Biology subjects

Clavel, T.

Publications and source records attributed to Clavel, T..

At least 19 recordsLinked to original sources

bioRxiv2026

A microbiota-derived protease links phage susceptibility to host epithelial responses

Bacteriophages are major ecological drivers of gut microbial ecology, yet whether bacterial mechanisms that determine phage susceptibility have consequences for the mammalian host remains poorly understood. Here, we identify dipeptidyl peptidase 11 (Dpp11a), the predominant active serine protease of the prevalent gut commensal Phocaeicola vulgatus, as an unexpected bacterial defence factor. Dpp11a protects against environmental proteases and confers resistance to bacteriophage infection. Metatranscriptomic analyses further reveal increased expression of both dpp11a and P. vulgatus-associated phage transcripts in ulcerative colitis stool samples, indicating that both components of this interaction are transcriptionally active in disease-associated human microbiomes. Using the microfluidic gut-on-a-chip co-culture model HuMiX, we show that the absence of Dpp11 is accompanied by altered epithelial tight-junction remodelling during phage-bacterial infection. Together, our findings reveal that the consequences of bacterial phage defence can extend beyond phage-bacterium interactions to the mammalian epithelium.

microbiology↗

bioRxiv2026

Swimming motility in the gut microbiota is diverse and increased in inflammation.

Swimming motility has long been studied as a virulence mechanism of enteric pathogens, while the resident microbiota's motility has only been inferred from proxies or explored through a few model species. This study presents a direct, functional analysis of gut bacterial motility in health and inflammation. Using phase-contrast microscopy and high-throughput 3D tracking, we quantified motile bacteria and characterized their swimming behaviours directly in diluted fresh gut content. In healthy mice, fewer than 3% of bacteria were motile along the digestive tract, and their swimming patterns were dominated not by the run-tumble behavior of model gut species but by diverse behaviours rich in reverses. In five mouse models with intestinal inflammation (spanning chemical, genetic, dietary and infectious etiologies) the motile fraction rose by at least 4-fold, correlating with elevated Lipocalin-2 where measured. Reverse-rich patterns remained prevalent in these inflamed conditions, with the notable exception of Salmonella infection. Paired metagenomics and metatranscriptomics showed enrichment of flagellar genes, while communities transferred into cecal water from inflamed mice raised their motile fraction within an hour, indicating that the rise reflects both enrichment of motile taxa and rapid modulation within existing populations. In vitro assays with human-derived isolates confirmed motility across several phyla, with variability down to strain level, and identified oxygen and viscosity as key modulators. These findings support increased motility as a hallmark of the inflamed gut and challenge established assumptions about gut bacterial motility.

microbiology↗

bioRxiv2026

Mixed acid fermentation products from Lachnospira eligens counteract myotube atrophy

