The effect of fecal microbiota transplantation on antibiotic-associated diarrhea and its impact on gut microbiota.

BACKGROUND: Antibiotic-associated diarrhea (AAD) refers to symptoms of diarrhea that cannot be explained by other causes after the use of antibiotics. AAD is thought to be caused by a disruption of intestinal ecology due to antibiotics. Fecal Microbiota Transplantation (FMT) is a treatment method that involves transferring microbial communities from the feces of healthy individuals into the patient's gut. METHOD: We selected 23 AAD patients who received FMT treatment in our department. Before FMT, we documented patients' bowel movement frequency, abdominal symptoms, routine blood tests, and inflammatory markers, and collected fecal samples for 16S rRNA sequencing to observe changes in the intestinal microbiota. Patients' treatment outcomes were followed up 1 month and 3 months after FMT. RESULTS: Out of the 23 AAD patients, 19 showed a clinical response to FMT with alleviation of abdominal symptoms. Among them, 82.61% (19/23) experienced relief from diarrhea, 65% (13/20) from abdominal pain, 77.78% (14/18) from abdominal distension, and 57.14% (4/7) from bloody stools within 1 month after FMT. Inflammatory markers IL-8 and CRP significantly decreased after FMT, but there were no noticeable changes in WBC, IL-6, and TNF-α before and after transplantation. After FMT, the abundance of Bacteroides and Faecalibacterium increased in patients' fecal samples, while the abundance of Escherichia-Shigella and Veillonella decreased. CONCLUSION: FMT has a certain therapeutic effect on AAD, and can alleviate abdominal symptoms and change the intestinal microbiota of patients.

Gastrointestinal Dysmotility Predisposes to Colitis through Regulation of Gut Microbial Composition and Linoleic Acid Metabolism.

Disrupted gastrointestinal (GI) motility is highly prevalent in patients with inflammatory bowel disease (IBD), but its potential causative role remains unknown. Herein, the role and the mechanism of impaired GI motility in colitis pathogenesis are investigated. Increased colonic mucosal inflammation is found in patients with chronic constipation (CC). Mice with GI dysmotility induced by genetic mutation or chemical insult exhibit increased susceptibility to colitis, dependent on the gut microbiota. GI dysmotility markedly decreases the abundance of Lactobacillus animlalis and increases the abundance of Akkermansia muciniphila. The reduction in L. animlalis, leads to the accumulation of linoleic acid due to compromised conversion to conjugated linoleic acid. The accumulation of linoleic acid inhibits Treg cell differentiation and increases colitis susceptibility via inducing macrophage infiltration and proinflammatory cytokine expression in macrophage. Lactobacillus and A. muciniphila abnormalities are also observed in CC and IBD patients, and mice receiving fecal microbiota from CC patients displayed an increased susceptibility to colitis. These findings suggest that GI dysmotility predisposes host to colitis development by modulating the composition of microbiota and facilitating linoleic acid accumulation. Targeted modulation of microbiota and linoleic acid metabolism may be promising to protect patients with motility disorder from intestinal inflammation.

Donor-recipient intermicrobial interactions impact transfer of subspecies and fecal microbiota transplantation outcome.

Studies on fecal microbiota transplantation (FMT) have reported inconsistent connections between clinical outcomes and donor strain engraftment. Analyses of subspecies-level crosstalk and its influences on lineage transfer in metagenomic FMT datasets have proved challenging, as single-nucleotide polymorphisms (SNPs) are generally not linked and are often absent. Here, we utilized species genome bin (SGB), which employs co-abundance binning, to investigate subspecies-level microbiome dynamics in patients with autism spectrum disorder (ASD) who had gastrointestinal comorbidities and underwent encapsulated FMT (Chinese Clinical Trial: 2100043906). We found that interactions between donor and recipient microbes, which were overwhelmingly phylogenetically divergent, were important for subspecies transfer and positive clinical outcomes. Additionally, a donor-recipient SGB match was indicative of a high likelihood of strain transfer. Importantly, these ecodynamics were shared across FMT datasets encompassing multiple diseases. Collectively, these findings provide detailed insight into specific microbial interactions and dynamics that determine FMT success.

Depletion of butyrate-producing microbes of the Firmicutes predicts nonresponse to FMT therapy in patients with recurrent Clostridium difficile infection.

