the relationship between the gut microbiome and disease remains to be established. METHODS: We conducted a cross-sectional study of 30 patients with COVID-19, 24 patients with influenza A(H1N1), and 30 matched healthy controls (HCs) to identify differences in the gut microbiota by 16S ribosomal RNA gene V3-V4 region sequencing. RESULTS: Compared with HCs, COVID-19 patients had significantly reduced bacterial diversity; a significantly higher relative abundance of opportunistic pathogens, such as Streptococcus, Rothia, Veillonella, and Actinomyces; and a lower relative abundance of beneficial symbionts. Five biomarkers showed high accuracy for distinguishing COVID-19 patients from HCs with an area under the curve (AUC) up to 0.89. Patients with H1N1 displayed lower diversity and different overall microbial composition compared with COVID-19 patients. Seven biomarkers were selected to distinguish the 2 cohorts (AUC = 0.94). CONCLUSIONS: The gut microbial signature of patients with COVID-19 was different from that of H1N1 patients and HCs. Our study suggests the potential value of the gut microbiota as a diagnostic biomarker and therapeutic target for COVID-19, but further validation is needed.

The fiber metabolite butyrate reduces gp130 by targeting TRAF5 in colorectal cancer cells.

BACKGROUND: Dietary fiber is effective for colorectal cancer (CRC) treatment. Interleukin-6 (IL-6) and its adaptors are potential targets for CRC therapy. Butyrate, a metabolite of dietary fiber, is a new, highly safe type of targeted drug. METHODS: In this study, Cell Counting Kit-8 cell viability and wound healing assays, western blot analysis, immunofluorescence staining, and xenograft tumor mouse models were used to evaluate the anticancer effect of butyrate and its possible mechanism in vivo and in vitro. RESULTS: Dietary fiber and sodium butyrate (NaB) decreased CRC burden by decreasing IL-6 receptor gp130 and blocking IL-6/JAK2/STAT3 axis activation in vitro and in vivo. Furthermore, NaB reduced the gp130 protein level by regulating its degradation rate via targeting TRAF5. CONCLUSIONS: The fiber metabolite butyrate inhibits CRC development by reducing gp130 via TRAF5.

Longitudinal investigation of carriage rates and genotypes of toxigenic Clostridium difficile in hepatic cirrhosis patients.

Toxigenic Clostridium difficile (C. difficile) carriers represent an important source in the transmission of C. difficile infection (CDI) during hospitalisation, but its prevalence and mode in patients with hepatic cirrhosis are not well established. We investigated longitudinal changes in carriage rates and strain types of toxigenic C. difficile from admission to discharge among hepatic cirrhosis patients. Toxigenic C. difficile was detected in 104 (19.8%) of 526 hepatic cirrhosis patients on admission, and the carriage status changed in a portion of patients during hospitalisation. Approximately 56% (58/104) of patients lost the colonisation during their hospital stay. Among the remaining 48 patients who remained positive for toxigenic C. difficile, the numbers of patients who were positive at one, two, three and four isolations were 10 (55.6%), three (16.7%), two (11.1%) and three (16.7%), respectively. Twenty-eight patients retained a particular monophyletic strain at multiple isolations. The genotype most frequently identified was the same as that frequently identified in symptomatic CDI patients. A total of 25% (26/104) of patients were diagnosed with CDI during their hospital stay. Conclusions: Colonisation with toxigenic C. difficile strains occurs frequently in cirrhosis patients and is a risk factor for CDI.

Risk factors for Clostridium difficile infection in cirrhotic patients.

