Antimicrobial Resistance · Gut MicrobiomeIs the Gut a Hidden Engine of Antimicrobial Resistance?

Antibiotics have lost their status as a guaranteed cure, and treatment failure is now a routine clinical experience. Misuse of antimicrobials in human medicine and animal husbandry, in both high- and low-income settings, has allowed multidrug-resistant (MDR) bacteria to spread to the point where antimicrobial resistance (AMR) is now described as a pandemic.¹

Perhaps one of the most concerning aspects of this crisis is how poorly it is understood by the public. In one Indian survey cited in the review, 45% of respondents used antibiotics to treat colds and 49% believed antibiotics could cure viral illnesses.^1,2

Dongre and colleagues position the gut microbiota as a central component of the resistome. Beyond its dominant Firmicutes and Bacteroidetes, the commensal community harbours low-abundance Enterobacteriaceae and Enterococcaceae, the lineages responsible for much nosocomial infection. Pathobionts such as Enterococcus faecium, Escherichia coli and Clostridioides difficile persist as asymptomatic colonisers, while MDR strains acquired through healthcare contact, food, water or animals may remain below detection thresholds until antibiotic selection pressure, host factors or metabolic shifts allow them to dominate. In this framing, the gut is both a reservoir of resistant organisms and a site where resistance is exchanged.¹

To understand this reservoir, the authors focus on three questions: how the gut microbiota acquires and spreads resistance genes, which exposures shape that reservoir, and which microbiome-directed strategies might prevent or reverse resistant colonisation.¹

While resistance can arise through chromosomal mutation and vertical inheritance, the review concentrates on horizontal gene transfer (HGT) of mobile genetic elements carrying antibiotic-resistance genes (ARGs). The gut offers near-optimal conditions for HGT: continuous nutrient flow, a stable temperature, biofilm formation, high species diversity and a bacterial density that rises from around 10¹ per gram of contents in the distal oesophagus to around 10¹² per gram in the colon.¹

Commensals themselves can carry clinically important genes. Faecalibacterium prausnitzii and Prevotella copri isolated from healthy adults were resistant to ceftriaxone and cefotaxime, with many of their ARGs sitting next to integrases or on plasmids, and vancomycin-resistance (vanB) transposons have been found in the commensals Eggerthella lenta and Clostridium innocuum.⁴ Efflux pump genes, including multi-antimicrobial extrusion (MATE) and macrolide-specific (Mac) pumps, are widespread in commensal genomes and contribute to their resistance.¹

Dysbiosis also alters the metabolic environment. Antibiotic-induced loss of short-chain fatty acid production raises luminal pH and favours Gram-negative colonisation, and a post-antibiotic rise in sialic acid supports the expansion of enterohaemorrhagic E. coli, Salmonella Typhimurium and C. difficile. In healthy Taiwanese adults, gut microbiota composition differed between carriers of third-generation cephalosporin-resistant Enterobacteriaceae and non-carriers, although overall diversity did not.^1,5

The review considers a broad range of exposures that shape the gut microbiota and its resistance genes. Antimicrobial use remains the dominant driver: consumption tracks ARG abundance and diversity across populations and continents, and over-the-counter access compounds misuse. Beyond reducing diversity, with highly variable recovery, antibiotic exposure reshapes the gut metabolome and increases susceptibility to infection. Residues excreted within 8–24 hours of dosing persist in soil and water and re-enter the food chain, and subtherapeutic exposure from food and the environment has itself been linked to dysbiosis.¹

Travel and the hospital

Travel is an efficient vector for resistance genes. In one study, 12 of 18 Swedish students who had tested negative before travelling to the Indian subcontinent returned carrying extended-spectrum β-lactamase (ESBL) producers,⁹ and Dutch travellers returning from South-East Asia and India showed significant acquisition of plasmid-mediated quinolone resistance genes.¹ US data show the same pattern: ciprofloxacin resistance affected 62.4% of Campylobacter infections linked to travel, against 14.4% of those acquired at home.^1,10

