The Genotoxin Colibactin Shapes Gut Microbiota in Mice

doi:10.21203/rs.2.23021/v1

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The Genotoxin Colibactin Shapes Gut Microbiota in Mice

https://doi.org/10.21203/rs.2.23021/v1

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published 26 Aug, 2020

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Background : The genotoxin colibactin produced by resident bacteria of the gut microbiota may have tumorigenic effect by inducing DNA double strand breaks in host cells. Yet, the effect of colibactin on gut microbiota composition and functions remains unknown.

Results: To address this point, we designed an experiment in which pregnant mice were colonized with: i) a commensal E. coli strain, ii) a commensal E. coli strain plus a genotoxic E. coli strain, iii) a commensal E. coli strain plus a non-genotoxic E. coli mutant strain unable to produce mature colibactin. Then, we analysed the gut microbiota in pups at day 15 and day 35 after birth. At day 15, mice that were colonized at birth with the genotoxic strain showed lower levels of Proteobacteria and belonging taxa, a modest effect on overall microbial diversity and no effect on gut microbiome. At day 35, mice that received the genotoxic strain showed lower Firmicutes and belonging taxa, together with a strong effect on overall microbial diversity and higher microbial functions related to DNA repair. Moreover, the genotoxic strain strongly affected gut microbial diversity evolution of receiving pups between day 15 and day 35.

Conclusions: our data show that colibactin, beyond targeting the host, may also exerce its genotoxic effect on the gut microbiota.

General Microbiology

colibactin

gut microbiota dysbiosis

microbiome

enterobacteria

The quantitative and qualitative alterations, named dysbiosis, of the gut microbiota are now considered key traits of multiple pathologies such as metabolic, inflammatory and infectious diseases [1]. Dysbioses can origin from several factors related to multiple habits such as antibiotics abuse, among the strongest. However, an increased fat-to-fiber alimentary ratio, which is a common inducer of metabolic diseases, represents the strongest trigger of gut microbiota alterations. In this context, it was shown that a high-fat/high sucrose diet was able to increase the intestinal adherence of Adherent Invasive Escherichia coli (AIEC) in mice, thus promoting AIEC infection [2]. Both proinflammatory and genotoxic strains belong to Escherichia coli, which is a dominant member of phylum Proteobacteria and colonizes the gut of both humans and animals at birth [3]. Only 40% of the whole genome of E. coli is conserved, which confers to these bacteria a huge molecular plasticity. The latter is characterized by the acquisition of mobile elements such as plasmids, transposons, phages and pathogenicity islands [4]. Genotoxic E. coli harbour in their genome a 52 kb polyketide synthase (pks) pathogenicity island with genes encoding a complex enzymatic machinery synthetising the genotoxin colibactin. The B2 phylogenetic group of E. coli is the one harbouring the most (30%) of pks + E. coli strains. The prevalence of the B2 group highly increased in the last decades and concomitantly with the progression of urbanization [5] and both autoimmune and allergic diseases [6]. This event induced a progressive passage from phylogenetic group A (with no pks + E. coli strains) to phylogroup B2. Colibactin is capable of inducing DNA double strand breaks in eukaryotic cells [7] and of generating DNA interstrand cross-links [8] and was shown to induce multiple alterations in the host such as: cell senescence [9, 10], increased E. coli-induced lymphopenia [11], altered intestinal homeostasis [12], modified tumor microenvironment [13], colon tumor growth [9]. Yet, whether colibactin may exert its genotoxic effect even on members of the gut microbiota remains unknown. To address this point, we set-up a model of mother-to-pup vertical transmission of both genotoxic and non-genotoxic E. coli, since these strains are already present at birth[3]. We studied the effects on both gut microbiota and microbiome on pups at day 15 and 35 after birth. Beyond colibactin, pks island genes are involved in the synthesis of multiple factors such as bacterial analgesic lipopeptide [14] and antibiotic molecules such as siderophore-microcins [15]. Given the strong importance of the mother as an E. coli transmissing factor [16], to get mice pups colonized by E. coli the most natural way, we decided to colonize the mother with the E. coli of interest. Therefore, to ascribe to the sole production of colibactin the putative effects on gut microbiota, we decided not to compare a pks + vs. a pks- E. coli strain but, rather, to generate two isogenic bacteria mutants on the basis of the E. coli SP15 strain [11] and to colonize the mother with these mutants.

Colibactin targets the gut microbiota at the onset of intestinal colonization by genotoxic E. coli.

