Thursday, July 17, 2025
No menu items!
HomeNatureIdentification of medication–microbiome interactions that affect gut infection

Identification of medication–microbiome interactions that affect gut infection

  • Ho, J. Y. Life course patterns of prescription drug use in the United States. Demography 60, 1549–1579 (2023).

    PubMed 

    Google Scholar
     

  • Weersma, R. K., Zhernakova, A. & Fu, J. Interaction between drugs and the gut microbiome. Gut 69, 1510–1519 (2020).

    CAS 
    PubMed 

    Google Scholar
     

  • Caruso, R., Lo, B. C. & Núñez, G. Host–microbiota interactions in inflammatory bowel disease. Nat. Rev. Immunol. 20, 411–426 (2020).

    CAS 
    PubMed 

    Google Scholar
     

  • Dehner, C., Fine, R. & Kriegel, M. A. The microbiome in systemic autoimmune disease: mechanistic insights from recent studies. Curr. Opin. Rheumatol. 31, 201–207 (2019).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Wong, S. H. & Yu, J. Gut microbiota in colorectal cancer: mechanisms of action and clinical applications. Nat. Rev. Gastroenterol. Hepatol. 16, 690–704 (2019).

    CAS 
    PubMed 

    Google Scholar
     

  • Khosravi, A. & Mazmanian, S. K. Disruption of the gut microbiome as a risk factor for microbial infections. Curr. Opin. Microbiol. 16, 221–227 (2013).

    PubMed 
    PubMed Central 

    Google Scholar
     

  • Lassalle, M., Zureik, M. & Dray-Spira, R. Proton pump inhibitor use and risk of serious infections in young children. JAMA Pediatr. 177, 1028–1038 (2023).

    PubMed 
    PubMed Central 

    Google Scholar
     

  • Roberts, M. B. & Fishman, J. A. Immunosuppressive agents and infectious risk in transplantation: managing the “net state of immunosuppression”. Clin. Infect. Dis. 73, e1302–e1317 (2021).

    PubMed 

    Google Scholar
     

  • Budnitz, D. S., Lovegrove, M. C., Shehab, N. & Richards, C. L. Emergency hospitalizations for adverse drug events in older Americans. New Engl. J. Med. 365, 2002–2012 (2011).

    CAS 
    PubMed 

    Google Scholar
     

  • Maier, L. et al. Extensive impact of non-antibiotic drugs on human gut bacteria. Nature 555, 623–628 (2018).

    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Vich Vila, A. et al. Impact of commonly used drugs on the composition and metabolic function of the gut microbiota. Nat. Commun. 11, 362 (2020).

    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Zimmermann, M., Zimmermann-Kogadeeva, M., Wegmann, R. & Goodman, A. L. Mapping human microbiome drug metabolism by gut bacteria and their genes. Nature 570, 462–467 (2019).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Verdegaal, A. A. & Goodman, A. L. Integrating the gut microbiome and pharmacology. Sci. Transl. Med. 16, eadg8357 (2024).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Zhong, W. et al. Age and sex patterns of drug prescribing in a defined American population. Mayo Clin. Proc. 88, 697–707 (2013).

    PubMed 

    Google Scholar
     

  • Hales, C. M., Servais, J., Martin, C. B. & Kohen, D. Prescription Drug Use Among Adults Aged 40–79 in the United States and Canada. NCHS Data Brief No. 347 (NCHS, 2019).

  • Kyu, H. H. et al. Global, regional, and national age-sex-specific burden of diarrhoeal diseases, their risk factors, and aetiologies, 1990–2021, for 204 countries and territories: a systematic analysis for the Global Burden of Disease Study 2021. Lancet Infect. Dis. 25, 519–536 (2025).


    Google Scholar
     

  • Jaakkola, J. J. K. Case-crossover design in air pollution epidemiology. Eur. Respir. J. 21, 81s–85s (2003).

    CAS 

    Google Scholar
     

  • Bohnhoff, M., Drake, B. L. & Miller, C. P. Effect of streptomycin on susceptibility of intestinal tract to experimental Salmonella infection. Proc. Soc. Exp. Biol. Med. 86, 132–137 (1954).

    CAS 
    PubMed 

    Google Scholar
     

  • Galán, J. E. Salmonella Typhimurium and inflammation: a pathogen-centric affair. Nat. Rev. Microbiol. 19, 716–725 (2021).