Hospitals are a second hub. A multicountry study of neonatal units in low- and middle-income countries found ESBL- and carbapenemase-producing bacteria colonising hospital surfaces, including a high-risk ST15 Klebsiella pneumoniae clone recovered repeatedly from the same ward in Pakistan and identical to isolates causing neonatal sepsis there.¹¹ Broad-spectrum antibiotic use, longer stays, surgery, intubation, mechanical ventilation, urinary catheters and hygiene practices all contribute to healthcare-associated infection risk.¹

Diet, environment and the host

Diet is a major determinant of gut composition across the lifespan. Rural and non-industrialised populations carry diverse ARG reservoirs despite little access to modern medicines, and the composition of those reservoirs differs from that of industrialised populations. In the study of 290 healthy US adults, aminoglycoside phosphotransferase genes fell as total calories and soluble fibre intake rose, and people with low ARG levels ate significantly more fibre than those with medium or high levels.⁸ Livestock use of tetracyclines, macrolides, β-lactams and sulfonamides adds to the pool: the same tet(Q) and tet(O) genes found in farm-animal faeces appear in the human gut resistome, and manure and sewage sludge spread antibiotics and ARGs into soil. Air pollutants, including fine particulate matter, ozone, nitrogen oxides and sulphur dioxide, have also been associated with altered gut composition and reduced diversity.¹

Host factors matter as well. Compared with young adults, older people have fewer bifidobacteria and more clostridia, lactobacilli, streptococci and Enterobacteriaceae, and age-related loss of diversity has been linked to greater infection susceptibility. Sex hormones influence gut composition, and pregnancy brings increased Proteobacteria and Actinobacteria with reduced richness; in one cohort of 41 mothers who delivered preterm, the gut contained more oral commensal bacteria than in matched women who delivered at term.^1,12

The review positions the prevention and treatment of dysbiosis as part of AMR control. For healthcare-associated infection, the authors prioritise hand hygiene, infection control and antibiotic stewardship, before surveying microbiome-directed therapies of widely varying maturity.¹

Faecal microbiota transplantation

Faecal microbiota transplantation (FMT), using fresh, frozen or encapsulated donor material, is described in the review as effective for C. difficile infection and able to displace dominant vancomycin-resistant Enterococcus. It has also been used to decolonise resistant bacteria, with studies reporting differences in remission of resistant colonisation between treated and untreated patients. Combined with antibiotics, FMT has been reported to be effective against Pseudomonas aeruginosa and K. pneumoniae infections and may reduce the risk of resistance developing.¹

Phages, bacteriocins and probiotics

Bacteriophage therapy dates back to 1917, when Félix d’Hérelle isolated phages from the faeces of patients recovering from dysentery; it fell out of favour once antibiotics arrived. Its renewed appeal lies in host specificity, and phages can be given orally, topically or intravenously. Bacteriocins — ribosomally synthesised antibacterial peptides already used as food preservatives — have treated P. aeruginosa lung infection in mouse models (pyocin) and prevented bovine mastitis with efficacy comparable to antibiotics.¹

Probiotics aim to restore microbial balance, while drug repurposing looks for existing non-antibiotic drugs that block resistance mechanisms or boost antibiotic activity; more than 20% of FDA-approved drugs have been reported to influence the growth of gut bacteria.¹³ The authors are clear that both approaches still need quality standards, regulatory frameworks and clinical trials before they can be relied on against AMR.¹

Smarter delivery

Prebiotics, synbiotics and postbiotics may work alongside new delivery platforms. Stimuli-responsive nanoparticles release their payload in response to pH, temperature or enzyme activity, and lipid-based carriers protect active compounds while improving absorption. Formulation matters: in an in vitro gastrointestinal model, survival of Lactiplantibacillus plantarum rose from 18.5% to 84.5% when it was microencapsulated.^1,14

This is a narrative review. It does not describe a systematic search strategy, inclusion criteria or quality appraisal, and it does not pool data, so the studies it cites may not represent the full evidence base and their relative strength is not graded. Much of the mechanistic evidence comes from in vitro work and animal models, and many of the figures quoted come from single studies in specific populations. The review is therefore best read as a map of mechanisms and research directions rather than as evidence for any particular intervention.¹