To understand whether the genotoxin colibactin may also target host gut microbiota, beyond the effects observed on host cells[7, 8], we applied a protocol of vertical mother-to-pups transmission (Supplementary Figure 1). Briefly, pregnant mothers were given by gavage either a non-genotoxic E. coli commensal strain (MG1655, phylogroup A, control group) or both MG1655 and the genotoxic E. coli SP15 strain (phylogroup B2, SP15clb+) or its non-genotoxic mutant (SP15clb-)). The molecular strategy applied to generate the two isogenic E. coli SP15 strains is reported in Supp.Fig.2. We analysed the overall putative changes in the gut microbiota of mice pups at 15 days after birth. The mother-to-pup transfer of the non-genotoxic E. coli SP15clb- strain was associated to a higher relative abundance of Proteobacteria. By contrast, the mother-to-pup transfer of the genotoxic E. coli SP15clb+ strain was associated to a higher relative abundance of family Lachnospiraceae (Fig.1A). Both the non-genotoxic and the genotoxic E. coli SP15 strains significantly affected the overall gut microbiota profile (Fig.1B). However, the overall gut microbiota diversity was unaffected, despite the significant reduction in the Menhininck index, regardless of genotoxicity of the E. coli SP15 strain (Fig.1C). Then, considering the putative antibiotic activity of colibactin[17], we focused on microbial taxa whose abudance was lower following the colonization with the genotoxic E. coli SP15 strain. As reported in Fig.2A-F, the phylum- Proteobacteria and all the other related taxa displayed a significantly lower abundance in mice colonized with the genotoxic E. coli SP15clb+ strain compared to the non-genotoxic E. coli SP15clb-. Next, we analysed the gut microbiome by performing a PICRUSt[18]-based functional analysis. As reported in Fig.3A-B, we identified microbial pathways significantly enriched in the control and in the group of mice pups co-colonized with the non-genotoxic E. coli SP15clb- strain, but not with group co-colonized with the genotoxic E. coli SP15clb+ strain. Overall, these data show that 15 days after birth E. coli genotoxic activity exerts an intra-species taxonomical but not functional impact on the gut microbiota.

Colibactin targets the gut microbiota and microbiome following intestinal colonization by genotoxic E. coli.

Then, to investigate whether the early impact of colibactin had long lasting consequences on gut microbiota composition, we analysed the overall putative changes in the gut microbiota of mice 35 days after birth. Differently from what observed above at day 15, the co-infection with the non-genotoxic E. coli SP15clb- strain was associated to a higher relative abundance of Firmicutes. By contrast, the co-infection with the genotoxic SP15clb+ strain was associated to a higher relative abundance of genus Alistipes and family Rikenellaceae (Fig.4A). A PCA showed a complete separation between the gut microbiota profile of mice co-colonized with the genotoxic E. coli SP15clb+ strain compared to the the other groups of mice (Fig.4B). In addition, the calculation of several diversity indices showed a precise cluster separation among the three gut microbiota profiles, with a general significant higher diversity induced by the genotoxic strain compared to the non-genotoxic one, except for the Berger-Parker index (Fig.4C). As for the reduction in microbial taxa the phylum Firmicutes and all the other related taxa displayed a significantly lower abundance in mice colonized with the genotoxic E. coli SP15clb+ strain compared to the non-genotoxic E. coli SP15clb- strain (Fig.5A-F). Next, we analysed the gut microbiome by performing a PICRUSt[18]-based functional analysis. As reported in Fig.6A-B, we identified microbial pathways significantly enriched in all the three groups. In detail, microbial pathways related to replication and repair, DNA repair and recombination proteins and DNA replication, among the totality identified, were found significantly enriched in the mice co-colonized with the genotoxic E. coli SP15clb+ strain (Fig.6B).

Overall, these data show that 35 days after birth, the E. coli genotoxic activity profoundly affect the gut microbiota at a both taxonomical and functional level and that it exerts an inter-species impact on the gut microbiota.

Evolution of gut microbiota and microbiome following intestinal colonization by genotoxic or non-genotoxic E. coli SP15 strain in mice.