IntroductionAcute myeloid leukemia (AML) is a hematological malignancy associated with muscle wasting. As the relative abundance of Lachnospira eligens was reduced in patients with AML compared to healthy individuals and correlated positively with muscle strength, we hypothesized that L. eligens positively impacts the muscle through the production of small metabolites reaching the systemic circulation. MethodsL. eligens levels were analyzed in two additional independent cohorts. Six L. eligens isolates were characterized through whole-genome sequencing to select clinically relevant strains. The composition of their culture supernatant was analyzed by metabolomics. The impact of L. eligens supernatant on dexamethasone- and interleukin-6-atrophied murine myotubes was assessed. Bioactive metabolites and their production mechanism were identified using among others bioactivity-guided fractionation. The underlying mechanism was also explored on the host side through myotubes transcriptome analysis and metabolic flux analysis. The relevance of bioactive metabolites and their production mechanism was evaluated through clinical data and samples analyses and in a mouse model of leukemia. ResultsThe levels of L. eligens are reduced in independent cohorts of patients with AML and its supernatant counteracts myotube atrophy. This anti-atrophic effect, conserved between strains of the same species, depends on the occurrence of mixed acid fermentation (MAF) in anoxic culture conditions and the presence of its acid end-products acetate, formate and D-lactate. Consistent with those results, blood levels of acetate are decreased and the relative abundance of fecal bacteria capable of performing aerobic respiration is increased in patients with AML. However, bacterial supernatant failed to prevent muscle atrophy and weakness in leukemic mice, likely due to insufficient sustained elevation of acid end-products in the blood. ConclusionThis work reveals the anti-atrophic effect of MAF end-products on myotubes and suggests the importance of considering gut electron acceptor levels (e.g. O2) in disorders affecting muscle health. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=133 SRC="FIGDIR/small/729780v1_ufig1.gif" ALT="Figure 1"> View larger version (40K): org.highwire.dtl.DTLVardef@112529eorg.highwire.dtl.DTLVardef@1ee1929org.highwire.dtl.DTLVardef@b5f389org.highwire.dtl.DTLVardef@187bc40_HPS_FORMAT_FIGEXP M_FIG Mixed acid fermentation products from Lachnospira eligens counteract myotube atrophy. Our study suggests that gut anaerobiosis is disrupted in treatment-naive patients with acute myeloid leukemia (AML), leading to decreased circulating acetate levels and a reduced relative abundance of L. eligens, which significantly correlated with muscle strength. In line with this framework, in vitro experiments demonstrate that the culture supernatant of L. eligens, which contains mixed acid fermentation (MAF) end-products such as acetate, effectively counteracts C2C12 myotube atrophy in the presence of pro-atrophying stimuli. Further mechanistic experiments indicate a causal role for MAF end-products in this anti-atrophying effect. Created with BioRender.com. Legend: solid frames: experimental results; dashed frames: hypothetical conclusions derived from results; black solid arrow: established correlation; black dashed arrows: hypothetical causation. C_FIG

microbiology↗

bioRxiv2026

A mixture of plant polyphenols unexpectedly aggravates liver metastasis of colorectal cancer in mice

Epidemiological studies suggest that vegetarian diets are associated with lower cancer incidence and mortality, an effect attributed in part to phytochemicals such as polyphenols and carotenoids. Although numerous in vitro experiments and investigations using immunodeficient rodent models report tumor-suppressive activities of phytochemicals, their impact on tumor progression in immunocompetent hosts remains insufficiently understood. Here, we examined the influence of a defined plant phytochemical mixture (PPM) on the growth of colon cancer liver metastases, both in vitro and in immunocompetent mice. Consistent with the prevailing literature, treatment of the murine colon cancer cell line MC38 with the PPM significantly reduced cell proliferation and survival in vitro. Strikingly, however, administration of the PPM to mice bearing MC38-derived hepatic metastases markedly accelerated tumor growth. Immunohistochemical analyses revealed a significantly increased accumulation of immune cells--specifically CD45 leukocytes and F4/80 macrophages--at the periphery of the metastatic lesions in PPM-treated animals. To assess the functional relevance of this inflammatory response, the PPM was combined with the anti-inflammatory drug prednisolone. This intervention resulted in significantly reduced metastatic burden, supporting the notion that the PPM exacerbates tumor progression through enhanced peritumoral inflammation. These findings highlight the importance of validating observations from cell culture and immunodeficient models in fully immunocompetent systems. They further emphasize that the immunomodulatory effects of plant phytochemicals warrant careful and comprehensive investigation.

cancer biology↗

bioRxiv2026

Macrophage renewal in the small intestine governs early-life control of streptococci

