Impact of Exocrine Pancreatic Insufficiency Associated With Acute Pancreatitis and Pancreatic Enzyme Replacement Therapy on Gut Microbiota, Immunological Changes and Quality of Life
Phase: NA
Conditions: Acute Pancreatitis, Exocrine Pancreatic Insufficiency, Gut Microbiota, Immunology
Sponsor: Unidade Local de Saúde de Coimbra, EPE

IMPACT OF EXOCRINE PANCREATIC INSUFFICIENCY ASSOCIATED WITH 
ACUTE PANCREATITIS AND PANCREATIC ENZYME REPLACEMENT 
THERAPY ON GUT MICROBIOTA, IMMUNOLOGICAL CHANGES AND QUALITY 
OF LIFE 
 
 
 
 
 
 
 
 
 
 
 
 
 
INFORMED CONSENT 
 
 
 
 
 
 
 
 
 
 
 
 
 
MARCH 17TH, 2021 

Impact of exocrine pancreatic insufficiency associated with acute pancreatitis and pancreatic enzyme 
replacement therapy on gut microbiota, immunological changes and quality of life 
_____________________________________________________________________________________ 
A longitudinal prospective study and blind randomized placebo-controlled clinical trial 
 
Short title: Exocrine pancreatic insufficiency after acute pancreatitis and pancreatic enzyme replacement 
therapy 
__________________________________________________________ 
 
Keywords 
Acute pancreatitis 
Pancreatic exocrine insufficiency 
Gut microbiota 
Immunology 
 
Abstract 
Introduction: Acute pancreatitis represents an acute inflammatory process of the pancreas, which 
undergoes local and systemic complications, associated with non-negligible morbidity and mortality, and 
significant economic and quality of life impact. Even after the recovery phase, the development and 
persistence of sequelae from the inflammatory/necrotic process, including exocrine and endocrine 
pancreatic insufficiencies, are frequent. Although well documented as consequence of other pancreatic 
conditions, exocrine pancreatic insufficiency (EPI) after acute pancreatitis is poorly studied and probably 
underdiagnosed. The prevalence, diagnosis, independent risk factors and therapeutic approaches for EPI 
after acute pancreatitis need further investigation. Recent evidence suggests the involvement of the 
pancreas-intestinal axis and immunological dysfunction in several pancreatic pathologies, although their 
role in the development of EPI after acute pancreatitis is still scarce. Pancreatic enzyme replacement 
therapy (PERT) is the only treatment currently available in EPI, but the timing for start and duration of this 
therapy in acute pancreatitis remain to be established. 
Objectives: Primary objectives: To determine the prevalence, clinical, analytical and nutritional 
biomarkers and duration of EPI after acute pancreatitis, as well as changes in gut microbiota and 
immunologic response, and quality of life in EPI and response to PERT after acute pancreatitis. Secondary 
objectives: To determine the prevalence and biomarkers associated with endocrine pancreatic 
insufficiency following acute pancreatitis and the presence of gut dysbiosis and immunologic changes in 
acute pancreatitis according to its severity. 
Methods: Prospective longitudinal study of total of patients consecutively admitted to the 
gastroenterology Department of Coimbra Hospital and University Centre with acute pancreatitis diagnosis 
and double-blind randomized placebo-controlled clinical trial of PERT in patients developing EPI after 
acute pancreatitis. This study will be conducted in 4 Phases: Phase 1 - Recruitment of patients with acute 
pancreatitis and stratification of them according to the severity of acute pancreatitis and development of 
EPI (12-month follow-up), diagnosed by fecal elastase-1, 13C-labeled mixed triglyceride breath test 
assessing exocrine pancreatic function and comparison of them with 72-hour fecal fat quantification, as 
gold standard; Phase 2 – Double-blind randomized placebo-controlled trial in patients with EPI after acute 
pancreatitis for PERT with assessment of efficacy and safety of this therapy 
at 1 and 6 months post-randomization; Phase 3 - Evaluation of richness, diversity and uniformity of gut 
microbiota by DNA sequencing using the hypervariable region of the 16S ribosomal RNA gene as a 
taxonomic identification marker and assessment of quality of life using SF-36 and QLC-C30-V.3 scales 
(validated versions for the Portuguese population) in EPI patients after acute pancreatitis, and the impact 
of PERT on clinical course, gut dysbiosis and quality of life of patients (at the diagnosis of acute 
pancreatitis, EPI and after PERT); and Phase 4 – Analysis of immunological changes through the study of 
cell populations by flow cytometry (CD4+, CD8+, B-cell, T-cell, natural killer cells, cells ratio) and cytokines, 
chemokines and growth factors by xMAP/Luminex, at the diagnosis of acute pancreatitis, EPI and after 
PERT. 
Expected results, impact and scientific outputs: Data on the prevalence of EPI after acute pancreatitis in 
its different forms of severity and the role of gut dysbiosis and immunologic changes remains unclear. It’s 
expected that an adequate and timely diagnosis of this clinical condition will allow an early start of therapy 
with positive impact on clinical course, immunologic and gut homeostasis, survival and quality of life. With 
this study we expect to obtain a prevalence of EPI at admission of 25-62%, which should decrease during 

