Prescription opioids induced microbial dysbiosis worsens severity of chronic pancreatitis and drives pain hypersensitivity

ABSTRACT

Opioids, such as morphine and oxycodone, are widely used for pain management associated with chronic pancreatitis (CP); however, their impact on the progression and pain sensitivity of CP has never been evaluated. This report investigates the impact of opioid use on the severity of CP, pain sensitivity, and the gut microbiome. C57BL/6 mice were divided into control, CP, CP with morphine/oxycodone, and either morphine or oxycodone alone groups. CP was induced by administration of caerulein (50ug/kg/h, i.p. hourly x7, twice a week for 10 weeks). The mouse-to-pancreas weight ratio, histology, and Sirius red staining were performed to measure CP severity. Tail flick and paw pressure assays were used to measure thermal and mechanical pain. DNA was extracted from the fecal samples and subjected to whole-genome shotgun sequencing. Germ-free mice were used to validate the role of gut microbiome in sensitizing acute pancreatic inflammation. Opioid treatment exacerbates CP by increasing pancreatic necrosis, fibrosis, and immune-cell infiltration. Opioid-treated CP mice exhibited enhanced pain hypersensitivity and showed distinct clustering of the gut microbiome compared to untreated CP mice, with severely compromised gut barrier integrity. Fecal microbiota transplantation (FMT) from opioid-treated CP mice into germ-free mice resulted in pancreatic inflammation in response to a suboptimal caerulein dose. Together, these analyses revealed that opioids worsen the severity of CP and induce significant alterations in pain sensitivity and the gut microbiome in a caerulein CP mouse model. Microbial dysbiosis plays an important role in sensitizing the host to pancreatic inflammation.

KEYWORDS:

• Chronic pancreatitis
• gastrointestinal microbiome
• opioid
• morphine
• oxycodone
• pain

Acknowledgments

We would like to thank April Mann (University of Miami) for reviewing the manuscript.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Author contributions

K.K., J.T., R.D., and S.R. designed the research studies; K.K., J.T., N.G., R.J., and S.S. conducted experiments and acquired data; K.K. and J.T. analyzed the data; K.K., J.T., R.D., and S.R. wrote and reviewed the manuscript.

Data availability statement

Sequence data were deposited in the Biostudies database (https://www.ebi.ac.uk/biostudies/) under accession number S-BSST1080 (https://www.ebi.ac.uk/biostudies/studies/S-BSST1080).

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/19490976.2024.2310291

Additional information

Funding

The work was supported by the National Institute of Diabetes and Digestive and Kidney Diseases [5R01DK117576].