Approximately 10% of individuals diagnosed with Clostridium difficile infection (CDI) show the resistance to fecal microbiota transplantation (FMT), with the underlying mechanisms remaining elusive. Deciphering the intricate microbiome profile within this particular subset of FMT-refractory patients via clinical FMT investigations assumes paramount importance, as it holds the key to designing targeted therapeutic interventions tailored for CDI, particularly recurrent CDI (rCDI). A cohort of twenty-three patients afflicted with rCDI, exhibiting congruent clinical baselines, was meticulously selected for FMT. Rigorous screening of thousands of healthy individuals identified ten FMT donors who met stringent health standards, while a total of 171 stool samples were collected to serve as healthy controls. To assess the influence of microbiome dynamics on FMT efficacy, fecal samples were collected from four donors over a continuous period of twenty-five weeks. After FMT treatment, seven individuals exhibited an inadequate response to FMT. These non-remission patients displayed a significant reduction in α-diversity indexes. Meanwhile, prior to FMT, the abundance of key butyrate-producing Firmicutes bacteria, including Christensenellaceae_R_7_group, Ruminococcaceae_unclassified, Coprococcus_2, Fusicatenibacter, Oscillospira, and Roseburia, were depleted in non-remission patients. Moreover, Burkholderiales_unclassified, Coprococcus_2, and Oscillospira failed to colonize non-remission patients both pre- and post-treatment. Conversely, patients with a favorable FMT response exhibited a higher relative abundance of Veillonella prior to treatment, whereas its depletion was commonly observed in non-remission individuals. Genera interactions in lower effectiveness FMT donors were more similar to those in non-remission patients, and Burkholderiales_unclassified, Coprococcus_2, and Oscillospira were frequently depleted in these lower effectiveness donors. Older patients were not conducive to the colonization of Veillonella, consistent with their poor prognosis after FMT. FMT non-remission rCDI patients exhibited distinct characteristics that hindered the colonization of beneficial butyrate-producing Firmicutes microbes. These findings hold promise in advancing the precision of FMT therapy for rCDI patients.

Middle Segment-Preserving Pancreatectomy to Avoid Pancreatic Insufficiency: Individual Patient Data Analysis of All Published Cases from 2003-2021.

Middle segment-preserving pancreatectomy (MPP) can treat multilocular diseases in the pancreatic head and tail while avoiding impairments caused by total pancreatectomy (TP). We conducted a systematic literature review of MPP cases and collected individual patient data (IPD). MPP patients (N = 29) were analyzed and compared to a group of TP patients (N = 14) in terms of clinical baseline characteristics, intraoperative course, and postoperative outcomes. We also conducted a limited survival analysis following MPP. Pancreatic functionality was better preserved following MPP than TP, as new-onset diabetes and exocrine insufficiency each occurred in 29% of MPP patients compared to near-ubiquitous prevalence among TP patients. Nevertheless, POPF Grade B occurred in 54% of MPP patients, a complication avoidable with TP. Longer pancreatic remnants were a prognostic indicator for shorter and less eventful hospital stays with fewer complications, whereas complications of endocrine functionality were associated with older patients. Long-term survival prospects after MPP appeared strong (median up to 110 months), but survival was lower in cases with recurring malignancies and metastases (median < 40 months). This study demonstrates MPP is a feasible treatment alternative to TP for selected cases because it can avoid pancreoprivic impairments, but at the risk of perioperative morbidity.

SmartPAN: In vitro and in vivo proof-of-safety assessments for an intra-operative predictive indicator of postoperative pancreatic fistula.

Pancreatic surgery is complicated by untreated fluid leakage, but no tenable techniques exist to detect and close leakage sites during surgery. A novel hydrogel called SmartPAN has been developed to meet this need and is here assessed for safety before trials on human patients. First, resazurin assays were used to test the cytotoxic effects of SmartPAN's active bromothymol blue (BTB) indicator and its solution of phosphate-buffered saline (PBS) on normal (HPDE: human pancreatic duct epithelial) or carcinomic (FAMPAC) human pancreatic cells. Cells incubated with BTB showed no significant reduction in cell viability below threshold safety levels. However, PBS had a mild cytotoxic effect on FAMPAC cells. Second, SmartPAN's pathological effects were evaluated in vivo by applying 4-ml SmartPAN to a porcine (Sus scrofa domesticus) model of pancreatic resection. There were no significant differences in macroscopic and microscopic pathologies between pigs treated with SmartPAN or saline. Third, measurements using HPLC-MS/MS demonstrate that BTB does not cross into the bloodstream and was eliminated from the body within 2 days of surgery. Overall, SmartPAN appears safe in the short term and ready for first-in-human trials because its components are either biocompatible or quickly neutralized by dilution and drainage.

