Abstract

Background Post-discharge morbidity and mortality is high in acute pancreatitis (AP) and pathophysiological mechanisms remain poorly understood.

Objectives We aim to investigate the composition of gut microbiota and clinical long-term outcomes of prospectively enrolled AP patients to predict post-discharge complications.

Design In this long-term follow-up study, we analysed clinical and microbiome data of 277 patients from the prospective multi-centre P-MAPS trial. Primary endpoint was the association of the microbial composition with post-discharge mortality, recurrent AP (RAP), progression to chronic pancreatitis (CP), pancreatic exocrine insufficiency (PEI), diabetes mellitus (DM) and pancreatic ductal adenocarcinoma (PDAC).

Results Buccal (n=238) and rectal (n=249) swabs were analysed by 16S rRNA and metagenomics sequencing using Oxford Nanopore Technologies. Median follow-up was 2.8 years. Distance-based redundancy analysis (dbRDA) with canonical analysis of principle coordinates (CAP) showed significant differences for β-diversity (Bray-Curtis) for post-discharge mortality (p=0.04), RAP (p=0.02), and DM (p=0.03). A ridge regression model including 11 differentially abundant species predicted post-discharge DM with an area under the receiving operating characteristic (AUROC) of 94.8% and 86.2% in the matched and entire cohort, respectively. Using this classifier, a positive predictive value of 66.6%, a negative predictive value of 96% and an accuracy of 95% was achieved.

Conclusion Our data indicate that the admission microbiome of AP patients correlates with post-discharge complications independent from multiple risk factors such as AP severity, smoking or alcohol. Microbiota at admission show excellent discriminative capacity to predict post-discharge DM and may thus open new stratification tools for a tailored risk assessment in the future.

Competing Interest Statement

The authors have declared no competing interest.

Clinical Trial

NCT04777812

Funding Statement

No external funding was received. All sequencing costs were covered by intramural funding of University Medical Center Goettingen, Forschungsfoerderungsprogramm 2021 Startfoerderung Klinische Studien. All authors and institutions received no payment or services from a third party for any aspect of the submitted work.

Author Declarations

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

Ethics committee of the University Medical Centre Goettingen, Germany gave ethical approval for this work, protocol number 11/7/19.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

Footnotes

Funding: No external funding was received. All sequencing costs were covered by intramural funding of University Medical Center Goettingen, Forschungsförderungsprogramm 2021 Startförderung Klinische Studien. All authors and institutions received no payment or services from a third party for any aspect of the submitted work.

Competing interests: All authors report no competing interests.

Ethics: Ethics committee/IRB of the University Medical Centre Göttingen, Germany gave ethical approval for this work (protocol number 11/7/19).

Data availability: All data produced in the present study are available upon reasonable request to the authors.

Study-trial number: This study was registered at clinical.trial.gov: NCT04777812.

Data Availability

All data produced in the present study are available upon reasonable request to the authors

AbbreviationsAUROCArea under the receiver-operating characteristicBMIBody mass indexCAPCanonical analysis on the principal coordinatesCPChronic PancreatitisCRAMPCathelicidin related antimicrobial peptideDMDiabetes MellitusDb-RDADistance-based redundancy analysisIRRIncidence rate ratioLEfSeLinear discriminant analysis effect sizeLOOCVLeave-one out cross validationMaAsLin2Microbiome Multivariable Association with Linear ModelsNCBINational center for biotechnology informationNODNon-obese diabetic (mice)NSAIDNon-steroidal anti-inflammatory drugONTOxford-Nanopore TechnologiesPDACPancreatic ductal adenocarcinomaPEIPancreatic exocrine insufficiencyP-MAPSPancreatitis – Microbiome As Predictor of SeverityPPIproton pump inhibitorsRACRevised Atlanta classificationRAPRecurrent Acute PancreatitisSCFAShort chain fatty acids