*Purpose: Chronic pancreatitis (CP) is characterized by exocrine insufficiency and severe abdominal pain. Total pancreatectomy with islet autotransplantation (TPIAT) relieves chronic pain and aids restoration of endocrine function. In patients with refractory CP and long-standing disease, endocrine dysfunction results in diabetes. Identification of 1) extent of inflammation/fibrosis and 2) islet stress before onset of endocrine dysfunction is paramount to improving metabolic outcomes after islet autotransplantation. MicroRNAs (miRNAs), short non-coding RNAs, are released by cells under various conditions into circulation, that can be used as biomarkers. In this study, we investigated circulating miRNA signatures in CP patients undergoing TPIAT.

*Methods: We extracted small RNA from plasma collected at admission of patients (n = 14) for TPIAT and healthy donors (n=3), constructed cDNA libraries and performed small RNA sequencing.

*Results: Our analyses revealed differential expression of miRNAs in patients, with 38 miRNAs (fold change, FC>1.5) elevated and 3 miRNAs (FC<0.6) reduced significantly. Of these, miRNAs with higher baseMean (>1000) were hsa-miR-148a-3p, hsa-miR-99b-5p, hsa-miR-221-3p, hsa-miR-122-5p, hsa-let-7e-5p and hsa-miR-1301-3p. Elevated hsa-miR-148a-3p, together with hsa-miR-375, is useful in detecting islet damage. In our cohort, hsa-miR-375 was downregulated significantly, thus indicating distinct profiles for these miRNAs. hsa-miR-221-3p was also elevated in another cohort of early stage CP patients, confirming our observations. Interestingly, elevated levels of hsa-miR-122-5p (liver specific miRNA), also elevated in other diseases, may indicate alterations in liver function. Elevated levels of hsa-miR-148a-3p, hsa-miR-99b-5p, hsa-miR-221-3p and hsa-miR-122-5p have been observed in obesity, prediabetes and type 2 diabetes. Of the miRNAs with p>0.05, hsa-miR-216b-5p, a pancreas enriched miRNA and a marker for acinar cell damage, was elevated in patients (FC=8.4, baseMean=1.62, p=0.07).

*Conclusions: Our observations reveal distinct circulating miRNA signatures in CP patients. Further investigations using larger sample sizes are necessary to identify CP specific miRNA signatures that can be used to monitor disease progression and endocrine function following TPIAT.

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