Long-Term Follow-Up Results of Fecal Microbiota Transplantation for Irritable Bowel Syndrome: A Single-Center, Retrospective Study.

Objective: This study aimed to investigate the long-term efficacy of fecal microbiota transplantation (FMT) in patients with irritable bowel syndrome (IBS). Study Methods: In this single-center long-term follow-up study, FMT treatment was administered to patients with moderate to severe IBS (IBS severity scoring system (IBS-SSS) > 175). After 1 year of treatment, it was decided whether to repeat FMT based on IBS-SSS score (IBS-SSS > 175). Baseline characteristics before and after FMT and questionnaires were completed at 1, 3, 6, 12, 24, 36, 48, and 60 months after FMT. The study outcomes included treatment efficacy rates, change of IBS-SSS, IBS-specific quality of life and fatigue, effect on stool frequency, Bristol Stool Scale for IBS-C and IBS-D, and side effects. Results: A total of 227 patients (47.58% IBS-C, 39.21% IBS-D, and 13.22% IBS-M) were recruited (142 females and 85 males with a mean age of 41.89 ± 13.57 years). The efficacy rates were 108 (51.92%), 147 (74.62%), 125 (74.41 %), 88 (71.54%), 78 (75.00%), 65 (73.03%), 45 (61.64%), and 37 (62.71%) at different follow-up time points. The total IBS-SSS score was 321.37 ± 73.89 before FMT, which significantly decreased after 1 month. The IBS-specific quality of life (IBS-QoL) score was 40.24 ± 11.34 before FMT, increased gradually, and was significantly higher at 3 months compared to before FMT. The total Fatigue Assessment Scale (FAS) score was 47 ± 8.64 before FMT and was significantly lower at 3 months. During follow-up, 89 (39.21%) side effects occurred that were alleviated by symptomatic treatment, and no serious adverse events were detected. Conclusion: Based on 60 months of long-term follow-up, the safety and efficacy of FMT for IBS was established. However, as the treatment effect declines over time, periodic and repetitive FMT is required for a sustained effect.

Gut Metagenome as a Potential Diagnostic and Predictive Biomarker in Slow Transit Constipation.

Slow transit constipation (STC) is one of the most frequent gastrointestinal diagnoses. In this study, we conducted a quantitative metagenomics study in 118 Chinese individuals. These participants were divided into the discovery cohort of 50 patients with STC and 40 healthy controls as well as a validation cohort of 16 patients and 12 healthy controls. We found that the intestinal microbiome of patients with STC was significantly different from that of healthy individuals at the phylum, genus, and species level. Patients with STC had markedly higher levels of Alistipes and Eubacterium and lower abundance of multiple species belonging to the Roseburia genus. Patients with STC gene expression levels and the Kyoto Encyclopedia of Genes and Genomes (KEGG) orthology pathway (such as fatty acid biosynthesis, butanoate metabolism, and methane metabolism pathways) enrichment were also substantially different from those of healthy controls. These microbiome and metabolite differences may be valuable biomarkers for STC. Our findings suggest that alteration of the microbiome may lead to constipation by changing the levels of microbial-derived metabolites in the gut. Above findings may help us in the development of microbial drugs.

Survival Benefit of Resection Surgery for Pancreatic Ductal Adenocarcinoma with Liver Metastases: A Propensity Score-Matched SEER Database Analysis.

