Engineered probiotic-mediated palmitoylethanolamide biosynthesis protects against colitis-associated liver injury
- 1Neuropharmacology and Behavioral Science Laboratory, Santa Lucia Foundation (IRCCS Fondazione Santa Lucia)
- 2Department of Physiology and Pharmacology “V. Erspamer”, Sapienza University of Rome
- 3Department of Clinical Medicine and Surgery, ‘Federico II’ University of Naples
Abstract
Chronic colitis promotes secondary liver injury through disruption of the gut–liver axis, whereby intestinal barrier breakdown enables portal translocation of microbial products that activate hepatic inflammatory and fibrogenic pathways. Palmitoylethanolamide (PEA), an endogenous ALIAmide acting primarily via PPAR-α, exerts anti-inflammatory and barrier-protective effects, but its clinical use is limited by poor oral bioavailability. We investigated whether mucosa-targeted, probiotic-mediated, in situ PEA biosynthesis could attenuate liver injury associated with chronic colitis. Male C57BL/6J mice were subjected to chronic dextran sulfate sodium (DSS) colitis and treated with an engineered Lactobacillus paracasei F19 strain expressing human NAPE-PLD (pNAPE-LP) plus ultra-low-dose palmitate, a control strain (pLP), or pNAPE-LP combined with the PPAR-α antagonist MK886. pNAPE-LP significantly increased colonic PEA levels and elevated circulating and hepatic PEA, confirming effective local production with systemic distribution. Treatment ameliorated colitis severity, restored tight-junction protein expression, and reduced endotoxemia. Importantly, pNAPE-LP attenuated colitis-associated liver injury by decreasing histological damage and collagen deposition, lowering transaminase levels, and reducing hepatic neutrophil infiltration. These effects were accompanied by the suppression of the hepatic TLR4/NF-κB/NLRP3 inflammasome axis, reduced caspase-1 activation, decreased IL-1β, TNF-α, and IL-6 levels, restored PPAR-α expression, and reduced Bax expression. The control strain was ineffective, and PPAR-α inhibition abolished both intestinal and hepatic protection. Collectively, these findings demonstrate that engineered probiotics acting as “living drug factories” can target the gut–liver axis via localized PEA biosynthesis, restoring barrier integrity and limiting hepatic inflammatory and fibrogenic signaling in chronic colitis.
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BibTeX
@article{palenca2026engineered,
title = {{Engineered probiotic-mediated palmitoylethanolamide biosynthesis protects against colitis-associated liver injury}},
author = {Irene Palenca and Silvia Basili Franzin and Giovanni Sarnelli and Giuseppe Esposito},
journal = {Frontiers in Pharmacology},
year = {2026},
month = oct,
doi = {10.3389/fphar.2026.1925341},
url = {https://www.frontiersin.org/articles/10.3389/fphar.2026.1925341/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Engineered probiotic-mediated palmitoylethanolamide biosynthesis protects against colitis-associated liver injury
AU - Irene Palenca
AU - Silvia Basili Franzin
AU - Giovanni Sarnelli
AU - Giuseppe Esposito
PY - 2026
DA - 2026/10/15
JO - Frontiers in Pharmacology
DO - 10.3389/fphar.2026.1925341
UR - https://www.frontiersin.org/articles/10.3389/fphar.2026.1925341/full
AB - Chronic colitis promotes secondary liver injury through disruption of the gut–liver axis, whereby intestinal barrier breakdown enables portal translocation of microbial products that activate hepatic inflammatory and fibrogenic pathways. Palmitoylethanolamide (PEA), an endogenous ALIAmide acting primarily via PPAR-α, exerts anti-inflammatory and barrier-protective effects, but its clinical use is limited by poor oral bioavailability. We investigated whether mucosa-targeted, probiotic-mediated, in situ PEA biosynthesis could attenuate liver injury associated with chronic colitis. Male C57BL/6J mice were subjected to chronic dextran sulfate sodium (DSS) colitis and treated with an engineered Lactobacillus paracasei F19 strain expressing human NAPE-PLD (pNAPE-LP) plus ultra-low-dose palmitate, a control strain (pLP), or pNAPE-LP combined with the PPAR-α antagonist MK886. pNAPE-LP significantly increased colonic PEA levels and elevated circulating and hepatic PEA, confirming effective local production with systemic distribution. Treatment ameliorated colitis severity, restored tight-junction protein expression, and reduced endotoxemia. Importantly, pNAPE-LP attenuated colitis-associated liver injury by decreasing histological damage and collagen deposition, lowering transaminase levels, and reducing hepatic neutrophil infiltration. These effects were accompanied by the suppression of the hepatic TLR4/NF-κB/NLRP3 inflammasome axis, reduced caspase-1 activation, decreased IL-1β, TNF-α, and IL-6 levels, restored PPAR-α expression, and reduced Bax expression. The control strain was ineffective, and PPAR-α inhibition abolished both intestinal and hepatic protection. Collectively, these findings demonstrate that engineered probiotics acting as “living drug factories” can target the gut–liver axis via localized PEA biosynthesis, restoring barrier integrity and limiting hepatic inflammatory and fibrogenic signaling in chronic colitis.
SN - 1663-9812
ER -