BACKGROUND: Cirrhotic patients are susceptible to Clostridium difficile infection (CDI), however, the high risk factors are not clear. The present study aimed to identify the risk factors in cirrhotic patients with CDI. METHODS: A total of 526 cirrhotic patients admitted to our hospital between May 2015 and October 2015 were included in this study. Stool samples were collected upon admission for the detection of CDI and toxin. CDI was monitored during the hospital stay. In total, 34 cases showed CDI. Then we analyzed the effects of age, sex, C. difficile colonization (CDC), multiple hospitalization, extended hospital stay, elevation of total bilirubin (TBIL), creatinine (Cr), Child-Pugh grade C, hepatic encephalopathy, hepatorenal syndrome, upper gastrointestinal hemorrhage, and exposure of antibiotics and proton pump inhibitor (PPI) on the CDI in cirrhotic patients. RESULTS: Patients in the CDI group had more frequent CDC, multiple hospitalization, and extended hospital stay compared to those in the non-C. difficile infection (NCDI) group. Patients in the CDI group had higher TBIL and Cr, and higher frequency of Child-Pugh grade C, hepatic encephalopathy, upper gastrointestinal hemorrhage compared with those in the NCDI group. Multiple logistic regression analysis indicated that age >60 years (OR=1.689; 95% CI: 1.135-3.128), multiple hospitalization (OR=3.346; 95% CI: 1.392-8.043), length of hospital stay >20 days (OR=1.564; 95% CI: 1.113-2.563), hypoproteinemia (OR=4.962; 95% CI: 2.053-11.996), CDC (OR=18.410; 95% CI: 6.898-49.136), hepatic encephalopathy (OR=1.357; 95% CI: 1.154-2.368), and exposure of antibiotics (OR=1.865; 95% CI: 1.213-2.863) and PPI (OR=3.125; 95% CI: 1.818-7.548) were risk factors of CDI. CONCLUSIONS: Age >60 years, multiple hospitalization, length of hospital stay >20 days, hypoproteinemia, CDC, hepatic encephalopathy, and exposure of antibiotics and PPI were risk factors for CDI in cirrhotic patients. These may contribute to the early diagnosis and monitoring of CDI in clinical practice.

Guillain-Barre syndrome caused by hepatitis E infection: case report and literature review.

BACKGROUND: Hepatitis E infection is a global disorder that causes substantial morbidity. Numerous neurologic illnesses, including Guillain-Barre syndrome (GBS), have occurred in patients with hepatitis E virus (HEV) infection. CASE PRESENTATION: We report a 58 year-old non-immunocompromised man who presented with progressive muscle weakness in all extremities during an episode of acute HEV infection, which was confirmed by measuring the anti-HEV IgM antibodies in the serum. Both cerebrospinal fluid examination and electrophysiological study were in agreement with the diagnosis of HEV-associated GBS. Following the treatment with intravenous immunoglobulin, the patient's neurological condition improved rapidly. CONCLUSIONS: HEV infection should be strongly considered in patients with neurological symptoms, especially those with elevated levels of liver enzymes.

A case of multiple recurrence of Clostridium difficile infection with severe hematochezia in an immunocompromised host.

Clostridium difficile infection (CDI) is increasing in incidence and severity. Clinically, diarrhea frequently occurs, but severe hematochezia is rarely seen with CDI. We describe here a hematopoietic stem cell transplantation (HSCT) recipient who experienced life-threatening gastrointestinal bleeding due to severe CDI. Subsequent stool surveillance and molecular typing observed the patient who had two episodes of recurrence with a new strain of C. difficile distinct from the initial infection. We analyze C. difficile strains obtained from the patient, and also discuss the diagnosis and treatment of this case.

Clostridium difficile carriage in healthy pregnant women in China.

Infection with Clostridium difficile has been shown to have particularly poor outcomes for pregnant women, including an increased risk of death. The purpose of this study was to investigate the prevalence, genotypic distribution, and characterization of C. difficile strains isolated from pregnant women without diarrhea in China. As part of this study, 3.7% (37 out of 1009) of samples acquired from pregnant females tested positive for C. difficile. Of these positive samples, 27.0% (10) were toxigenic isolates containing both toxin A and toxin B genes (A+B+), 13.5% (5) of the variant strains contained the toxin B gene (A-B+) only, while the rest were non-toxigenic isolates (59.5%, 22 isolates). Among the non-pregnant women without diarrhea tested, 1.4% (9 of 651) contained toxigenic isolates (all of which were A+B+). Sixteen different sequence types (STs) were isolated during the course of this study. ST-37 (ribotype 017) and ST-54 (ribotype 012) were the most frequent toxigenic types observed in pregnant women. All strains showed susceptibility to the antibiotics metronidazole and vancomycin. The resistance rates of toxigenic C. difficile strains isolated from pregnant females to clindamycin, erythromycin, moxifloxacin, levofloxacin, and rifampicin were 20%, 46.7%, 13.6%, 46.7% and 13.3%, respectively. There was no significant difference between resistance rates of toxigenic and non-toxigenic strains with respect to their susceptibility to these antibiotics. However, when compared with the same data from non-pregnant women, toxigenic strains from pregnant women showed lower resistance rates to clindamycin (P < 0.05).