Guidelines do not recommend resection surgery for oligometastatic pancreatic ductal adenocarcinoma (PDAC). However, reports in small samples of selected patients suggest that surgery extends survival. Thus, this study aims to gather evidence for the benefits of cancer-directed surgery (CDS) by analyzing a national cohort and identifying prognostic factors that aid the selection of candidates for CDS or recruitment into experimental trials. Data for patients with PDAC and hepatic metastasis were extracted from the population-based Surveillance, Epidemiology, and End Results database (SEER). The bias between CDS and non-CDS groups was minimized with Propensity Score Matching (PSM), and the prognostic role of CDS was investigated by comparing Kaplan-Meier estimators and Cox proportional hazard models. A total of 12,018 patients were extracted from the database, including 259 patients who underwent CDS that were 1:1 propensity score-matched with patients who did not receive CDS. CDS appeared to significantly prolong median overall survival from 5 to 10 months. Multivariate analysis revealed chemotherapy as a protective prognostic, whilst survival was impaired by old age and tumors that were poorly differentiated (Grades III-IV). These factors can be used to select patients likely to benefit from CDS treatment, which may facilitate recruitment into randomized controlled trials.

Efficacy of Pasireotide for Prevention of Postoperative Pancreatic Fistula in Pancreatic Surgery: a Systematic Review and Meta-analysis.

BACKGROUND: Pasireotide was recently suggested for the prevention of postoperative pancreatic fistula (POPF) after pancreatic surgery. However, its efficacy remains to be controversially dicussed. Therefore, we conducted a systematic review and meta-analysis to assess the efficacy of pasireotide for preventing POPF after pancreatic surgery. METHOD: A systematic literature search was conducted in PubMed, Web of Science, and The Cochrane Library to identify clinical studies investigating the efficacy of pasireotide after pancreatic surgery. The identified studies were critically appraised, and meta-analyses were then performed. The study was performed in accordance with PRISMA guidelines and was registered at the PROSPERO study database (CRD42018112334). RESULTS: Four studies with a total of 919 patients were included: 418 with pasireotide treatment and 501 controls. Meta-analysis showed that pasireotide could reduce neither clinically relevant POPF rate (OR = 0.78; 95% CI, 0.49-1.24; P = 0.29) nor overall POPF rate (OR = 0.94; 95% CI, 0.60-1.48; P = 0.80) after pancreatic resections. There were no significant differences in delayed gastric emptying, mortality, and postoperative hospital stay after pancreatic surgery. However, pasireotide reduces readmission after pancreatic surgery (OR = 0.61; 95% CI, 0.44-0.85; P = 0.004). Subgroup analyses revealed that prophylactic use of pasireotide did not reduce the incidence of clinically relevant POPF after pancreaticoduodenectomy or distal pancreatectomy compared with the control. CONCLUSION: Based on the available evidence, use of pasireotide may not reduce clinically relevant POPF as well as it may not improve postoperative course substantially after pancreatic surgery. Further investigator-initiated high-quality trials are needed.

SmartPAN: A novel polysaccharide-microsphere-based surgical indicator of pancreatic leakage.

Postoperative pancreatic fistula is a major surgical complication that can follow pancreatic resection. Postoperative pancreatic fistula can develop as a consequence of leaking pancreatic fluid, which calls for an intraoperative indicator of leakage. But suitable indicators of pancreatic leakage have yet to be found. This study details the evidence-based development and early efficacy assessments of a novel pancreatic leakage indicator (SmartPAN), following the IDEAL framework of product development. We developed 41 SmartPAN prototypes by combining indicators of pancreatic fluid with a polysaccharide-microsphere matrix. The prototypes were assessed in vitro using porcine (Sus scrofa domesticus) pancreatic tissue and ex vivo with human pancreatic fluid. From these initial tests, we chose a hydrogel-based compound that uses the pH indicator bromothymol blue to detect alkali pancreatic fluid. This prototype was then assessed in vivo for usability, effectiveness and reliability using a porcine model. Treatment groups were defined by SmartPAN-reaction at initial pancreatic resection: indicator-positive or negative. Indicator-positive individuals randomly received either targeted closure of leakage sites or no further closure. We assessed SmartPAN's reliability and effectiveness by monitoring abdominal drainage for amylase and with relaparotomy after 48 h. SmartPAN responses were consistent between both surgical procedures and conformed to amylase measurements. In conclusion, we have developed the first surgery-ready indicator for predicting the occurrence of pancreatic leakage during pancreatic resection. SmartPAN can enable targeted prophylactic closure in a simple and reliable way, and thus may reduce the impact of postoperative pancreatic fistula by guiding peri- and post-operative management.

The lncRNA ENSG00000254041.1 promotes cell invasiveness and associates with poor prognosis of pancreatic ductal adenocarcinoma.