    PubMed 
    PubMed Central 

    Google Scholar
     

  • Wagner, S. et al. Organization and coordinated assembly of the type III secretion export apparatus. Proc. Natl Acad. Sci. USA 107, 17745–17750 (2010).

    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Dobkin, J. F., Saha, J. R., Butler, V. P., Neu, H. C. & Lindenbaum, J. Digoxin-inactivating bacteria: identification in human gut flora. Science 220, 325–327 (1983).

    ADS 
    CAS 

    Google Scholar
     

  • Haiser, H. J. et al. Predicting and manipulating cardiac drug inactivation by the human gut bacterium Eggerthella lenta. Science 341, 295–298 (2013).

    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Hackam, D. J. et al. Host resistance to intracellular infection: mutation of natural resistance-associated macrophage protein 1 (Nramp1) impairs phagosomal acidification. J. Exp. Med. 188, 351–364 (1998).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Huh, J. R. et al. Digoxin and its derivatives suppress TH17 cell differentiation by antagonizing RORγt activity. Nature 472, 486–490 (2011).

    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Xiao, S. et al. Small-molecule RORγt antagonists inhibit T helper 17 cell transcriptional network by divergent mechanisms. Immunity 40, 477–489 (2014).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Spits, H. et al. Innate lymphoid cells—a proposal for uniform nomenclature. Nat. Rev. Immunol. 13, 145–149 (2013).

    CAS 
    PubMed 

    Google Scholar
     

  • Ivanov, I. I. et al. Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell 139, 485–498 (2009).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Zindl, C. L. et al. IL-22-producing neutrophils contribute to antimicrobial defense and restitution of colonic epithelial integrity during colitis. Proc. Natl Acad. Sci. USA 110, 12768–12773 (2013).

    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Flannigan, K. L. et al. IL-17A-mediated neutrophil recruitment limits expansion of segmented filamentous bacteria. Mucosal Immunol. 10, 673–684 (2017).

    CAS 
    PubMed 

    Google Scholar
     

  • Raffatellu, M. et al. Simian immunodeficiency virus-induced mucosal interleukin-17 deficiency promotes Salmonella dissemination from the gut. Nat. Med. 14, 421–428 (2008).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Ivanov, I. I., Tuganbaev, T., Skelly, A. N. & Honda, K. T cell responses to the microbiota. Annu. Rev. Immunol. 40, 559–587 (2022).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Araujo, L. P. et al. Context-dependent role of group 3 innate lymphoid cells in mucosal protection. Sci. Immunol. 9, eade7530 (2024).

    CAS 
    PubMed 

    Google Scholar
     

  • Salzman, N. H. et al. Enteric defensins are essential regulators of intestinal microbial ecology. Nat. Immunol. 11, 76–83 (2010).

    CAS 
    PubMed 

    Google Scholar
     

  • Vaishnava, S. et al. The antibacterial lectin RegIIIγ promotes the spatial segregation of microbiota and host in the intestine. Science 334, 255–258 (2011).

    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Jonsson, H., Hugerth, L. W., Sundh, J., Lundin, E. & Andersson, A. F. Genome sequence of segmented filamentous bacteria present in the human intestine. Commun. Biol. 3, 485 (2020).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Atarashi, K. et al. Th17 cell induction by adhesion of microbes to intestinal epithelial cells. Cell 163, 367–380 (2015).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Raffatellu, M. et al. Lipocalin-2 resistance of Salmonella enterica serotype Typhimurium confers an advantage during life in the inflamed intestine. Cell Host Microbe 5, 476 (2009).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Pazgier, M., Hoover, D. M., Yang, D., Lu, W. & Lubkowski, J. Human β-defensins. Cell. Mol. Life Sci. 63, 1294–1313 (2006).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Frye, M., Bargon, J., Lembcke, B., Wagner, T. O. & Gropp, R. Differential expression of human α- and β-defensins mRNA in gastrointestinal epithelia. Eur. J. Clin. Invest. 30, 695–701 (2000).

    CAS 
    PubMed 

    Google Scholar
     

  • Semple, F. & Dorin, J. R. β-Defensins: multifunctional modulators of infection, inflammation and more? J. Innate Immun. 4, 337–348 (2012).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Salzman, N. H., Underwood, M. A. & Bevins, C. L. Paneth cells, defensins, and the commensal microbiota: a hypothesis on intimate interplay at the intestinal mucosa. Semin. Immunol. 19, 70–83 (2007).