followup. Alcoholic etiology, severity of acute pancreatitis and the presence of pancreatic necrosis should 
be positively associated with the presence of EPI after acute pancreatitis. The prevalence of endocrine 
pancreatic insufficiency (pre-diabetes or diabetes mellitus) should be up to 40%. Nutritional deficits 
(single or multiple), breath test assessing exocrine pancreatic function and fecal elastase-1 are also 
expected to be positively associated with the development of EPI. It’s expected that patients with acute 
pancreatitis developing EPI will have significant changes on gut microbiota and immunologic response, 
and PERT and/or gut microbiota modulating therapy, including prebiotics, probiotics, symbiotics and fecal 
microbiota transplantation, and probably targeted immunotherapies may have a beneficial impact on all 
patients or groups at risk, such as EPI, severe or necrotizing acute pancreatitis by reverting gut and 
immunologic dysbiosis, and improving quality of life. 
 
Literature review 
Acute pancreatitis, an acute inflammatory process of the pancreas, is associated with significant mortality 
and morbidity.1-3 It can lead to local and systemic complications related to the inflammatory/necrotic 
process, including exocrine pancreatic insufficiency (EPI) and endocrine pancreatic insufficiency (diabetes 
mellitus), recurrent pancreatitis and chronic pancreatitis. These complications can arise and/or persist 
even after hospital discharge.4-8 The main manifestation of EPI is weight loss secondary to malnutrition 
due to micronutrient, fat-soluble vitamin and lipoprotein deficiencies.5,6,9 Although EPI is well 
established in the context of chronic pancreatitis, pancreatic cancer and pancreatectomy, its occurrence 
in the background of acute pancreatitis remains unknown and probably underdiagnosed.5 Data on the 
prevalence of EPI following acute pancreatitis are scarce and controversial, ranging from 20 to 71%.3,5,6 
Some studies list alcohol etiology, the severity of acute pancreatitis and the presence of pancreatic 
necrosis as risk factors associated with EPI.5,6 However, the knowledge in this area is equally scarce and 
uncertain. Acute pancreatitis complications, including EPI, can lead to a significant economic impact and 
impaired quality of life.5,6,10 
In clinical practice, there is no a universally easy and reliable test for the diagnosis of EPI.5,6,11,12 Gold 
standard diagnosis implies direct tests or 72-hour fecal fat quantification. However, their clinical 
applicability is limited. Valid alternatives such as fecal elastase-1 and 13C-labeled mixed triglyceride 
breath test assessing exocrine pancreatic function have gained special interest and wide use for their 
availability, cost and ease of application.12 Based on fecal elastase-1, EPI has been reported at 26.5%, 
26.1% and 9.4% for a follow-up of <12months, 12-36months and >36months, respectively.5,6 Recent 
evidence suggests an increasing importance of the pancreas-intestinal axis in pancreatic pathology given 
the central role of the pancreas in controlling metabolism via its exocrine and endocrine pancreatic 
functions, possibly due to bacterial metabolites as short-chain fatty acids, immune modulation and 
pancreatic excretion of antimicrobials. Changes in gut microbiota have been more documented for 
pancreatic cancer and type 1 diabetes mellitus.13,14 Recently, [ZhHeLiCaHuLi19] showed that severe 
acute pancreatitis can also course with gut dysbiosis by decreased Firmicutes and Bacteroidetes and 
increased Protobacteria.15 However, the presence and implications of gut dysbiosis associated with acute 
pancreatitis and EPI following acute pancreatitis increasing risk of gut-derived infection, remains unclear. 
In recent years, efforts have been dedicated to find early predictors, alone or in association, of severity, 
organ dysfunction, and development of complications in patients with acute pancreatitis. In fact, our 
study group has also been dedicating itself to this thematic, having carried out studies and reflections with 
publications in international and national journals, identifying C-reactive protein (CRP),16,17 red cell 
distribution width (RDW) and RDW to total serum calcium ratio,7 as main early predictors (at admission 
of patients and within the first 24 hours of hospitalization) of severity in acute pancreatitis. However, no 
single biomarker or score demonstrated high accuracy in early prediction of severity or prognosis of acute 
pancreatitis to be used in clinical practice7,16,17 and, additionally, there are no studies on early predictors 
in the development of the EPI complication after acute 
pancreatitis. Important immunological changes, which may become biomarkers, have been described as 
associated with severe acute pancreatitis, such as interleukin(IL)-6, IL-8, IL- 10 and CRP. Recent studies 
have shown that IL-6 ≥28.90pg/mL in the first 48 hours (sensitivity:62.9%; specificity:80.0%), and the 
growth 
differentiation 
factor(GDF)-15 
>3183.36pg/mL 
(sensitivity:89.5%; 
specificity:76.9%), 
pentraxin(PTX)-3 >1.05pg/mL (sensitivity:85.0%; specificity:88.0%) and hepatocyte growth factor(HGF) 
>3020.1pg/mL (sensitivity:60.0%; specificity:92.8%) at admission were good predictors of severity in acute 
pancreatitis.18-20 However, there are no data on the main immunological changes associated with the 
development of EPI following acute pancreatitis. Pancreatic enzyme replacement therapy (PERT), the only 
treatment currently available for EPI secondary to other causes than acute pancreatitis, has benefit in EPI 