Pancreatic cancer (PC) mainly occurs after 60 years of age, and its prognosis remains poor despite modest improvements in recent decades. Long non-coding RNAs (lncRNAs) are well known as a class of transcripts involved in cancer occurrence and progression. The process of epithelial to a mesenchymal (EMT) phenotype in tumor cell increases their migratory and invasive properties, resulting in facilitating metastasis. Here, we reanalyzed RNA-seq data from the TCGA PC database and identified that ENSG00000254041.1 increasingly expressed in samples with elevated EMT signature score. Then, the evaluated expression and prognostic significance of ENSG00000254041.1 were verified in our cohort. Meanwhile, multivariate analysis suggested that ENSG00000254041.1 was independent factors for predicting the prognosis of PC, apart from advanced stage (III/IV). Moreover, functional assay revealed that knock down of ENSG00000254041.1 significantly decreased proliferation, invasion and chemoresistance of PC cells (SW1990 and BxPC-3), while overexpression of ENSG00000254041.1 in PC cells (Panc-1) resulted in the opposite effects. Western blot showed that knockdown of ENSG00000254041.1 expression in PC cells caused a significant downregulation of vimentin, Snail and SOX4, and upregulation of E-cadherin; also, ENSG00000254041.1 overexpression in PC cells resulted in opposite effects. In conclusion, these findings indicated that ENSG00000254041.1 promotes PC progression, and might provide a potential biomarker for predicting the prognosis of PC.

Survival analysis of patients with spinal chordomas.

This study was aimed to analyze the survival of patients with spinal chordomas. Patients' data in the Surveillance, Epidemiology, and End Results (SEER) database were retrieved and analyzed statistically. There were 765 patients with spinal chordomas between 1974 and 2013. The overall survival did not improve significantly over decades for patients receiving surgery and radiotherapy (SR) (P = 0.221). There were significant differences in overall survival among subgroups of patients receiving surgery (S), radiotherapy (R), and neither S nor R (NSR) (P = 0.031, 0.037, and 0.031, respectively). Cancer-specific survival did not change significantly among subgroups of patients receiving R (P = 0.411), while it increased steadily among subgroups of patients receiving S, SR, and NSR (P < 0.001, 0.001, and 0.049, respectively). In the multivariate Cox regression model, younger onset age (hazard ratio [HR] 1.052, P < 0.001), surgery (HR 0.291, P = 0.001), and tumor location of the sacrum (HR 0.401, P = 0.002) were associated with a better overall survival. Similarly, younger onset age (HR 1.036, P = 0.029), surgery (HR 0.221, P = 0.009), and tumor location of the sacrum (HR 0.287, P = 0.002) were also associated with a higher cancer-specific survival. The changes in overall and cancer-specific survival over time differ among different treatment groups. Younger onset age, surgical strategy, and tumor location of the sacrum may be correlated with a higher overall and cancer-specific survival.

Prognostic factors to survival of patients with chondroblastic osteosarcoma.

This study was aimed to reveal the changes in survival rates and prognostic factors to survival of chondroblastic osteosarcoma (COS).Patients from the Surveillance, Epidemiology, and End Results (SEER) database were retrieved. Kaplan-Meier survival analysis and Cox proportional hazard model were used during analysis.There were significant differences on overall survival between subtypes of osteosarcoma (P < .001*). Overall survival of COS did not change significantly during last forty years (P = .610), and cancer-specific survival increased to a plateau in 1980s and then remained stable (P = .058). Younger onset age, patients of white race, well and moderately differentiated tumors, and surgery independently predicted better overall (Hazard ratio [HR]: 1.034, P < .001*; HR: 0.538, P = .004*; HR: 0.240, P = .020* and HR: 0.350, P < .001*, respectively) and cancer-specific (HR: 1.031, P = .002*; HR: 0.592, P = .036*; HR: 0.098, P = .027* and HR: 0.253, P < .001*, respectively) survival. Metastasis at diagnosis independently predicted worse overall (HR: 3.108, P < .001*) and cancer-specific (HR: 4.26, P < .001*) survival compared to no metastasis.Younger onset age, white race, well and moderately differentiated tumors, no metastasis at diagnosis and surgical resection can independently predict better overall and cancer-specific survival of COS.