Butterbur Extract Shields the Stomach From Painkiller Damage in Rat and Cell Studies

A humble vegetable long served on tables across East Asia may hold an unexpected answer to one of modern medicine’s most common side effects. New research published in the Journal of Agriculture and Food Research reports that an ethanol extract of Petasites japonicus, a plant known in Korea and Japan as a dietary staple and traditional remedy, substantially protected rats from gastric ulcers induced by indomethacin, a non-steroidal anti-inflammatory drug notorious for eroding the stomach lining. The study, led by Byungdoo Hwang and colleagues at Chung-Ang University, combined chemical profiling, experiments in human gastric cell lines, an animal model, and computational docking to build a multi-layered case for the plant’s gastroprotective power.

The clinical problem the researchers targeted is widespread. Non-steroidal anti-inflammatory drugs such as indomethacin relieve pain, fever, and inflammation, but they do so partly by inhibiting cyclooxygenase-1, an enzyme that helps produce the prostaglandins that keep the gastric mucosa healthy. Stripping away that protection leaves the stomach wall exposed to acid and pepsin, and indomethacin additionally ignites inflammatory signaling cascades that kill epithelial cells. Current countermeasures, chiefly proton pump inhibitors like omeprazole, suppress acid secretion by blocking the gastric H+/K+-ATPase, but long-term use of these drugs carries its own concerns, motivating the search for gentler, food-based alternatives.

Petasites japonicus offered an intriguing candidate. The plant has traditionally been used in East Asia for tension headaches and gastrointestinal spasms, and in Europe and North America for migraines, bronchial asthma, and seasonal allergic rhinitis. Its leaves and stems are rich in phenolic acids, including chlorogenic acid and fukinolic acid, along with several dicaffeoylquinic acid derivatives. To capture these compounds efficiently, the team reflux-extracted one kilogram of dried, ground plant material with either water or 50 percent aqueous ethanol at 50 degrees Celsius for five hours. High-performance liquid chromatography then quantified the phenolic content of each preparation.

The solvent choice mattered considerably. The 50 percent ethanol extract contained 42.48 milligrams of fukinolic acid per gram, compared with 25.35 milligrams in the water extract, while chlorogenic acid levels were nearly identical at roughly 13.5 milligrams per gram. Adding in the dicaffeoylquinic derivatives, the ethanol extract delivered a total polyphenol content of 80.21 milligrams per gram against 53.31 for water. On that chemical basis, the researchers selected the ethanol extract for all biological testing, reasoning that its richer phenolic payload would better represent the plant’s active potential.

In the laboratory, the extract proved strikingly protective. When human gastric adenocarcinoma AGS cells and Hs746T gastric carcinoma cells were exposed to 800 micromolar indomethacin for three hours, viability collapsed to 55.4 percent and 69.2 percent of control levels respectively. Pretreatment with the extract for one hour beforehand significantly blunted that damage, lifting viability to 71.9 percent in AGS cells at 50 micrograms per milliliter and 82.4 percent in Hs746T cells at 100 micrograms per milliliter. Crucially, the extract showed no cytotoxicity on its own across the entire 1 to 100 micrograms per milliliter range tested, and the researchers noted that dietary polyphenols naturally reach comparable concentrations in the gastric lumen before absorption.

Molecular analysis revealed three converging mechanisms. First, indomethacin sharply reduced MUC5AC, the predominant mucin glycoprotein that forms the stomach’s protective mucus barrier, dropping it to 0.65-fold in AGS cells and 0.48-fold in Hs746T cells; extract pretreatment restored those levels substantially. Second, the extract suppressed indomethacin-driven upregulation of acid secretion machinery, including the histamine H2 receptor gene HRH2 and subunits of the proton pump, ATP4A and ATP4B, which assemble into the H+/K+-ATPase that pumps acid into the stomach. Third, it dampened inflammation: indomethacin had boosted expression of inducible nitric oxide synthase and cyclooxygenase-2 and triggered phosphorylation of the transcription factor NF-κB and its inhibitor IκB-α, but the extract pulled all of these markers back down in a dose-dependent manner. Upstream, the extract also quieted the MAPK kinases ERK, JNK, and p38, whose indomethacin-induced phosphorylation reached as high as 8.24-fold in AGS cells before treatment brought it down.

