Common drugs, sweeteners and pesticides can act as antibiotics on gut bacteria

For more than a century, the term antibiotic has carried a narrow meaning: a drug designed to kill bacteria, deployed by clinicians to treat infection. A new review argues that this definition has become untenable. Writing in Nature Reviews Gastroenterology & Hepatology, Jacobo de la Cuesta-Zuluaga, Kiran R. Patil and Lisa Maier synthesize a decade of evidence showing that a startlingly broad range of compounds never intended as antimicrobial agents, including common prescription medicines, dietary substances, food additives, artificial sweeteners, pesticides and industrial chemicals, exhibit genuine antibacterial activity. The authors refer to these as non-antibiotic antimicrobials, and their accumulating impact on the human gut microbiome is, they contend, one of the most underappreciated forces shaping human health.

The empirical foundation for this view was laid by large-scale laboratory screens, most notably a 2018 study in which the team around Lisa Maier and Kiran Patil tested roughly 1,000 marketed drugs against representative strains of human gut bacteria and found that about a quarter inhibited at least one commensal microbe. Subsequent work extended the map beyond pharmaceuticals. Recent screens have shown that industrial and agricultural chemicals also suppress gut bacteria in vitro, and that some per- and polyfluoroalkyl substances, the persistent so-called forever chemicals, are actively bioaccumulated by human gut microbes. Even dietary xenobiotics, transformed by resident bacteria, can restructure microbial communities. The boundary between the pharmacy, the food supply and the chemical environment, the review makes clear, is biologically porous.

What distinguishes non-antibiotic antimicrobials from true antibiotics is not the fact of antibacterial activity but its spectrum and potency. Unlike antibiotics, which are typically active at low concentrations and target a broad range of organisms, non-antibiotic antimicrobials tend to act at higher doses and against a narrower set of microbes. Paradoxically, that narrow set often excludes the Enterobacteriaceae, the family containing many classic pathogens for which new antibiotics are urgently needed, while hitting beneficial commensals harder. This inverted selectivity means that everyday exposure to these compounds can quietly erode the protective, health-associated fraction of the microbiome while leaving opportunistic pathogens relatively unscathed, creating ecological vacancies that resistant or disease-associated organisms can exploit.

The molecular mechanisms underlying these effects are only beginning to be resolved, but several recurring strategies have emerged. Some non-antibiotics share drug targets with classical antibiotics or, more intriguingly, bind bacterial counterparts of the human proteins they were designed to hit. Others mimic essential metabolites, poisoning microbial enzymes through molecular masquerade, or hijack bacterial transport systems to gain entry into cells. Individual examples are illuminating: the artificial sweetener saccharin has been shown to disrupt bacterial cell envelope stability and interfere with DNA replication dynamics; nonsteroidal anti-inflammatory drugs target DNA replication; the antidiabetic drug acarbose impairs gut Bacteroides growth by inhibiting intracellular glucosidases; and the Parkinson’s drug entacapone disrupts gut microbial homeostasis through iron sequestration. Yet for the majority of non-antibiotic antimicrobials, the microbial targets remain unknown, a knowledge gap the authors identify as a central obstacle to rational risk assessment.

Crucially, the antimicrobial activity of these compounds cannot be understood in isolation from the host. Microbiome composition varies enormously between individuals, and a drug that devastates one person’s community may barely perturb another’s. Host conditions further modulate outcomes: intestinal pH, bile salt exposure, nutrient availability, body temperature and the community’s biogeography all alter both drug activity and microbial susceptibility. Proton-pump inhibitors, for example, appear to increase the risk of Clostridioides difficile infection primarily by altering gut pH rather than through direct effects on the microbiome, a reminder that host-conditioned mechanisms can masquerade as microbiome effects. Conversely, some drugs act on the host in ways that reshape the gut environment, as with corticosteroids that impair mucin production, or statins whose microbiome-linked effects on metabolic health are still being mapped.

