The Gut Microbiome and Colistin Resistance: A Hidden Driver of Antimicrobial Failure

Abstract

Colistin, a polymyxin antibiotic reintroduced as a last-resort therapy against multidrug-resistant Gram-negative bacteria, is increasingly being compromised by the emergence of plasmid-mediated colistin resistance genes (mcr-1 to mcr-10). The human gut microbiota serves as a major reservoir and transmission hub for these resistance determinants, even among individuals without prior colistin exposure. This review explores the mechanisms, dissemination, and clinical implications of mcr-mediated colistin resistance within the gut microbiota, highlighting its role in horizontal gene transfer, colonization, and environmental persistence. A comprehensive synthesis of the recent literature was conducted, focusing on epidemiological studies, molecular mechanisms, neonatal implications and decolonization strategies. The intestinal tract supports the enrichment and exchange of mcr genes among commensal and pathogenic bacteria, especially under antibiotic pressure. Colistin use in agriculture has amplified gut colonization with resistant strains in both animals and humans. Surveillance gaps remain, particularly in neonatal populations, where colonization may occur early and persist silently. Promising interventions, such as fecal microbiota transplantation and phage therapies, are under investigation but lack large-scale clinical validation. The gut microbiome plays a central role in the global spread of colistin resistance. Mitigating this threat requires integrated One Health responses, improved diagnostics for gut colonization, and investment in microbiome-based therapies. A proactive, multisectoral approach is essential to safeguard colistin efficacy and address the expanding threat of mcr-mediated resistance.

Keywords: antimicrobial resistance (AMR); colistin resistance; gut microbiota; horizontal gene transfer (HGT); mcr genes; neonatal colonization; plasmid-mediated resistance.

Figure 1

mcr gene prevalence and impact of colistin on the gut microbiome. (Left) Heatmap showing the prevalence of mcr genes in humans and food sources across different countries, expressed as the percentage of positive samples among those tested. (Right) Schematic overview of colistin administration and its effects on gut microbiota composition, including dysbiosis characterized by relative increases (↑) or decreases (↓) in specific bacterial taxa. Colistin exposure is associated with enrichment of Treponema, Acidaminococcus, Lactobacillus, and Mycoplasma, along with reductions in Prevotella and Bacteroides. Colistin use can also drive the selection of resistance genes to other antibiotic classes. Created in BioRender. Pasare, A. (2025) https://BioRender.com/vq0ic4j; Accessed on 31 August 2025.

Figure 2

Horizontal transfer of mcr genes within the gut microbiota. The gastrointestinal tract provides an ideal environment for plasmid-mediated gene exchange. Commensal bacteria such as E. coli, Enterobacter, and Citrobacter spp. can harbor mcr-positive plasmids (e.g., IncI2, IncX4, IncHI2), which are then transferred to pathogenic or opportunistic species such as K. pneumoniae during co-colonization. Mobile genetic elements, including insertion sequences (ISApl1) and transposons, facilitate movement of resistance genes across species. Close physical proximity of microbes, biofilm formation, and antibiotic exposure enhance the frequency of conjugation and recombination. This dynamic gene flow highlights the gut as both a reservoir and an amplifier of colistin resistance. Created in BioRender. Pasare, A. (2025) https://BioRender.com/8oungut; Accessed on 31 August 2025.

Figure 3

Neonatal gut colonization and antimicrobial resistance risks. Newborns can acquire mcr-positive Enterobacterales from mothers, hospital environments, or caregivers, often without prior colistin exposure. Their immature immunity, fragile gut barrier, and frequent antibiotic use in NICUs increase the risk of progression from silent carriage to invasive infections (e.g., sepsis). Early colonization may also affect long-term immunity and growth, while colonized neonates can serve as reservoirs for hospital and community transmission. Created in BioRender. Pasare, A. (2025) https://BioRender.com/1a1bmxv; Accessed on 31 August 2025. AMR—antimicrobial resistance.

Figure 4

Strategies under investigation to eradicate mcr-positive Enterobacterales from the gut. Approaches include non-absorbable antibiotics, fecal microbiota transplantation to restore colonization resistance, bacteriophage therapy targeting resistant strains, CRISPR-Cas systems to selectively remove resistance genes, probiotics/next-generation biotherapeutics to rebalance the microbiota, and antimicrobial peptides or nanoparticles with activity against mcr-mediated resistance. These interventions are promising but remain largely experimental. Created in BioRender. Pasare, A. (2025) https://BioRender.com/ml031w1; Accessed on 31 August 2025.