A gut bacterium may restore the intestinal drug barrier that weakens with age

Why it matters: Older adults have more adverse drug reactions, often blamed on declining liver and kidney function. The intestinal efflux transporter P-glycoprotein (P-gp, encoded by ABCB1) is another, potentially modifiable contributor. It sits on the surface of gut lining cells and pumps drugs back into the gut, limiting absorption. Weaker P-gp raises systemic exposure to substrate drugs such as direct oral anticoagulants and digoxin. The cause of this age-related decline has been unclear.

What was studied: The team combined clinical pharmacology, human single-cell data and mouse experiments. They pooled pharmacokinetic studies of P-gp substrate drugs and used population PK and physiologically based PK modeling of dabigatran, a P-gp probe drug. They also pooled randomized trials of anticoagulants and analyzed published single-cell transcriptomes of human intestinal epithelium across age groups. In C57BL/6 mice, they compared young (3 months) and old (22–26 months) animals, measuring P-gp by western blot, mRNA and immunohistochemistry in the jejunum and ileum. They also exposed Caco-2 cells to fecal water from young, middle-aged and old mice and from young versus elderly humans. The abstract states that integrated multi-omics and antibiotic-pretreated mouse models were then used to find the responsible microbes and metabolites.

Key results: Pooled data showed roughly 2-fold higher drug exposure and about 150% greater inter-individual variability in older adults. Dabigatran modeling indicated lower intestinal P-gp activity in patients 75 and older than in those aged 60–74, independent of demographics, cardiac output and renal function. Simulations suggested that impaired jejunal and ileal P-gp alone could double exposure. In pooled anticoagulant trials, patients 75 and older had more major bleeding, and co-administered P-gp inhibitors added further risk. Single-cell data showed ABCB1 expression falling with age. Old mice had significantly lower P-gp protein and mRNA in both jejunum and ileum, and less membrane-localized P-gp by immunohistochemistry. Per the abstract, Odoribacter splanchnicus is depleted with age. It encodes GDP-mannose 4,6-dehydratase (GMDS) and GDP-L-fucose synthase (TSTA3) and so can make GDP-L-fucose. This metabolite promotes eIF4E phosphorylation and activates c-Jun-driven ABCB1 expression, restoring xenobiotic efflux.

Implications: The findings outline a microbiota-metabolite-transporter axis that maintains intestinal detoxification. Supplementing the bacterium or its metabolite could, in principle, help prevent drug toxicity in older adults.

Caveats: The mechanistic evidence is from mice and cell models, with human data largely correlative and pharmacometric. The text available for this review ended partway through the results, so details of the fecal-water, metabolomic and rescue experiments are taken from the abstract. Whether raising GDP-L-fucose or O. splanchnicus changes drug exposure or safety in people is untested.