    CAS 
    PubMed 

    Google Scholar
     

  • Rezende, R. M. & Weiner, H. L. History and mechanisms of oral tolerance. Semin. Immunol. 30, 3–11 (2017).

    CAS 
    PubMed 

    Google Scholar
     

  • Rivas, M. N. & Chatila, T. A. Regulatory T cells in allergic diseases. J. Allergy Clin. Immunol. 138, 639–652 (2016).

    PubMed Central 

    Google Scholar
     

  • Kongkaew, C., Sakunrag, I. & Jianmongkol, P. Non-compliance with digoxin in patients with heart failure and/or atrial fibrillation: a systematic review and meta-analysis of observational studies. Arch. Cardiovasc. Dis. 105, 507–516 (2012).

    PubMed 

    Google Scholar
     

  • Dearing, M. D. & Weinstein, S. B. Metabolic enabling and detoxification by mammalian gut microbes. Annu. Rev. Microbiol. 76, 579–596 (2022).

    CAS 
    PubMed 

    Google Scholar
     

  • Chiu, K., Warner, G., Nowak, R. A., Flaws, J. A. & Mei, W. The impact of environmental chemicals on the gut microbiome. Toxicol. Sci. 176, 253–284 (2020).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Rothschild, D. et al. Environment dominates over host genetics in shaping human gut microbiota. Nature 555, 210–215 (2018).

    ADS 
    CAS 
    PubMed 

    Google Scholar
     

  • David, L. A. et al. Diet rapidly and reproducibly alters the human gut microbiome. Nature 505, 559–563 (2014).

    ADS 
    CAS 
    PubMed 

    Google Scholar
     

  • Bäumler, A. J. & Sperandio, V. Interactions between the microbiota and pathogenic bacteria in the gut. Nature 535, 85–93 (2016).

    ADS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Woodward, M. Epidemiology: Study Design and Data Analysis 3rd edn (CRC Press, 2013).

  • Hou, J. et al. Temporal trends in clinical evidence of 5-year survival within electronic health records among patients with early-stage colon cancer managed with laparoscopy-assisted colectomy vs open colectomy. JAMA Netw. Open 5, e2218371 (2022).

    PubMed 
    PubMed Central 

    Google Scholar
     

  • Corrigan-Curay, J., Sacks, L. & Woodcock, J. Real-world evidence and real-world data for evaluating drug safety and effectiveness. JAMA 320, 867–868 (2018).

    PubMed 

    Google Scholar
     

  • Fralick, M., Kesselheim, A. S., Avorn, J. & Schneeweiss, S. Use of health care databases to support supplemental indications of approved medications. JAMA Intern. Med. 178, 55–63 (2018).

    PubMed 

    Google Scholar
     

  • Pletcher, M. J. et al. Randomized controlled trials of electronic health record interventions: design, conduct, and reporting considerations. Ann. Intern. Med. 172, S85–S91 (2020).

    PubMed 

    Google Scholar
     

  • Lewer, D. et al. Fatal opioid overdoses during and shortly after hospital admissions in England: a case-crossover study. PLoS Med. 18, e1003759 (2021).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Shuto, H. et al. Medication use as a risk factor for inpatient falls in an acute care hospital: a case-crossover study. Br. J. Clin. Pharmacol. 69, 535–542 (2010).

    PubMed 
    PubMed Central 

    Google Scholar
     

  • Pindyck, T. et al. Validation of acute gastroenteritis-related international classification of diseases, clinical modification codes in pediatric and adult US populations. Clin. Infect. Dis. 70, 2423–2427 (2020).

    PubMed 

    Google Scholar
     

  • Cadieux, G. et al. Accuracy of syndrome definitions based on diagnoses in physician claims. BMC Public Health 11, 17 (2011).

    PubMed 
    PubMed Central 

    Google Scholar
     

  • Gu, Z., Eils, R. & Schlesner, M. Complex heatmaps reveal patterns and correlations in multidimensional genomic data. Bioinformatics 32, 2847–2849 (2016).

