Pharmacomicrobiomics of GLP-1 receptor agonist gastrointestinal tolerability: integrating host genetics and the gut microbiome

Gastrointestinal (GI) adverse events, such as nausea, vomiting, diarrhea, and constipation, remain a dominant barrier to the sustained use of GLP-1 receptor agonists (GLP-1 RAs), driving discontinuation independently of the drug’s metabolic benefits. Two host-side biological systems have been independently established as determinants of this variability. The first is host genetics, anchored by a 2026 genome-wide association study in which GLP1R variants predicted both weight-loss efficacy and nausea or vomiting risk, while a GIPR signal for vomiting was restricted to tirzepatide users. The second system is the gut microbiome, which regulates endogenous GLP-1 secretion through short-chain fatty acid and bile acid signaling and is itself reshaped by GLP-1 RA exposure. Pharmacomicrobiomics integrates host genetic and microbiome data to explain drug response. In the literature surveyed for this review, these two determinants are consistently examined in parallel rather than jointly: we did not identify a study, in GLP-1 RA therapy or in another drug class, that fit a ‘host-genotype-by-microbiome’ interaction model against a drug tolerability outcome. Published methodological studies have suggested why such a study would be challenging: both interaction detection and the measurement unreliability associated with single-timepoint microbiome profiling impose substantial sample size penalties. This review summarizes what host genetics and the microbiome individually do and do not explain about GLP-1 RA tolerability, and describes the study design features, paired genotyping, repeat-sample metagenomics, and prospective symptom capture that a future joint analysis would require.