Oliceridine and morphine differentially modulate the gut microbiota-intestinal barrier axis in a rat postoperative...

Oliceridine is a novel G protein-biased μ-opioid receptor agonist with potentially improved gastrointestinal tolerability compared with conventional opioids. However, its impact on postoperative intestinal homeostasis-specifically the gut microbiota and intestinal barrier-remains poorly understood.

A postoperative pain model was established in male Sprague-Dawley rats using the Brennan plantar incision method. Animals were randomly assigned to four groups: non-incision control (CON), plantar incision plus normal saline, plantar incision plus oliceridine (OLI, 1 mg/kg subcutaneous bolus followed by continuous infusion at 1 mg/kg/day for 72 h), and plantar incision plus morphine (MF, 5 mg/kg subcutaneous bolus followed by continuous infusion at 5 mg/kg/day for 72 h). Analgesic efficacy was assessed by mechanical withdrawal threshold (MWT) and area under the curve (AUC). Intestinal morphology, epithelial Claudin-1 expression by immunofluorescence (n = 4 per group), gut microbiota composition (16S rRNA gene sequencing, n = 6 per group), and host ileal transcriptomic profiles (RNA-seq, n = 3 per group) were evaluated.

Oliceridine and morphine produced comparable analgesia, as reflected by MWT AUC (P < 0.0001 vs. NS; OLI vs. MF: P = 0.8770). Both opioids alleviated postoperative mechanical hypersensitivity. Compared with NS, opioid treatment increased the relative abundance of Limosilactobacillus and Lactobacillus and decreased Streptococcus. Exploratory microbiome analysis identified a potential Lactobacillus-related signal, but no genus-level difference between the OLI and MF groups remained significant after multiple-testing correction. Transcriptomic analysis revealed distinct ileal gene-expression profiles between the OLI and MF groups. Relative to MF, OLI was associated with higher expression of genes related to epithelial barrier integrity and brush border function and lower expression of genes involved in immune-related pathways. Histologically, both opioids attenuated intestinal injury compared with NS, with no significant difference between OLI and MF. In contrast, relative Claudin-1 fluorescence intensity was significantly higher in the OLI group than in the MF group (P = 0.036), providing protein-level support for the barrier-related transcriptomic findings. Integrated correlation analysis identified associations between Lactobacillus-related taxa and host genes linked to barrier function and metabolism (|r| > 0.6, P < 0.01).

Oliceridine and morphine produced comparable analgesia. Exploratory microbiome analysis identified a potential Lactobacillus-related signal, but no genus-level differences remained significant after multiple-testing correction. Oliceridine was associated with a distinct ileal transcriptomic profile and higher Claudin-1 fluorescence intensity than morphine, although histological injury did not differ between the two groups. The functional significance of these molecular differences requires further investigation.