    CAS 
    PubMed 

    Google Scholar
     

  • Goodman, A. L. et al. Identifying genetic determinants needed to establish a human gut symbiont in its habitat. Cell Host Microbe 6, 279–289 (2009).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • King, A. M. et al. Aspergillomarasmine A overcomes metallo-β-lactamase antibiotic resistance. Nature 510, 503–506 (2014).

    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Kolde, R. pheatmap: Pretty heatmaps. R package v.1.0.12 (CRAN, 2019).

  • Wotzka, S. Y. et al. Escherichia coli limits Salmonella Typhimurium infections after diet shifts and fat-mediated microbiota perturbation in mice. Nat. Microbiol. 4, 2164–2174 (2019).

    PubMed 
    PubMed Central 

    Google Scholar
     

  • Velazquez, E. M. et al. Endogenous Enterobacteriaceae underlie variation in susceptibility to Salmonella infection. Nat. Microbiol. 4, 1057–1064 (2019).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Hoiseth, S. K. & Stocker, B. A. Aromatic-dependent Salmonella typhimurium are non-virulent and effective as live vaccines. Nature 291, 238–239 (1981).

    ADS 
    CAS 
    PubMed 

    Google Scholar
     

  • Caballero-Flores, G., Pickard, J. M., Fukuda, S., Inohara, N. & Núñez, G. An enteric pathogen subverts colonization resistance by evading competition for amino acids in the gut. Cell Host Microbe 28, 526–533 (2020).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Zhao, P. et al. Digoxin improves steatohepatitis with differential involvement of liver cell subsets in mice through inhibition of PKM2 transactivation. Am. J. Physiol. Gastrointest. Liver Physiol. 317, G387–G397 (2019).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Teijeiro, A., Garrido, A., Ferre, A., Perna, C. & Djouder, N. Inhibition of the IL-17A axis in adipocytes suppresses diet-induced obesity and metabolic disorders in mice. Nat. Metab. 3, 496–512 (2021).

    CAS 
    PubMed 

    Google Scholar
     

  • Patel, S., Preuss, C. V. & Bernice, F. in StatPearls https://www.ncbi.nlm.nih.gov/books/NBK459263/ (StatPearls Publishing, 2024).

  • Sun, H., Kamanova, J., Lara-Tejero, M. & Galán, J. E. A family of Salmonella type III secretion effector proteins selectively targets the NF-κB signaling pathway to preserve host homeostasis. PLoS Pathog. 12, e1005484 (2016).

    PubMed 
    PubMed Central 

    Google Scholar
     

  • Sun, Z. et al. Requirement for RORγ in thymocyte survival and lymphoid organ development. Science 288, 2369–2373 (2000).

    ADS 
    CAS 
    PubMed 

    Google Scholar
     

  • Mombaerts, P. et al. RAG-1-deficient mice have no mature B and T lymphocytes. Cell 68, 869–877 (1992).

    CAS 
    PubMed 

    Google Scholar
     

  • Madison, B. B. et al. Cis elements of the villin gene control expression in restricted domains of the vertical (crypt) and horizontal (duodenum, cecum) axes of the intestine. J. Biol. Chem. 277, 33275–33283 (2002).

    CAS 
    PubMed 

    Google Scholar
     

  • Behringer, R. Manipulating the Mouse Embryo: A Laboratory Manual (Cold Spring Harbor Laboratory Press, 2014).

  • Meade, K. G. & O’Farrelly, C. β-Defensins: farming the microbiome for homeostasis and health. Front. Immunol. 9, 3072 (2019).

    PubMed 
    PubMed Central 

    Google Scholar
     

  • Horvat, B., Osborn, M. & Damjanov, I. Expression of villin in the mouse oviduct and the seminiferous ducts. Histochemistry 93, 661–663 (1990).

    CAS 
    PubMed 

    Google Scholar
     

  • Rutlin, M. et al. The Villin1 gene promoter drives Cre recombinase expression in extraintestinal tissues. Cell. Mol. Gastroenterol. Hepatol. 10, 864–867 (2020).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Kaminski, J. et al. High-specificity targeted functional profiling in microbial communities with ShortBRED. PLoS Comput. Biol. 11, e1004557 (2015).

    PubMed 
    PubMed Central 

    Google Scholar
     

  • Suzek, B. E., Wang, Y., Huang, H., McGarvey, P. B. & Wu, C. H. UniRef clusters: a comprehensive and scalable alternative for improving sequence similarity searches. Bioinformatics 31, 926–932 (2015).