Group B Streptococcus (GBS) is both a common intestinal colonizer that is transmitted intergenerationally, and a primary cause of neonatal sepsis worldwide. However, the innate immune mechanisms that restrict the pathogen at the intestinal barrier early in life remain poorly understood. Using an enteral GBS-colonization model in infant mice, we found that lamina-propria (LP) macrophages controlled both GBS-colonization densities and invasion in an age-dependent fashion. LP macrophages turnover and differentiation were strongly impacted by topology. In the small intestine, monocytes infiltration of the LP occurred from birth on in response to perinatally acquired microbiota, whereas in the colon it was driven by the weaning reaction. Moreover, macrophages of the small intestine mounted a robust, MyD88-dependent inflammatory response to GBS, while those of the colon remained largely unaffected. Together, these findings demonstrate that region-specific macrophage dynamics early in life critically influence host-pathogen-interactions during GBS-colonization.

immunology↗

bioRxiv2026

Neonatal liver niches program T cell tolerance

After birth, the immune system must learn to tolerate a rapidly changing milieu of commensals and self while remaining ready for pathogens. Here we characterize the neonatal liver as a central hub in this process: In postnatal week 1-2, the liver hosts a developmentally encoded, microbiota-independent expansion of regulatory T cells (Tregs) that coexists with microbiota-tuned conventional wave of activated CD4 T cells (Tconvs). Mechanistically, the Treg expansion is governed by MHCII-mediated antigen presentation by CCR7+ cDC1s, which establish tolerogenic DC:T cell clusters in the liver parenchyma, allowing for local expansion and control via PD-L1 checkpoints that selectively increase Tregs without unleashing Tconvs. Importantly, this transient, neonatal program predisposes hepatotropic viral infections to progress toward chronic disease but also protects the adult liver from steatotic disease. These data position the neonatal liver as a unique site of early life T-cell education with timing-sensitive implications for early-life interventions.

immunology↗

bioRxiv2025

The adhesion molecules β7 integrin and L-selectin contribute to cholestatic liver disease in male mice

Background & AimsPrimary sclerosing cholangitis (PSC) is a long-term progressive disease, often occurring in conjunction with inflammatory bowel disease (IBD). Dysregulated immune cell migration and gut microbiota alterations are implicated in disease progression. Livers of PSC patients show upregulation of the endothelial ligand mucosal addressin cell-adhesion molecule-1 (MAdCAM-1). Here we examined the role of the leukocytic adhesion molecules (AM) {beta}7 integrin and L-selectin, both binding partners of MAdCAM-1, in an experimental mouse model resembling aspects of human PSC. MethodsWild type (WT), {beta}7 integrin-deficient ({beta}7-/-), L-selectin-deficient (L-sel-/-), and L-selectin/{beta}7 integrin double-deficient (L-sel-/-/{beta}7-/-) male mice were compared in the model of 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-induced cholangiopathy. The extent of pathology was evaluated by serum parameters, histology, flow cytometry, and expression of inflammatory mediators. Fecal microbiota changes were assessed by 16S rRNA amplicon sequencing and intestinal permeability was measured by FITC-dextran assay. ResultsAM-deficient mice were markedly protected from DDC-induced cholangiopathy. Hepatic immune cell populations of AM-deficient mice differed significantly from those of WT mice. Adoptively transferred {beta}7-/- CD8+ T cells caused significantly less liver damage than CD8+ WT T cells in DDC-treated {beta}7-/- mice. DDC-feeding caused substantial changes in fecal microbiota profiles, which differed between the mouse strains, and a strong increase in intestinal permeability that was significantly lower in {beta}7-/- than WT mice. Conclusions{beta}7 integrin and L-selectin contribute to DDC-induced cholangiopathy with {beta}7 integrin-expressing CD8+ T cells playing a crucial role in promoting pathogenesis. In addition, AM-expressing immune cells may contribute to the inflammatory process by causing unfavorable gut microbiota shifts and destabilizing the gut barrier. Synopsis{beta}7 integrin- and/or L-selectin-deficient mice are less susceptible to 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-induced experimental cholangiopathy. {beta}7 integrin-expressing CD8+ T cells contribute to DDC-induced pathogenesis. {beta}7 integrin promotes DDC-induced gut barrier dysfunction and microbiota shifts, potentially exacerbating hepatic injury.