Demographics and prognosis of patients with pyogenic liver abscess due to Klebsiella pneumonia or other species.

Background: Pyogenic liver abscess (PLA) is a potentially life-threatening intra-abdominal infection. We compared the clinical features, treatments, and prognoses of patients who had Klebsiella pneumonia pyogenic liver abscess (KPPLA) and non-Klebsiella pneumonia pyogenic liver abscess (non-KPPLA). Methods: A retrospective analysis was used to compare the medical records of KPPLA and non-KPPLA patients with positive pus cultures at a single hospital in China from January 2017 to December 2019. Results: We examined 279 patients with definitively established PLA, 207 (74.2 %) with KPPLA, and 72 with non-KPPLA. The non-KPPLA group had a higher Charlson comorbidity index, longer hospital stay, longer duration of fever, and greater hospital costs. Multivariate analysis showed that alcohol intake (OR: 2.44, P = 0.048), cancer (OR: 4.80, P = 0.001), ICU admission (OR: 10.61, P = 0.026), resolution of fever OR: 1.04, P = 0.020), and a positive blood culture (OR: 2.87, P = 0.029) were independent predictors of primary treatment failure. Percutaneous needle aspiration (PNA) and pigtail catheter drainage (PCD) provided satisfactory outcomes, but PNA led to shorter hospital stays and reduced costs, especially in KPPLA patients whose abscesses were smaller than 10 cm. Conclusion: KPPLA and non-KPPLA patients had some differences in comorbidities and treatment strategies, and non-KPPLA patients had a significantly worse prognosis.

Close contact behaviors of university and school students in 10 indoor environments.

Close contact routes, including short-range airborne and large-droplet routes, play an important role in the transmission of SARS-CoV-2 in indoor environments. However, the exposure risk of such routes is difficult to quantify due to the lack of data on the close contact behavior of individuals. In this study, a digital wearable device, based on semi-supervised learning, was developed to automatically record human close contact behavior. We collected 337,056 s of indoor close contact of school and university students from 194.5 h of depth video recordings in 10 types of indoor environments. The correlation between aerosol exposure and close contact behaviors was then evaluated. Individuals in restaurants had the highest close contact ratio (64%), as well as the highest probability of face-to-face pattern (78%) during close contact. Accordingly, university students showed greater exposure potential in dormitories than school students in homes, however, a lower exposure was observed in classrooms and postgraduate student offices in comparison with school students in classrooms. In addition, restaurants had the highest aerosol exposure volume for both short-range inhalation and direct deposition on the facial mucosa. Thus, the classroom was established as the primary indoor environment where school students are exposed to aerosols.

Disordered Intestinal Microbial Communities During Clostridioides difficile Colonization and Subsequent Infection of Hepatic Cirrhosis Patients in a Tertiary Care Hospital in China.

Patients with hepatic cirrhosis are more susceptible to Clostridioides difficile infection (CDI) and colonization with Clostridioides difficile (C. difficile). Asymptomatic C. difficile colonization is thought to predispose to subsequent CDI. However, the dynamic gut microbiota changes remain unclear. In this study, we used 16S rRNA gene sequencing to longitudinally monitor alterations in the intestinal microbiota of 22 hepatic cirrhosis patients with toxigenic C. difficile colonization at admission (pre-CDI) and developed CDI during hospitalization, subdivided into pre-CDI and CDI. 21 hospitalized cirrhotic patients without C. difficile colonization served as controls (HC). Compared with HC, pre-CDI and CDI samples had significantly decreased microbial richness and diversity, a significantly higher relative abundance of opportunistic pathogen Enterococcus, and a lower relative abundance of beneficial symbionts, such as Faecalibacterium, Dorea, and Roseburia. Three biomarkers showed high accuracy for distinguishing pre-CDI samples from HC with an area under the curve (AUC) up to 0.81. In conclusion, our study explored the changes of the gut microbiome before and after CDI. The gut microbial richness as well as diversity in CDI patients were notably reduced, relative to controls. Imbalance of the intestinal flora may be related to the risk for development of CDI. Identifying key members of the gut microbiota and illustrating their roles and mechanisms of action in CDI development are important avenues for future research.

