Antibiotic‐Induced Dysbiosis of the Gut Microbiota Shifts Host Tryptophan Metabolism and Increases the Susceptibility of Mice to Pulmonary Infection With <scp><i>Pseudomonas aeruginosa</i></scp>
Pseudomonas aeruginosa is an opportunistic bacterium that mainly infects those who have previously been treated with antibiotics. We hypothesised that antibiotic treatment disrupts tryptophan metabolism, leading to increased susceptibility to P. aeruginosa infection. Our results showed that mice receiving antibiotics exhibited intestinal dysbiosis with alterations in host tryptophan metabolism, a higher mortality rate and a higher bacterial load compared to eubiotic mice. In the lungs of the dysbiotic mice, there was an increase in IDO1 (Indoleamine 2,3-dioxygenase 1) activity and an accumulation of kynurenine after infection, and IDO1<sup>-/-</sup> mice were resistant to infection after induction of dysbiosis. Importantly, dysbiosis led to increased expression and activation of AHR (Aryl Hydrocarbon Receptor) in an IDO1-dependent manner. Blocking AHR activation in dysbiotic mice resulted in a lower bacterial load. Our data showed that increased AHR activation by kynurenine was associated with decreased phagocytosis of P. aeruginosa by macrophages and neutrophils. In conclusion, our results indicate that dysbiosis resulting from prolonged antimicrobial treatment alters tryptophan metabolism, leading to activation of the IDO1-AHR axis and increasing susceptibility to P. aeruginosa infection. Furthermore, these data suggest that IDO1 or AHR are potential host targets for the prevention of opportunistic infections in patients undergoing antimicrobial therapy.
Authors
- Micheli Fagundes (ORCID: https://orcid.org/0000-0001-9418-2842)
- Alessandra Mattos Saliba (ORCID: https://orcid.org/0000-0001-7378-8562)
- Luciene Barbosa (ORCID: https://orcid.org/0000-0003-2026-994X)
- Celso Martins Queiroz‐Junior (ORCID: https://orcid.org/0000-0002-7884-7709)
- Mauro Martins Teixeira (ORCID: https://orcid.org/0000-0002-6944-3008)
- Danielle G. Souza (ORCID: https://orcid.org/0000-0002-7478-5934)
- Fernão Castro Braga (ORCID: https://orcid.org/0000-0001-9468-376X)
- Juliana Divina Almeida Raposo (ORCID: https://orcid.org/0000-0003-4442-8351)
- Rafaela R.A. Batista (ORCID: https://orcid.org/0000-0002-5136-693X)
- Larissa Marcely Gomes Cassiano (ORCID: https://orcid.org/0000-0002-6941-0863)
- Caio T. Fagundes (ORCID: https://orcid.org/0000-0002-6747-5233)
- J.A.R.G. Barbosa (ORCID: https://orcid.org/0000-0002-0534-481X)
- Rosângela Maria Neves Bezerra (ORCID: https://orcid.org/0000-0001-5089-651X)
- Roney S. Coimbra (ORCID: https://orcid.org/0000-0002-9204-0573)
- Raquel Duque do Nascimento Arifa (ORCID: https://orcid.org/0000-0003-0888-2282)
- Markus Kohlhoff (ORCID: https://orcid.org/0000-0001-5982-6083)
- Camila Bernardo de Brito (ORCID: https://orcid.org/0000-0002-4571-7238)
- Andréia C. Santos (ORCID: https://orcid.org/0000-0002-0289-9051)
- Bárbara Maria de Amorim‐Santos (ORCID: https://orcid.org/0000-0003-1118-1049)
- Carlos Eduardo Dias Igídio (ORCID: https://orcid.org/0000-0002-7480-5405)
Institutions
- Universidade Federal de Minas Gerais (BR)
- Universidade do Estado do Rio de Janeiro (BR)
- Fundação Oswaldo Cruz (BR)
Publication Details
- Journal
- Immunology
- Published
- 2025-05-19
- DOI
- https://doi.org/10.1111/imm.13932
- Citations
- 3
- Primary Topic
- Tryptophan and brain disorders
- Type
- article
- Field-Weighted Citation Impact
- 1.73
Funders
- Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
- Conselho Nacional de Desenvolvimento Científico e Tecnológico
- Fundação de Amparo à Pesquisa do Estado de Minas Gerais