immunology↗

bioRxiv2025

Intercellular adhesion molecule-1 protects against adipose tissue inflammation and insulin resistance but promotes liver inflammation and hepatic fibrosis in mice

Metabolic dysfunction associated steatotic liver disease (MASLD) presents a growing global health problem with a range of manifestations, including steatosis, steatohepatitis, and cirrhosis. It is strongly associated with obesity, disease progression being promoted not only by hepatic leukocyte accumulation but also by inflammatory signals from adipose tissue and an altered gut microbiome. To determine the contribution of intercellular adhesion molecule-1 (ICAM-1) to MASLD pathogenesis, mice with an ICAM-1 mutation (Icam1tmBay) were compared to wild type (WT) mice in a Western-style diet (WD) model. WD-induced MASLD was accompanied by increased ICAM-1 expression in liver, epididymal white adipose tissue (EWAT), and intestine in WT mice. WD-fed Icam1tmBay mice exhibited increased circulating neutrophils, higher frequencies of inflammatory leukocytes in EWAT, and a worsened glucose tolerance when compared to WT mice. In contrast, the mutation resulted in reduced WD-induced liver damage and less accumulation of intrahepatic leukocytes. WD-feeding caused substantial changes in fecal microbiota with decreased microbial diversity that differed between the mouse strains. In conclusion, ICAM-1 positively regulates adipose tissue homeostasis and protects from insulin resistance but promotes liver damage in diet-induced obesity. This points to various organ-specific roles for ICAM-1 and the potential of liver-specific targeting of ICAM-1 for treatment of MASLD.

immunology↗

bioRxiv2025

Function-Based Selection of Synthetic Communities Enables Mechanistic Microbiome Studies

Understanding the complex interactions between microbes and their environment requires robust model systems such as synthetic communities (SynComs). We developed a functionally directed approach to generate SynComs by selecting strains that encode key functions identified in metagenomes. This approach enables the rapid construction of SynComs tailored to any ecosystem. To optimize community design, we implemented genome-scale metabolic models, providing in silico evidence for cooperative strain coexistence prior to experimental validation. Using this strategy, we designed multiple host-specific SynComs, including those for the rumen, mouse, and human microbiomes. By weighting functions differentially enriched in diseased versus healthy individuals, we constructed SynComs that capture complex host-microbe interactions. Notably, we designed an inflammatory bowel disease SynCom of 10 members that successfully induced colitis in gnotobiotic IL10-/- mice, demonstrating the potential of this method to model disease-associated microbiomes. Our study establishes a targeted framework for designing SynComs to advance mechanistic insights into host-microbe interactions. HighlightsO_LIAutomated functional selection of SynComs based on metagenomic data C_LIO_LIEcosystem-specific SynComs capture the functional landscape of microbiota C_LIO_LIColitis-inducing SynCom developed as a model for inflammatory bowel diseases C_LI

microbiology↗

bioRxiv2025

Benchmarking of shotgun sequencing depth highlights strain-level limitations of metagenomic analysis

Shallow metagenomics promises taxonomic and functional insights into samples at an affordable price. To determine the depth of sequencing required for specific analysis, benchmarking is required using defined microbial communities. We used complex mixtures of DNA from cultured gut bacteria and analysed taxonomic composition, strain-level resolution, and functional profiles at up to eleven sequencing depths (0.1-50.0 Gb). Reference-based analysis provided accurate taxonomic, and strain-level insights at 0.5-1.0 Gb. In contrast, de-novo metagenome-assembled genome (MAG) reconstruction required deep sequencing (>10 Gb), and even high-quality MAGs were chimeric, with 54.5 to 81.8 % accurately representing the original strains, depending on the bioinformatic approach used. However, the issue of chimeric MAGs can be reduced by using strain-aware assembly methods or long-read sequencing. Functionally, 2 Gb provided reliable insights at the pathway level, but sufficient proteome coverage was only achieved at or above 10 Gb. Library preparation and host DNA contamination were identified as confounders in shallow metagenomic analysis. This comprehensive analysis using complex mock communities provides guidance to an increasing community of scientists interested in using shallow metagenomics, and highlights the limitations of MAGs in accurately capturing strain-level diversity.