Next, we evaluated the effects of the infection with the above reported E. coli strains on the evolution of gut microbiota and microbiome, by comparing the two time points at day 15 and day 35 after birth. On a taxonomical level, mice that received E. coli MG1655 strain displayed increased abundance of the family Lachnospiraceae at day 35 after birth (Suppl.Fig.3A); in terms of overall diversity, the infection with E. coli MG1655 did not induce a net separation between the two time points of 15 and 35 days (Suppl.Fig.3B), albeit some microbial functions were found significantly enriched (Suppl.Fig.3C). Mice that received the non-genotoxic E. coli SP15clb- strain displayed increased abundance of the phyla Firmicutes and Deferribacteres at day 35 after birth (Suppl.Fig.4A). The overall microbial diversity between the two time points of day 15 and day 35 was not affected (Suppl.Fig.4B), albeit some microbial functions were found significantly enriched (Suppl.Fig.4C). By contrast, mice that received the genotoxic E. coli SP15clb+ strain displayed increased level of the phyla Deferribacteres and Tenericutes at day 35 after birth (Suppl.Fig.5A) and a net microbial diversity separation between the two time points of dy 15 and day 35, with cellular processes related to signalling as the identified microbial function found significantly enriched (Suppl.Fig.5C). Overall, these data show that the genotoxic E. coli SP15clb+ strain affected the gut microbiota diversity to a greater extent compared to the other E. coli strains.

In this study we report the effects of the genotoxin colibactin on both gut microbiota and microbiome in mice pups whose mothers have been colonized with either a genotoxic or a non-genotoxic E. coli strain. We adopted this protocol to follow the natural mother-to-pup vertical transmission, which is among the strongest factor for E. coli dissemination in further generations [16]. The genotoxin colibactin was demonstrated to act on eukaryotic cells by affecting DNA stability [7, 8] and to affect the host at multiple levels [9–13]. These effects are likeky to be blunted by an efficient intestinal mucus barrier, since an adherent mucus layer on epithelial cells was shown to dampen colibactin-induced DNA double strands breaks in vitro [19].

It was recently reported that another genotoxin, the cytolethal distending toxin produced by the human clinical isolate C. jejuni81-176, may affect both the microbial composition and gene expression profile of the gut microbiota of 1% dextran sulfate sodium-fed germ-free (GF) Apc^Min/+ mice colonized with C. jejuni81-176 [20]. Beyond these evidences, we investigated whether colibactin may also exert its action against other bacteria of the gut microbiota, which was not known. Our data show a time-dependent double targeting action on gut microbes: i) 15 days after birth, the maternally acquired E. coli genotoxic strain appears to exert an intra-species effect on gut microbes, by targeting bacteria from taxa belonging to the phylum Proteobacteria, to which E. coli belongs; ii) then, 35 days after birth, the action of colibactin appears directed against bacteria from Proteobacteria-unrelated taxa of the gut microbiota, such as those belonging to the phylum Firmicutes, showing an inter-species effect. Therefore, our data showing that colibactin may also target the gut microbiota support the putative antibiotic activity of colibactin [17], which may first be devoted to help genotoxic bacteria creating their own niche. Then, once the niche created, the genotoxic activity of bacteria may help them expanding their niche by targeting gut microbes of unrelated taxa. This interpretation is also supported by the effects of colibactin we observed on the gut microbiome at day 35 after birth, where microbial pathways related to DNA repair were the most affected. This evidence is in line with the capacity of colibactin to affect DNA stability [7, 8] and thus induce the DNA repairing machinery.

In terms of the evolution of the gut microbiota, the genotoxin colibactin strongly changed the overall microbial diversity from day 15 to day 35 in mice which received the genotoxic E. coli strain, compared to mice which received the non-genotoxic E. coli strain.

Our data suggest that, in mice, the bacterial genotoxin colibactin may exert its activity even against the gut microbiota, beyond its known effects on the host [7, 9]. The implication of this evidence may help understanding the benefits that the acquisition of genotoxicity may provide to pks + bacteria, such as the establishing and expanding of their own niche, within the complex microbial ecosystem which is the intestine.

Animal model and tissue collection

The animal model used in this study was already published[12]. Briefly, primiparous timed-pregnant Swiss CD1 mice were purchased from Janvier labs, housed separately under specific-pathogen-free conditions with access to food and water supplemented with streptomycin (5g/L) ad libitum. Pregnant females were inoculated once with 10⁹ bacteria by intragastric gavage the day before parturition. Mice were sacrificed in a fed state by cervical dislocation; then, caecal tissues were collected and snap-frozen in liquid nitrogen. All animal experimental procedures were approved by the local ethical committee (protocol n° CE2017031317082461V3) of Purpan University Hospital (Toulouse, France). All experiments were performed in accordance with relevant guidelines and regulations.

