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The Yin and Yang of pathogens and probiotics: interplay between Salmonella enterica sv. Typhimurium and Bifidobacterium infantis during co-infection - PubMed

  • ️Mon Jan 01 2024

The Yin and Yang of pathogens and probiotics: interplay between Salmonella enterica sv. Typhimurium and Bifidobacterium infantis during co-infection

Claire Shaw et al. Front Microbiol. 2024.

Abstract

Probiotic bacteria have been proposed as an alternative to antibiotics for the control of antimicrobial resistant enteric pathogens. The mechanistic details of this approach remain unclear, in part because pathogen reduction appears to be both strain and ecology dependent. Here we tested the ability of five probiotic strains, including some from common probiotic genera Lactobacillus and Bifidobacterium, to reduce binding of Salmonella enterica sv. Typhimurium to epithelial cells in vitro. Bifidobacterium longum subsp. infantis emerged as a promising strain; however, S. Typhimurium infection outcome in epithelial cells was dependent on inoculation order, with B. infantis unable to rescue host cells from preceding or concurrent infection. We further investigated the complex mechanisms underlying this interaction between B. infantis, S. Typhimurium, and epithelial cells using a multi-omics approach that included gene expression and altered metabolism via metabolomics. Incubation with B. infantis repressed apoptotic pathways and induced anti-inflammatory cascades in epithelial cells. In contrast, co-incubation with B. infantis increased in S. Typhimurium the expression of virulence factors, induced anaerobic metabolism, and repressed components of arginine metabolism as well as altering the metabolic profile. Concurrent application of the probiotic and pathogen notably generated metabolic profiles more similar to that of the probiotic alone than to the pathogen, indicating a central role for metabolism in modulating probiotic-pathogen-host interactions. Together these data imply crosstalk via small molecules between the epithelial cells, pathogen and probiotic that consistently demonstrated unique molecular mechanisms specific probiotic/pathogen the individual associations.

Keywords: Salmonella; arginine; bifidobacteria; host-microbe association; nitric oxide; probiotic.

Copyright © 2024 Shaw, Weimer, Gann, Desai and Shah.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.

Figures

Figure 1
Figure 1

Adhesion to and invasion of Caco2 cells by S. Typhimurium. (A) Efficacy of different strains t block Salmonella host association. Treatments with “*” are significantly different (p ≤ 0.5) as compared to control (Caco2 cells incubated with Salmonella alone). Error bars indicate standard error from 4 replicates. (B) Effect of presence of B. infantis on the relative adhesion and invasion of S. Typhimurium to Caco2 cells. Control (Caco2 cells incubated with S. Typhimurium); Sal-Pre + Bif (Caco2 cells pre-incubated for 30 min with S. Typhimurium and then with B. infantis for 30 more minutes); Bif-Pre+ Sal (Caco2 cells pre-incubated with B. infantis for 30 minutes and then with S. Typhimurium for 60 more minutes); Sal+Bif (Caco2 cells incubated with S. Typhimurium and B. infantis together for 60 minutes); Sal+Bif Incubated (S. Typhimurium and B. infantis were first incubated together for 60 minutes and then incubated with Caco2 cells for 120 minutes). Treatments that do not share an alphabet are significantly different (p ≤ 0.05). The % numbers of the x axis represents the fraction of total host associated bacteria that were intracellular (invaded). Error bard indicate standard error from three replicates.

Figure 2
Figure 2

Log2 ratios of differentially expressed genes (adj-p ≤ 0.1); caspase 8, 9, 3/7 activity and phosphorylation status of Akt in epithelial cells when they are exposed to B. infantis. For gene expression data, red represents induction while blue represents repression of genes when epithelial cells were exposed to B. infantis.

Figure 3
Figure 3

(A) Dendogram visualizing similarity between global gene expression profiles of Cac02 cells. The number at each cluster edge represents Approximately Unbiased % p value estimated by multiscale bootstrap resampling 1,000 times. (Host=Cac02 cells incubated with no microbes, Host+Bif=Cac02 cells incubated with B. infantis, Host+Sal=Cac02 cells incubated with S. Typhimurium, Host+Bif+Sal=Cac02 cells simultaneously incubated with 1:1 ratio of B. infantis and S. Typhimurium. The time in minutes represent the time after infection at which the gene expression was determined. (B) Dendogram constructed by hierarchical clustering of small metabolite profile of all the host microbe interaction samples. The number at each cluster edge represents Approximately Unbiased % p value estimated by multiscale bootstrap resampling 1,000 times (Host = Cac02, Bif = B. infantis, Sal = S. Typhimurium). The time in minutes represent the time after infection at which the metabolite profile was determined. “E” represents the extracellular metabolite profile from culture supernatant, while “I” represent the intracellular metabolite profile of all the cells in co-culture.

Figure 4
Figure 4

Log2 ratios of gene expression intensities of S. Typhimurium and selected small metabolite peak areas when Cac02 cells were treated with either S. Typhimurium alone or with a co-culture of S. Typhimurium and B. infantis. Induction of genes represent that the gene was induced in Salmonella in presence of B. infantis as compared to its absence.

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