Modulation of Lactobacillus rhamnosus GG on the gut microbiota and metabolism in mice with Clostridioides difficile infection.

Clostridioides difficile infection (CDI) is a common nosocomial infection and is an urgent threat to public health. Vancomycin is the preferred antibiotic treatment for CDI but is associated with recurrence. Lactobacillus rhamnosus GG is an adjunctive treatment for gastroenteritis and diarrhea and exerts its effects by modulating the immune responses and repairing the intestinal barrier. This study explored the effect of LGG on restoring the intestinal microbiota in mouse models. Primary and recurrent CDI models were constructed, and LGG was administered to C57BL/6 mice. Structural changes in the mouse gut microbiota were determined using 16S rRNA gene analysis based on Illumina sequencing. In the CDI model, 6 days after infection, 33.3% mortality, significant weight loss and colonic injury were observed. LGG can ameliorate these events. In the R-CDI mouse model, vancomycin combined with LGG prevented weight loss, improved the histopathological scores, and effectively reduced the mortality. LGG + vancomycin administration promoted the recovery of the intestinal flora by inhibiting Enterococcus and counteracting the side effects of vancomycin treatment. In both the preventive and therapeutic CDI mouse models, the oral LGG strain showed the ability to protect against primary and recurrent infections, indicating that probiotics have potential for treating intestinal diseases. Overall, these observations suggest that LGG can be applied as a preventive treatment for CDI or in combination with antibiotics to reduce recurrence.

Short- and Long-Term Effects of Different Antibiotics on the Gut Microbiota and Cytokines Level in Mice.

Background: Antibiotics are the first line of treatment for infectious diseases. However, their overuse can increase the spread of drug-resistant bacteria. The present study analyzed the impact of different types of antibiotics on the gut microbiome and cytokines level of mice. Methods: A total of five groups of 8-week-old male BALB/c mice (n = 35) were treated with piperacillin-tazobactam (TZP), ceftriaxone (CRO), tigecycline (TGC), levofloxacin (LEV) or normal saline (Ctrl), respectively, for up to 4 weeks. Fecal samples were analyzed by bacterial 16S rRNA gene sequencing for bacterial identification. Blood samples were used for the determination of 23 serum cytokines using multiplex immunoassay. Results: Exposure to antibiotics was shown to affect the normal weight gain of mice. Significant changes in gut composition caused by TZP, CRO and TGC treatment included the decreased abundance of Bacteroidetes (p < 0.01), Muribaculaceae (p < 0.01) and Lachnospiraceae (p < 0.01), and the increased abundance of Proteobacteria (p < 0.05), Enterobacteriaceae (including Klebsiella and Enterobacter) (p < 0.01) and Enterococcaceae (including Enterococcus) (p < 0.01). After 4-week treatment, the TZP, CRO and LEV groups had significantly lower concentrations of several serum cytokines. Correlation analysis of the top 30 bacterial genera and cytokines showed that Enterococcus and Klebsiella were strongly positively correlated with tumor necrosis factor-α (TNF-α), interleukins (IL) IL-12p70 and IL-1ß. Desulfovibrio, Candidatus Saccharimonas, norank_f__norank_o__Clostridia_UCG-014, Lactobacillus, and Roseburia were strongly negatively correlated with these cytokines. Conclusion: This study demonstrates the effects of various antibiotics on the intestinal microflora and immune status of mice. Compared with TZP, CRO and TGC, LEV had minimal impact on the gut microbiota. In addition to TGC, long-term TZP, CRO and LEV intervention can lead to a decrease in serum cytokine levels, which may depend on the intestinal microflora, antibiotic used and the duration of treatment.