secondary to chronic pancreatitis,21 post-pancreatic surgery6,22,23 and non-resectable pancreatic 
cancer.24 However, its use in EPI following acute pancreatitis lacks clinical evidence, needs further studies 
and its routine application in clinical practice is currently not recommended.5,6 Some studies have been 
shown improvement in survival of patients with EPI 
secondary to severe or necrotizing acute pancreatitis and patients undergoing necrosectomy.23,25 When 
to start PERT and for how long to obtain clinical and nutritional benefits and 
the reversal of gut dysbiosis and immunologic changes in EPI following acute pancreatitis remain to be 
elucidated. Future prospective studies addressing these key issues are indispensable to determine the 
prevalence of EPI following an acute pancreatitis event and its predictors, as well as a 
double blind randomized placebo-controlled trial to assess the impact, efficacy and safety of PERT and its 
repercussions on gut microbiota, immunological status, clinical and nutritional course and patients’ 
quality of life. In the future, new therapeutic targets may be explored in EPI following acute pancreatitis, 
such as manipulation of gut microbiota including prebiotics, probiotics, symbiotics and perhaps fecal 
microbiota transplantation and probably targeted immunotherapies. PERT and these new therapies could 
be applied to all patients after acute pancreatitis or in high-risk groups, including EPI. 
 
Plan and methods 
A. Study hypothesis 
The authors hypothesize that exocrine pancreatic insufficiency (EPI) is a frequent and underdiagnosed 
complication of acute pancreatitis. Homeostasis of gut microbiota and immunological status are 
significantly altered in acute pancreatitis, mainly due to its severity and EPI development with important 
implications in clinical and nutritional course and quality of life. Pancreatic enzyme replacement therapy 
(PERT) and eventually new therapies modulating gut microbiota and targeted immunotherapies may 
reverse gut dysbiosis and immunological changes with impact on acute pancreatitis clinical course and 
improve quality of life. 
 