The authors acknowledge important gaps. The direction in which resistance genes move between different microbial communities is still poorly understood, the effects of environmental factors such as antibiotic pollution on AMR dynamics are not fully established, and effective interventions for low- and middle-income countries with limited healthcare and sanitation infrastructure need further research. They highlight dual RNA sequencing, CRISPR-Cas9 screening, metaproteomics, metabolomics, single-cell omics, organoid and organ-on-a-chip models, and computational modelling as tools to close these gaps.¹

1. Dongre, D. S., Saha, U. B., & Saroj, S. D. (2025). Exploring the role of gut microbiota in antibiotic resistance and prevention. Annals of Medicine, 57(1), 2478317. https://doi.org/10.1080/07853890.2025.2478317
2. Bhardwaj, K., Shenoy M, S., Baliga, S., Unnikrishnan, B., & Baliga, B. S. (2021). Knowledge, attitude, and practices related to antibiotic use and resistance among the general public of coastal south Karnataka, India – A cross-sectional survey. Clinical Epidemiology and Global Health, 11, Article 100717. https://doi.org/10.1016/j.cegh.2021.100717
3. Crémet, L., Bourigault, C., Lepelletier, D., Guillouzouic, A., Juvin, M.-E., Reynaud, A., Corvec, S., & Caroff, N. (2012). Nosocomial outbreak of carbapenem-resistant Enterobacter cloacae highlighting the interspecies transferability of the bla_OXA-48 gene in the gut flora. Journal of Antimicrobial Chemotherapy, 67(4), 1041–1043. https://doi.org/10.1093/jac/dkr547
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6. De Oliveira, D. M. P., Forde, B. M., Kidd, T. J., Harris, P. N. A., Schembri, M. A., Beatson, S. A., Paterson, D. L., & Walker, M. J. (2020). Antimicrobial resistance in ESKAPE pathogens. Clinical Microbiology Reviews, 33(3), Article e00181-19. https://doi.org/10.1128/CMR.00181-19
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10. Geissler, A. L., Bustos Carrillo, F., Swanson, K., Patrick, M. E., Fullerton, K. E., Bennett, C., Barrett, K., & Mahon, B. E. (2017). Increasing Campylobacter infections, outbreaks, and antimicrobial resistance in the United States, 2004–2012. Clinical Infectious Diseases, 65(10), 1624–1631. https://doi.org/10.1093/cid/cix624
11. Nieto-Rosado, M., Sands, K., Portal, E. A. R., Thomson, K. M., Carvalho, M. J., Mathias, J., Milton, R., Dyer, C., Akpulu, C., Boostrom, I., Hogan, P., Saif, H., Sanches Ferreira, A. D., Hender, T., Portal, B., Andrews, R., Watkins, W. J., Zahra, R., Shirazi, H., … Walsh, T. R. (2024). Colonisation of hospital surfaces from low- and middle-income countries by extended spectrum β-lactamase- and carbapenemase-producing bacteria. Nature Communications, 15. https://doi.org/10.1038/s41467-024-46684-z
12. Sinha, T., Brushett, S., Prins, J., & Zhernakova, A. (2023). The maternal gut microbiome during pregnancy and its role in maternal and infant health. Current Opinion in Microbiology, 74, Article 102309. https://doi.org/10.1016/j.mib.2023.102309
13. Fekete, E. E., Figeys, D., & Zhang, X. (2023). Microbiota-directed biotherapeutics: Considerations for quality and functional assessment. Gut Microbes, 15(1), Article 2186671. https://doi.org/10.1080/19490976.2023.2186671
14. Surono, I., Verhoeven, J., Verbruggen, S., & Venema, K. (2018). Microencapsulation increases survival of the probiotic Lactobacillus plantarum IS-10506, but not Enterococcus faecium IS-27526 in a dynamic, computer-controlled in vitro model of the upper gastrointestinal tract. Journal of Applied Microbiology, 124(6), 1604–1609. https://doi.org/10.1111/jam.13740
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16. National Department of Health & Department of Agriculture, Forestry and Fisheries. (2018). South African antimicrobial resistance national strategy framework: A One Health approach 2018–2024. Republic of South Africa. https://www.medbox.org/document/republic-of-south-africa-antimicrobial-resistance-national-strategy-framework-2018-2024