Strain construction

E. coli strain SP15 is an extraintestinal pathogenic E. coli (ExPEC) strain of serotype O18:K1 isolated from a patient with neonatal meningitis [21]. Strain SP15 harbors the pks island and was previously shown to produce colibactin [22]. Gene inactivation of clbP was engineered by using the lambda Red recombinase method [23] using primers clbP-P1 and clbP-P2 (Fig.S2) followed by excision of the kanamycin resistance cassette, as previously described [23], to produce strain SP15Δclb-. The functional wild-type clbP gene and the clbP gene that was site directed mutagenized to inactivate the catalytic site of the ClbP enzyme were PCR amplified from vectors pBRSK-clbP and pBRSK-clbP-S95A[24], respectively, using primers clbP-F-Bam and pBRSK-F-Bam (Fig.S2). The resulting PCR products were restricted by BamHI and cloned into vector pCM17 [25] digested by BamHI. The resulting plasmids pCM17-clbP and pCM17-clbP-S95A were transformed into strain SP15Δclb-. The resulting strains SP15clb+ and SP15clb- were demonstrated to produce and to not produce colibactin, respectively.

Taxonomic analysis of the caecum microbiota by MiSeq

Total DNA was extracted[26] from caeca at both day 15^th and day 35^th after birth. The 16S rRNA gene V3-V4 regions were targeted by the 357wf-785R primers and analyzed by MiSeq at RTLGenomics (http://rtlgenomics.com/, Texas, USA). An average of 19,825 sequences was generated per sample. A complete description of the applied bioinformatic filters is available at http://www.rtlgenomics.com/docs/Data_Analysis_Methodology.pdf. Cladograms were drawn by the Huttenhower Galaxy web application (http://huttenhower.sph.harvard.edu/galaxy/) via the LEfSe algorithm [27].

Statistical analysis

Results are presented as mean±SEM. Statistical analyses were performed by 2-ANOVA followed by a two-stage linear step-up procedure of Benjamini, Krieger and Yekutieli to correct for multiple comparisons by controlling the False Discovery Rate (<0.05) or Kruskal-Wallis test plus a two-stage step-up method of Benjamini, Krieger and Yekutieli correction for multiple comparisons by controlling the False Discovery Rate (<0.05) or Mann-Whitney test, as indicated in the figure legend, by using GraphPad Prism version 7.00 for Windows Vista (GraphPad Software, San Diego, CA). Significant values considered when P<0.05 or as reported after corrections. For cladograms, the alpha value for the factorial Kruskal-Wallis test among classes and the alpha value for the pairwise Wilcoxon test between subclasses have been changed to P<0.01, as shown on figures. Principal component analyses were drawn and diversity indices calculated with the software PAST3, version 3.19 (https://folk.uio.no/ohammer/past/). Heat-maps based on a Pearson distance and a complete linkage were drawn with the PermutMatrix software[28].

Figure S1. Time-line of the experimental protocol employed in the co-infection model of vertical mother-to-pup transmission. Figure S2. Molecular strategy used to generate the non-genotoxic and genotoxic E. coli SP15 strains. Figure S3. 15-to-35 days after birth caecum microbiota evolution of mice pups which received MG1655 E. coli. Figure S4. 15-to-35 days after birth caecum microbiota evolution of mice which received MG1655 and E. coli SP15clb- strains. Figure S5. 15-to-35 days after birth caecum microbiota evolution of mice which received MG1655 and E. coli SP15clb+ strains.

Acknowledgements

We thank the zootechnie-Purpan INSERM/UPS US006 CREFRE for excellent mouse managing. We thank Prof. Kaper JB and Ms. Jane Michalski Wilhelm for kindly providing plasmid pCM17.

Authors’ contributions

S.T., L.L., D.G. and P.M. performed mouse experiments; P.F. and M.S. extracted DNA from murine caeca; M.S. analysed gut microbiota and microbiome, prepared figures and wrote the manuscript; E.O. conceived and supervised the study. All authors gave final approval of the version to be published.

Funding

ANR-17-CE35-0010 to EO.

Competing interests

The authors declare that no conflict of interest exists.

Author details

¹IRSD, Université de Toulouse, INSERM, INRA, ENVT, UPS, Toulouse, France. ²CHU Toulouse, Hôpital Purpan, Service de bactériologie-hygiène, 31024, Toulouse, France.

*corresponding authors : [email protected], https://orcid.org/0000-0003-4644-8532,Tel: +33 5 62 74 45 25 ; [email protected], https://orcid.org/0000-0002-3017-0081 Tel: + 33 5 67 69 04 15.

^$equal contribution

Availability of data and materials. All data are available in the main text or the supplementary materials and via the following repositories: Sequence Read Archive (SRA) database https://submit.ncbi.nlm.nih.gov/subs/sra/ with the assigned identifier PRJNA593936.

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

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Journal Publication

published 26 Aug, 2020

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The Genotoxin Colibactin Shapes Gut Microbiota in Mice

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