B. Objectives 
Primary objectives 
- To determine the prevalence and duration of EPI following acute pancreatitis, and analytical and 
nutritional biomarkers related to the development of this complication; 
- To evaluate when to start, the efficacy, safety and the duration of PERT in patients with EPI following 
acute pancreatitis; 
- To assess changes in gut microbiota in EPI following acute pancreatitis and response to PERT; 
- To assess changes in immunologic response in EPI following acute pancreatitis and response to PERT; 
- To assess quality of life in EPI following acute pancreatitis and response to PERT. 
 
Secondary objectives 
- To determine the prevalence and biomarkers associated with the development of endocrine pancreatic 
insufficiency following acute pancreatitis (type 3 diabetes mellitus, including 
new-onset pre-diabetes and/or diabetes mellitus); 
- To evaluate changes in gut microbiota according to acute pancreatitis severity; 
- To evaluate immunological changes according to acute pancreatitis severity. 
 
C. Expected results, study clinical impact and scientific outputs 
Data on the prevalence and biomarkers of EPI after acute pancreatitis in its different forms of severity and 
the role of gut dysbiosis and immunologic changes remains unclear. An adequate and timely diagnosis of 
this clinical condition will allow an early start of therapy with positive impact on clinical course, 
immunological and gut homeostasis, survival and quality of life. Therefore, a study on the prevalence and 
biomarkers of EPI in patients with acute pancreatitis, a randomized placebo-controlled trial to determine 
the timing for start and duration of PERT in EPI and the implications of PERT on gut microbiota and 
immunological response is urgently needed. 
EPI is expected to be a frequent complication of acute pancreatitis, which is likely to increase with acute 
pancreatitis severity, with significant changes on gut microbiota and immunologic response and an 
impaired quality of life. Results of this study may have important clinical implications in clinical practice 
regarding changes in gut microbiota and immunological status, and clinical and nutritional implications of 
EPI following acute pancreatitis; when to start and for how long PERT should be applied and repercussions 
of this therapy in clinical course, reverting gut dysbiosis and immunological changes, and improving 

quality of life; and the possible benefit of additional unexplored therapies such as gut microbiota 
modulating therapy including probiotics, prebiotics, symbiotics, fecal microbiota transplantation and 
targeted immunotherapies. These therapies could have a positive impact in all patients or high-risk group 
of patients with acute pancreatitis including EPI. 
 
D. Methodology and Stages of project development 
D.1. Type of study 
Unicentric longitudinal prospective study. Regarding the evaluation of gut microbiota and immunological 
changes, the study will also be blind, as the researcher responsible for sequencing and immunological 
analyses will not know patients’ EPI status. For evaluation the response to PERT in patients with acute 
pancreatitis and EPI, the study will be doubleblind (for the patient who will not know which therapy he 
will be taking (PERT/placebo) and for the researchers responsible for sequencing and immunological 
analyses) randomized placebo-controlled clinical trial. The trial will be registered on the 
https://clinicaltrials.gov platform. 
 
D.2. Study population 
Patients with the first episode of acute pancreatitis 
 
D.3. Study design 
This project will take place in 4 distinct phases:  
 
Phase 1: Recruitment of patients with acute pancreatitis and stratification of them according to the 
severity of acute pancreatitis and development of EPI (12-month follow-up). 
All patients admitted to the Gastroenterology Department of Coimbra Hospital and University Centre by 
the first episode of acute pancreatitis will be included, consecutively, according to the revised Atlanta 
criteria 20124 and taking into account the inclusion/exclusion criteria and the minimum number of 
patients needed to obtain statistical power. 
 
Inclusion criteria: Definitive diagnosis of acute pancreatitis, according to revised Atlanta criteria 2012.4 
 
Exclusion criteria: Age <18years; History of allergy, hypersensitivity or contraindication to use of PERT; 
Prior acute pancreatitis; Other causes that may occur with EPI, including celiac disease, diabetic 
gastroparesis, chronic pancreatitis, cystic fibrosis, pancreatic neoplasia, ampuloma, somatostatinoma, 
somatostatin analog therapy, small bowel pathology, inflammatory bowel disease, and rare diseases 
associated with exocrine pancreatic insufficiency (Zollinger-Ellison syndrome, Shwachman-Diamond 
syndrome, 
Johanson-Blizzard 
syndrome); 
Prior 
gastrointestinal 
or 
pancreatic 
surgery 
or 
endoscopic/surgical therapy for obesity; medication with orlistat or acarbose; Respiratory pathology 
(severe chronic obstructive pulmonary disease), hepatic (Child-Pugh C cirrhosis) or biliary (obstructive 
jaundice) severe pathology; Non-compliance for PERT (when indicated); Uncontrolled thyroid 
pathology; Refusal/incapacity to give informed consent; and Follow-up period <12months after acute 
pancreatitis diagnosis. 
 