microbiology↗

bioRxiv2025

Robust genome-based delineation of bacterial genera

BackgroundGenomic analysis has become essential in bacterial taxonomy, enabling fast classification of bacteria. However, quantifiable measures to make informed decision on the taxonomic placement of bacterial taxa above the level of species are rare, which hampers the stability of knowledge in databases and articles. In this work, we focused on bacterial classification at the genus level and revisited the concept of Percentage Of Conserved Proteins (POCP). Whilst POCP is broadly used as an overall genome relatedness index, the underlying tool and method of calculation differ, resulting in disparate implementations and misnomers unfit for the increasing wealth of public genomes available. ResultsWe evaluated 10 protein alignments methods and found evidence for a scalable yet robust alternative to BLASTP for POCP based on 2,358,466 pairwise comparisons of 4,767 genomes across 35 families. However, we showed that certain combinations of tools and parameters are not suited for POCP calculations owing to drastic over-or underestimation. Therefore, we bring forward a clearer definition of POCP using only unique matches, termed POCPu, that showed better genus delineation than with POCP. We suggested tentative family-specific thresholds when the standard of 50% was not resolutive enough. ConclusionsWe propose that faster bacterial genus delineation should be calculated with DIAMOND using very-sensitive settings and only unique matches (POCPu). We advise microbiologists to carefully assess that the tools used for genus assignment match their biological assumptions to avoid misguided inferences.

microbiology↗

bioRxiv2025

Modulation of intestinal bile acids influences colonic mucosal responses

BackgroundElevated levels of secondary bile acids produced by the gut microbiome, in particular deoxycholic acid (DCA), influence epithelial cell proliferation and accelerate the development of colorectal cancer (CRC) under adverse dietary conditions, such as long-term, high fat intake. However, their effects on the intestinal epithelium have not been studied in detail. AimTo determine gut epithelial responses to bile acid modulation in vivo and in situ. MethodsWe performed targeted colonization of gnotobiotic mice followed by single-cell RNA sequencing (scRNA-Seq) of colonic epithelial cells combined with immunostaining of human biopsies from: (i) an observational patient cohort with hyperproliferative polyps or cancer; (ii) an interventional study with bile acid-scavenging drugs. ResultsColonization of mice with a synthetic bacterial community together with the 7-dehydroxylating species Extibacter muris resulted in DCA production. ScRNA-Seq of colonic epithelial cells revealed increased cell density of bile acid-sensitive enterocytes but fewer stem cells, goblet cells, and transit amplifying cells in mice exposed to DCA. This was associated with increased expression of pyruvate dehydrogenase kinase (Pdk4) and decreased expression of mucin (Muc2). PDK expression was also increased in human hyperplastic polyps and adenomas, whilst MUC2 expression was reduced in adenomas and carcinomas compared to normal mucosa. In addition, human exposure to bile acid sequestrants was associated with enhanced epithelial proliferation. ConclusionThis study provides insight into intestinal epithelial cell responses to bile acids and their potential clinical relevance.

physiology↗

bioRxiv2024

Broad diversity of human gut bacteria accessible via a traceable strain deposition system