The animal experiments translated these cellular findings into whole-body protection. Fifty male Sprague-Dawley rats were divided into control, indomethacin, omeprazole, and two extract-dose groups, with the test substances given orally once daily for seven days before a single 75 milligrams per kilogram dose of indomethacin. After quality-control exclusions, seven rats per group were analyzed. Macroscopic examination showed extensive hemorrhagic lesions in the indomethacin group, but the ulcer index fell to 0.58-fold at 50 milligrams per kilogram of extract and 0.40-fold at 100 milligrams per kilogram. Histological scoring told the same story: severe mucosal erosion, epithelial disruption, submucosal edema, and leukocyte infiltration in the indomethacin group scored 4.0, while extract treatment reduced the score to 1.3 and 0.7 at the two doses, with the lower dose matching omeprazole’s 1.3.

Tissue analyses confirmed the same molecular signature seen in culture. Indomethacin cut gastric MUC5AC protein to 0.58-fold of control, but extract restored it to 0.85-fold and 0.99-fold at the two doses. The drug raised Hrh2 mRNA to 3.28-fold and Atp4b to 1.16-fold; the higher extract dose brought these down to 1.88-fold and 0.85-fold respectively, the latter essentially matching control levels. Inflammatory chemistry followed suit: gastric nitric oxide rose from 3.52 to 5.86 micromolar under indomethacin and TNF-α from 1.39 to 1.98 picograms per milliliter, while extract treatment reduced both, and phosphorylated NF-κB, IκB-α, ERK, JNK, and p38 all declined dose-dependently in tissue lysates.

To probe how the plant’s signature compounds might act directly on drug targets, the team docked chlorogenic acid and fukinolic acid against the H+/K+-ATPase, the histamine H2 receptor, cyclooxygenase-2, and the TNF-α trimer, using omeprazole, cimetidine, and aspirin as reference ligands. The phenolic acids bound the proton pump through the residue Cys813 and the H2 receptor through Asp98, and their strongest predicted affinities came at cyclooxygenase-2, where chlorogenic acid scored −9.3 and fukinolic acid −9.0 kilocalories per mole, comfortably outperforming aspirin’s −6.7. Both compounds also showed moderate binding at the TNF-α trimer interface. The authors caution that docking is predictive and that the whole extract, not isolated compounds, produced the observed effects, with future work needed to isolate individual contributions.

The dose translation is perhaps the most striking practical detail. Applying US Food and Drug Administration body-surface-area conversion, the highest rat dose of 100 milligrams per kilogram corresponds to a human equivalent dose of 16.22 milligrams per kilogram, roughly 973 milligrams daily for a 60-kilogram adult. Based on the extraction yield, that amount equates to eating approximately 6.5 grams of fresh Petasites japonicus leaves and stems, an entirely ordinary dietary quantity. The authors acknowledge limitations, including the cancer-derived nature of the cell lines and the absence of direct measurements of gastric juice volume, pH, and acidity, and they call for follow-up studies using primary cells, gastric organoids, or pylorus-ligated models. Even so, the convergence of preserved mucus barriers, dampened acid-pump genes, and suppressed NF-κB and MAPK signaling across cells, rats, and simulations makes a compelling case that this everyday vegetable deserves attention as a functional food ingredient for protecting the stomach against painkiller injury.

Subject of Research: Gastroprotective effects of Petasites japonicus ethanol extract against NSAID-induced gastric ulcer

Article Title: Gastroprotective effects of a dietary Petasites japonicus ethanol extract against indomethacin-induced gastric injury via regulation of mucosal defense, acid secretion-related targets, and inflammation

Article References: Hwang, B., Hwang, S.-K., Kim, J.-Y., Song, J.-H., Son, Y.-J., Kim, H., Jung, W., Lee, J. J., Cho, S.-C., Chung, H., & Moon, S.-K. (2026). Gastroprotective effects of a dietary Petasites japonicus ethanol extract against indomethacin-induced gastric injury via regulation of mucosal defense, acid secretion-related targets, and inflammation. Journal of Agriculture and Food Research, 31, Article 103325. https://doi.org/10.1016/j.jafr.2026.103325

Image Credits: AI Generated

DOI: 10.1016/j.jafr.2026.103325

Keywords: Petasites japonicus, gastric ulcer, indomethacin, NSAIDs, MUC5AC, NF-κB, MAPK, proton pump, chlorogenic acid, fukinolic acid, functional food, gastroprotection