Sample size calculation: For an estimated prevalence of EPI in the adult population of 25% and a drop-out 
rate of 10%, it was determined that for a 95% confidence level and 10% sampling error, it will be necessary 
to include 42 patients in each of the therapeutic arms (PERT vs placebo), making a total of 84 patients. 
 
Diagnosis of EPI and stratification of patients: See Task 1. 
 
Phase 2: Double-blind randomized placebo-controlled trial for patients with EPI after acute pancreatitis 
for PERT and collection of stool and blood samples before and after 
PERT/placebo (6 months post-randomization). 
Randomization of patients with EPI following acute pancreatitis for PERT vs placebo. The efficacy, safety 
and compliance of PERT will be evaluated at 1 (for adjusting PERT dose) and 6 months after PERT start. 
 
Phase 3: Analysis of gut microbiota and assessment of quality of life, and the impact of PERT on clinical 
and nutritional course, gut dysbiosis and patients’ quality of life (at the diagnosis of acute pancreatitis, EPI 
and after PERT). Evaluation of richness, diversity and uniformity of gut microbiota by DNA sequencing 

using the hypervariable region of the 16S rRNA gene. Assessment of quality of life using validated 
Portuguese versions of SF-36 and QLC-C30-V.3 Assess of PERT impact on clinical and nutritional course, 
gut dysbiosis and patients’ quality of life. 
 
Phase 4: Analysis of immunological changes and the impact of PERT on clinical and nutritional course and 
immunological status (at the diagnosis of acute pancreatitis, EPI and after PERT). Evaluation of 
immunological changes through the study of cell populations by flow cytometry (CD4+, CD8+, B-cell, T-
cell, natural killer cells, cells ratio) and cytokines, chemokines and growth factors by xMAP/Luminex. 
Assess PERT impact on clinical and nutritional course and immunological changes. 
 
D.4. Statistical analysis 
Using of Statistical Package for the Social Sciences (SPSS) version 25.0 (IL, USA). The statistical significance 
level will be for a p-value < 0.05. The distribution of data normality will be evaluated by Kolmogorov-
Smirnov or Shapiro-Wilk tests. Continuous variables will be expressed as mean and standard deviation or 
median and interquartile range. Categorical variables will be expressed as frequency and percentage. 
Univariable analysis will be performed using the Kruskal-Wallis test or Anova test (continuous variables) 
and Qui-squared test test (categorical variables). The Wilcoxon or Friedman test and the t-Student or 
Anova test will be used to compare paired data. Cox regression multivariable analysis will be used to 
determine the independent factors associated with exocrine and endocrine pancreatic insufficiencies. 
Analysis of PERT efficacy will be performed per-Protocol (PP), excluding 
loss of follow-up and PERT non-compliance. The temporal evaluation of EPI and PERT response will be 
evaluated through Kaplan-Meier survival curves. The genome sequences will be grouped in OTU according 
to their similarity. The alpha taxonomic richness and diversity of stool samples will be expressed in 
observed species and Shannon index. The composition of fecal microbiota will be expressed in rarefaction 
curves and comparison of the differences in OTU richness with the t-Welch test. Immunological findings 
will be expressed by radar charts and representative FACS dot-plots. Additional statistical analysis will be 
defined a posteriori. 
 
D.5. Ethical aspects 
The project will be subject to the standards of good clinical practice and will at all times comply with the 
ethical precepts in the World Medical Association Helsinki’s Declaration and updates, including the Oviedo 
agreement. This study was approved by Ethical Committee of University of Coimbra (Ref n.º CE-
169/2019). Written informed consent will be obtained from all patients. The confidentiality of the data 
will be respected at all times, by means of the anonymity of the data in the database, in accordance with 
the General Data Protection (UE 2016/679) and updates. 
 
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