PH-taxis drives aerobic bacteria in duodenum to migrate into the pancreas with tumors

Hiroaki Shirai,Kosuke Tsukada,Cocoro Ito

doi:10.1038/s41598-022-05554-8

Abstract

As oral or intestinal bacteria have been found in pancreatic cystic fluid and tumors, understanding bacterial migration from the duodenum into the pancreas via hepato-pancreatic duct is critical. Mathematical models of migration of aerobic bacteria from the duodenum to the pancreas with tumors were developed. Additionally, the bacterial distributions under the pH gradient and those under flow were measured in double-layer flow based microfluidic device and T-shaped cylinders. Migration of aerobic bacteria from the duodenum into pancreas is counteracted by bile and pancreatic juice flow but facilitated by pH-taxis from acidic duodenum fluid toward more favorable slightly alkaline pH in pancreatic juice. Additionally, the reduced flow velocity in cancer patients, due to compressed pancreatic duct by solid tumor, facilitates migration. Moreover, measured distribution of GFP E. coli under the pH gradient in a microfluidic device validated pH-tactic behaviors. Furthermore, Pseudomonas fluorescens in hydrochloride solution, but not in bicarbonate solution, migrated upstream against bicarbonate flow of > 20 μm/s, with an advancement at approximately 50 μm/s.

Highlights

As oral or intestinal bacteria have been found in pancreatic cystic fluid and tumors, understanding bacterial migration from the duodenum into the pancreas via hepato-pancreatic duct is critical
Human pancreatic ductal adenocarcinomas (PDACs) contain aerobic bacteria at higher levels than healthy pancreases[9,10,11,12,13,14] (Table S1), which commonly favor neutral pH, such as Pseudomonas putida[15], Citrobacter freundii[16], Klebsialla pneumoniae[17], and Streptococcus[18]. These bacteria in tumors contribute to cancer treatment[10,11,12,13,14]; for example, Gammaproteobacteria found in pancreatic cancer induced resistance to the widely used chemotherapeutic drug gemcitabine by converting it into inactive form with their enzymes[10]
A solid tumor occurring at the pancreatic duct (PDAC) both reduces the function of pancreatic juice secretions and compresses the pancreatic duct and reduces pancreatic juice flow rates[29,30,31]

Summary

Introduction

As oral or intestinal bacteria have been found in pancreatic cystic fluid and tumors, understanding bacterial migration from the duodenum into the pancreas via hepato-pancreatic duct is critical. Mathematical models of migration of aerobic bacteria from the duodenum to the pancreas with tumors were developed. The reduced flow velocity in cancer patients, due to compressed pancreatic duct by solid tumor, facilitates migration. Human pancreatic ductal adenocarcinomas (PDACs) contain aerobic bacteria at higher levels than healthy pancreases[9,10,11,12,13,14] (Table S1), which commonly favor neutral pH, such as Pseudomonas putida[15], Citrobacter freundii[16], Klebsialla pneumoniae[17], and Streptococcus[18]. Bacterial random motility alone cannot win the fluid flow even at the velocity of cancer patients in literature[29,30,31]

Objectives

Methods

Results

Discussion

Conclusion