Akkermansia muciniphila Ameliorates Clostridioides difficile Infection in Mice by Modulating the Intestinal Microbiome and Metabolites.

Clostridioides difficile is a common cause of nosocomial infection. Antibiotic-induced dysbiosis in the intestinal microbiota is a core cause of C. difficile infection (CDI). Akkermansia muciniphila plays an active role in maintaining gastrointestinal balance and might offer the protective effects on CDI as probiotics. Here, we investigated the effects and mechanisms of A. muciniphila on CDI. C57BL/6 mice (n = 29) were administered A. muciniphila Muc T (3 × 109 CFUs, 0.2 mL) or phosphate-buffered saline (PBS) by oral gavage for 2 weeks. Mice were pretreated with an antibiotic cocktail and subsequently challenged with the C. difficile strain VPI 10463. A. muciniphila treatment prevented weight loss in mice and reduced the histological injury of the colon. And it also alleviated inflammation and improved the barrier function of the intestine. The administration effects of A. muciniphila may be associated with an increase in short-chain fatty acid production and the maintenance of bile acids' steady-state. Our results provide evidence that administration of A. muciniphila to CDI mice, with an imbalance in the microbial community structure, lead to a decrease in abundance of members of the Enterobacteriaceae and Enterococcaceae. In short, A. muciniphila shows a potential anti-CDI role by modulating gut microbiota and the metabolome.

Regulatory long non-coding RNAs of hepatic stellate cells in liver fibrosis (Review).

Liver fibrosis (LF) is a continuous wound healing process caused by numerous chronic hepatic diseases and poses a major threat to human health. Activation of hepatic stellate cells (HSCs) is a critical event in the development of hepatic fibrosis. Long non-coding RNAs (lncRNAs) that are involved in HSC activation, participate in the development of LF and are likely to be therapeutic targets for LF. In the present review, the cellular signaling pathways of LF with respect to HSCs were discussed. In particular, this present review highlighted the current knowledge on the role of lncRNAs in activating or inhibiting LF, revealing lncRNAs that are likely to be biomarkers or therapeutic targets for LF. Additional studies should be performed to elucidate the potential of lncRNAs in the diagnosis and prognosis of LF and to provide novel therapeutic approaches for the reversion of LF.

The faecal metabolome in COVID-19 patients is altered and associated with clinical features and gut microbes.

Although SARS-CoV-2 can invade the intestine, though its effect on digestion and absorption is not fully understood. In the present study, 56 COVID-19 patients and 47 age- and sex-matched healthy subjects were divided into a discovery cohort and a validation cohort. Blood, faeces and clinical information were collected from the patients in the hospital and at discharge. The faecal metabolome was analysed using gas chromatography-mass spectrometry, and Spearman's correlation analyses of clinical features, the serum metabolome, and the faecal micro- and mycobiota were conducted. The results showed that, the faeces of COVID-19 patients were enriched with important nutrients that should be metabolized or absorbed, such as sucrose and 2-palmitoyl-glycerol; diet-related components that cannot be synthesized by humans, such as 1,5-anhydroglucitol and D-pinitol; and harmful metabolites, such as oxalate, were also detected. In contrast, purine metabolites such as deoxyinosine and hypoxanthine, low-water-soluble long-chain fatty alcohols/acids such as behenic acid, compounds rarely occurring in nature such as D-allose and D-arabinose, and microbe-related compounds such as 2,4-di-tert-butylphenol were depleted in the faeces of COVID-19 patients. Moreover, these metabolites significantly correlated with altered serum metabolites such as oxalate and gut microbesincluding Ruminococcaceae, Actinomyces, Sphingomonas and Aspergillus. Although levels of several faecal metabolites, such as sucrose, 1,5-anhydroglucitol and D-pinitol, of discharged patients were not different from those of healthy controls (HCs), those of oxalate and 2-palmitoyl-glycerol did differ. Therefore, alterations in the faecal metabolome of COVID-19 patients may reflect malnutrition and intestinal inflammation and warrant greater attention. The results of present study provide new insights into the pathogenesis and treatment of COVID-19.