Biomolecules · 7 authors, 1 centre
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PLGA-encapsulated OH-CATH30 antimicrobial peptide microspheres effectively treated E. coli-induced enteritis in mice, reducing inflammation and restoring gut microbiota balance. The microspheres demonstrated comparable efficacy to gentamicin sulfate while avoiding antibiotic-associated dysbiosis. This oral delivery system overcomes the stability limitations of free antimicrobial peptides, offering a promising alternative for treating intestinal infections.
**Background:** Escherichia coli overgrowth can disrupt gut microbiota balance and cause enteritis, with antibiotic resistance limiting treatment options. Antimicrobial peptides (AMPs) like OH-CATH30 from king cobra venom show broad-spectrum activity but are unstable in the gastrointestinal tract. Poly(lactic-co-glycolic acid) (PLGA) microspheres can protect AMPs and enable sustained release. This study evaluated PLGA-OH-CATH30 microspheres for oral treatment of E. coli-induced enteritis in mice.
**Methods:** Sixty 8-week-old male Kunming mice were used. Fifty mice received two oral gavages of E. coli ATCC25922 (1×10^8 CFU/mL, 0.2 mL each) 6 hours apart to induce enteritis; 10 mice received normal saline as healthy controls. Twelve hours after the last gavage, 40 infected mice were randomly divided into four groups (n=10 each): model group (MG, no treatment), gentamicin sulfate group (GS, 0.2 mg/day), free OH-CATH30 group (OC, 0.2 mg/day), and PLGA-OH-CATH30 microsphere group (POC, 1.1 mg/day containing 0.2 mg peptide). Treatments were given orally for 5 consecutive days. Body weight was recorded daily. After treatment, blood was collected for complete blood count, serum biochemistry (ALT, ALP, TBIL, BUN, CREA), and cytokine measurement (IL-10, IL-6, TNF-α, IL-1β by ELISA). Spleen index was calculated. Fecal E. coli counts were determined by culture on MacConkey agar. Histopathology of jejunum, cecum, and colon was assessed by H&E staining. Gut microbiota was analyzed by 16S rRNA gene sequencing (V3-V4 region) on the Illumina NovaSeq 6000 platform.
**Key Results:** Six of 50 infected mice died; surviving mice showed diarrhea, lethargy, and fur loss. Body weight decreased in all infected groups during days 1-2 (p<0.01 vs. control), then increased from day 3 onward. POC and GS groups showed more pronounced weight gain than OC and MG groups, approaching control levels by day 5. Spleen index was significantly elevated in MG and OC groups vs. control, but not in POC and GS groups. Fecal E. coli counts were markedly reduced in POC and GS groups compared to MG and OC groups. Blood leukocyte count and neutrophil percentage were elevated in MG and OC groups but normalized in POC and GS groups. Liver (ALP, TBIL) and kidney (CREA, BUN) function markers were altered in MG vs. control but remained normal in POC and GS groups. Serum IL-10 was significantly reduced in MG and OC groups vs. control, while IL-6, TNF-α, and IL-1β were increased; POC and GS treatments normalized these cytokines. Histopathology showed severe mucosal damage, inflammatory cell infiltration, and villous disruption in MG group, with marked improvement in POC and GS groups, but not in OC group. 16S rRNA sequencing revealed that POC and GS groups had reduced alpha diversity (Chao, Ace, Shannon, Simpson indices) compared to control. PCoA showed significant separation among groups (p<0.005). At phylum level, MG and OC groups had decreased Firmicutes and Bacteroidetes and increased Proteobacteria; POC treatment increased Bacteroidetes and decreased Proteobacteria. GS group showed a marked decline in Firmicutes and increase in Bacteroidota. At genus level, MG had elevated Escherichia-Shigella and Parasutterella; POC treatment reduced these and increased Blautia and Lactobacillus. LEfSe analysis identified Gammaproteobacteria and Burkholderiales as enriched in MG, while Phocaeicola vulgatus and Bacteroides caecimuris were enriched in POC group.
**Clinical Implications:** PLGA-OH-CATH30 microspheres effectively treat E. coli-induced enteritis in mice, reducing inflammation, preserving intestinal barrier integrity, and restoring gut microbiota balance. The microspheres show comparable efficacy to gentamicin sulfate without causing antibiotic-associated dysbiosis. This oral delivery system overcomes the stability limitations of free antimicrobial peptides, offering a promising alternative for treating intestinal infections, particularly those caused by antibiotic-resistant strains. The findings support further development of PLGA-encapsulated AMPs for veterinary and potentially human clinical applications in inflammatory bowel diseases.