    CAS 
    PubMed 

    Google Scholar
     

  • Edgar, R. C. Search and clustering orders of magnitude faster than BLAST. Bioinformatics 26, 2460–2461 (2010).

    CAS 
    PubMed 

    Google Scholar
     

  • Tawk, C. et al. Infection leaves a genetic and functional mark on the gut population of a commensal bacterium. Cell Host Microbe 31, 811–826 (2023).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Kuznetsov, D. et al. OrthoDB v11: annotation of orthologs in the widest sampling of organismal diversity. Nucleic Acids Res. 51, D445–D451 (2023).

    CAS 
    PubMed 

    Google Scholar
     

  • Yan, K. et al. Obeticholic acid decreases intestinal content of Enterococcus in rats with cirrhosis and ascites. Hepatol. Commun. 5, 1507–1517 (2021).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Kozich, J. J., Westcott, S. L., Baxter, N. T., Highlander, S. K. & Schloss, P. D. Development of a dual-index sequencing strategy and curation pipeline for analyzing amplicon sequence data on the miseq illumina sequencing platform. Appl. Environ. Microbiol. 79, 5112–5120 (2013).

    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Bolyen, E. et al. Reproducible, interactive, scalable and extensible microbiome data science using QIIME 2. Nat. Biotechnol. 37, 852–857 (2019).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Callahan, B. J. et al. DADA2: high-resolution sample inference from Illumina amplicon data. Nat. Methods 13, 581–583 (2016).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Ii, M. S. R. et al. RESCRIPt: reproducible sequence taxonomy reference database management. PLoS Comput. Biol. 17, e1009581 (2021).


    Google Scholar
     

  • Pruesse, E. et al. SILVA: a comprehensive online resource for quality checked and aligned ribosomal RNA sequence data compatible with ARB. Nucleic Acids Res. 35, 7188–7196 (2007).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Quast, C. et al. The SILVA ribosomal RNA gene database project: improved data processing and web-based tools. Nucleic Acids Res. 41, D590–D596 (2013).

    CAS 
    PubMed 

    Google Scholar
     

  • Fernandes, A. D. et al. Unifying the analysis of high-throughput sequencing datasets: characterizing RNA-seq, 16S rRNA gene sequencing and selective growth experiments by compositional data analysis. Microbiome 2, 15 (2014).

    PubMed 
    PubMed Central 

    Google Scholar
     

  • Lozupone, C. A., Hamady, M., Kelley, S. T. & Knight, R. Quantitative and qualitative β diversity measures lead to different insights into factors that structure microbial communities. Appl. Environ. Microbiol. 73, 1576–1585 (2007).

    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Oksanen, J. et al. vegan: Community ecology package. R package v.2.6-4 (CRAN, 2024).

  • Liu, Y.-X. et al. EasyAmplicon: an easy-to-use, open-source, reproducible, and community-based pipeline for amplicon data analysis in microbiome research. iMeta 2, e83 (2023).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Kumar, A. et al. The serotonin neurotransmitter modulates virulence of enteric pathogens. Cell Host Microbe 28, 41–53 (2020).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Kim, D., Paggi, J. M., Park, C., Bennett, C. & Salzberg, S. L. Graph-based genome alignment and genotyping with HISAT2 and HISAT-genotype. Nat. Biotechnol. 37, 907–915 (2019).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Pertea, M. et al. StringTie enables improved reconstruction of a transcriptome from RNA-seq reads. Nat. Biotechnol. 33, 290–295 (2015).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Love, M. I., Huber, W. & Anders, S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 15, 550 (2014).

    PubMed 
    PubMed Central 

    Google Scholar
     

  • Milacic, M. et al. The Reactome Pathway Knowledgebase 2024. Nucleic Acids Res. 52, D672–D678 (2023).

    PubMed Central 

    Google Scholar
     

  • Castanza, A. S. et al. Extending support for mouse data in the Molecular Signatures Database (MSigDB). Nat. Methods 20, 1619–1620 (2023).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Subramanian, A. et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc. Natl Acad. Sci. USA 102, 15545–15550 (2005).

    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • RELATED ARTICLES

    Most Popular

    Recent Comments