The clinical consequences of these interactions are now measurable in populations. Population-level metagenomic studies have shown that medications leave distinct, reproducible signatures on the gut microbiome, and that drugs taken years before sampling can still act as hidden confounders in microbiome research. One 2025 study reported that non-antibiotics disrupt colonization resistance against enteropathogens, and a companion analysis identified medication-microbiome interactions that affect gut infection outcomes. At the same time, the microbiome can alter drug efficacy in both directions: gut bacterial tyrosine decarboxylases deplete levodopa in Parkinson’s disease, microbial metabolism of the anti-inflammatory mesalazine diminishes its benefit in inflammatory bowel disease, and microbiome-derived metabolites such as inosine and 3-indole-3-acetic acid modulate responses to cancer immunotherapy and chemotherapy. Drug, microbe and host form a three-body problem, the review argues, that medicine has traditionally treated as a two-body one.

Perhaps the most alarming dimension is the contribution of non-antibiotic antimicrobials to the spread of antibiotic resistance. Laboratory and animal studies have shown that antidepressants, antipsychotics, antiepileptic drugs and artificial sweeteners can all promote the horizontal transfer of antibiotic resistance genes, accelerate plasmid conjugation, induce mutagenesis or select for efflux-based resistance in Escherichia coli. Because these compounds are consumed chronically by billions of people and persist in the environment, they may exert a continuous, diffuse selection pressure that quietly amplifies the resistome in human guts and beyond, independent of any antibiotic prescription. The review frames this as a planetary-scale problem, noting that microbiomes across human, animal and environmental habitats are connected by gene flow, so resistance selected anywhere can eventually matter everywhere.

Dietary chemicals occupy a particularly contested middle ground in this landscape. Emulsifiers such as carboxymethylcellulose have been shown in controlled-feeding studies to damage the human gut microbiota and metabolome, while artificial sweeteners have been reported to induce glucose intolerance in mice and personalized, microbiome-dependent glucose responses in humans, though some trials of saccharin and sucralose in healthy adults have found no detectable microbiome effects at all. Pesticide exposure has been associated with altered gut microbiota and metabolites in observational studies of both the general population and occupationally exposed workers. This inconsistency, the authors suggest, reflects the context-dependence that pervades the entire field: identical exposures can yield different outcomes depending on a person’s baseline microbiome, diet, host physiology and co-exposures to other xenobiotics.

The translational implications are substantial. The authors call for integrated stewardship of all xenobiotics, not just antibiotics, across medicine, agriculture, industry and the environment. Practically, that means incorporating microbiome effects into drug development and safety testing, using new high-throughput anaerobic screening methods and defined microbial community models to identify antimicrobial activity before compounds reach patients, deploying chemical-genetic and proteomic tools to pin down microbial targets, and developing computational models of xenobiotic metabolism that can predict how individual microbiomes will respond to given drugs. For clinicians, the immediate lesson is more modest but no less important: non-antibiotic prescriptions are microbiome interventions, and polypharmacy should be recognized as a combinatorial, dose-dependent perturbation of the gut ecosystem.

What the review ultimately delivers is a reframing. Antimicrobial activity, once considered the defining property of a specialized class of drugs, is revealed to be a generic hazard of the chemical world that modern humans inhabit, arising because human and bacterial biochemistry share enough common machinery that molecules designed for one can wound the other. The benefits of these compounds, in treating psychiatric illness, diabetes, cancer and countless other conditions, are real and immense, and the authors are careful not to argue that non-antibiotic antimicrobials should be abandoned. The task, they conclude, is to move from unwitting to deliberate management: to know which compounds disturb the microbiome, through which mechanisms, in whom, and with what downstream consequences for infection risk, chronic disease and resistance, so that the hidden chemistry between our drugs, our food, our environment and our microbes can finally be conducted with open eyes.

Subject of Research: Antimicrobial effects of non-antibiotic compounds on the human gut microbiome and host health

Article Title: Drug–microbiome–host interactions: antimicrobial effects of non-antibiotic compounds

Article References: de la Cuesta-Zuluaga, J., Patil, K. R., & Maier, L. (2026). Drug–microbiome–host interactions: antimicrobial effects of non-antibiotic compounds. Nature Reviews Gastroenterology & Hepatology. https://doi.org/10.1038/s41575-026-01258-w

Image Credits: AI Generated

DOI: 10.1038/s41575-026-01258-w

Keywords: gut microbiome, non-antibiotic drugs, antimicrobial resistance, microbiome–drug interactions, artificial sweeteners, pesticides, colonization resistance, pharmacomicrobiomics, xenobiotics, dysbiosis, horizontal gene transfer, drug metabolism