Numerous bacteria in the human gut microbiome remain unknown and/or have yet to be cultured. While collections of human gut bacteria have been published, few strains have been made publicly available. A major hurdle in making strains publicly available is their deposition to public culture collections. We propose a framework for the bulk-deposition of strains to culture collections, which removes many of the barriers previously identified (www.dsmz.de/bulk-deposit). Using this bulk-deposition system we have created a publicly available collection of human gut isolates. The Human intestinal Bacteria Collection (HiBC) (www.hibc.rwth-aachen.de) contains 340 strains representing 198 species within 29 families and 7 phyla, of which 29 previously unknown species are taxonomically described and named. These included two butyrate-producing species of Faecalibacterium and new dominant species associated with health and inflammatory bowel disease, Ruminococcoides intestinale and Blautia intestinihominis, respectively. Plasmids were prolific within the HiBC isolates, with almost half (46%) of strains containing plasmids, with a maximum of six within a strain. This included a broadly occurring plasmid (pBAC) that exists in three diverse forms across Bacteroidales species. Megaplasmids were identified within two strains, the pMMCAT megaplasmid is globally present within multiple Bacteroidales species. This collection of easily searchable and publicly available gut bacterial isolates will facilitate functional studies of the gut microbiome.

microbiology↗

bioRxiv2024

Lineage-specific microbial protein prediction enables large-scale exploration of protein ecology within the human gut

Microbes use a range of genetic codes and gene structures, yet these are ignored during metagenomic analysis. This causes spurious protein predictions, preventing functional assignment which limits our understanding of ecosystems. To resolve this, we developed a lineage-specific gene prediction approach that uses the correct genetic code based on the taxonomic assignment of genetic fragments, removes partial predictions, and optimises prediction of small proteins. Applied to 9,634 metagenomes and 3,594 genomes from the human gut, this approach increased the landscape of captured expressed microbial proteins by 78.9%, including previously hidden functional groups. Optimised small protein prediction captured 3,772,658 small protein clusters, many with antimicrobial activity. Integration of the protein sequences and sample metadata into a tool, InvestiGUT, enables association of protein prevalence with host parameters. Accurate prediction of proteins is critical for understanding the functionality of microbiomes, hence this work will enhance understanding mechanistic interactions between microbes and hosts.

bioinformatics↗

bioRxiv2023

A gut meta-interactome map reveals modulation of human immunity by microbiome effectors

The molecular mechanisms by which the gut microbiome influences human health remain largely unknown. Pseudomonadota is the third most abundant phylum in normal gut microbiomes. Several pathogens in this phylum can inject so-called virulence effector proteins into host cells. We report the identification of intact type 3 secretion systems (T3SS) in 5 - 20% of commensal Pseudomonadota in normal human gut microbiomes. To understand their functions, we experimentally generated a high-quality protein-protein meta-interactome map consisting of 1,263 interactions between 289 bacterial effectors and 430 human proteins. Effector targets are enriched for metabolic and immune functions and for genetic variation of microbiome-influenced traits including autoimmune diseases. We demonstrate that effectors modulate NF-{kappa}B signaling, cytokine secretion, and adhesion molecule expression. Finally, effectors are enriched in metagenomes of Crohns disease, but not ulcerative colitis patients pointing toward complex contributions to the etiology of inflammatory bowel diseases. Our results suggest that effector-host protein interactions are an important regulatory layer by which the microbiome impacts human health.

microbiology↗

bioRxiv2023

Secondary bile acid production by gut bacteria promotes Western diet-associated colorectal cancer

Western diet is an important risk factor for the development of sporadic colorectal cancer (CRC). Dietary fat stimulates bile acid (BA) production by the host and their conversion to secondary BAs by 7-dehydroxylating (7DH+) bacteria, but causal proof of their tumor-promoting effects in vivo is lacking. To address this, we performed feeding studies in a genetically engineered pig model of CRC combined with multi-omics analyses and gnotobiotic mouse studies. Western diet worsened the disease phenotype in APC1311/+ pigs. This was accompanied by microbiota changes, increased levels of the secondary bile acid deoxycholic acid (DCA), and higher colonic epithelial cell proliferation. The latter was counteracted by using the BA-scavenging drug colestyramine. Metagenomic analysis across multiple cohorts revealed higher occurrence of bai (BA inducible) operons from Clostridium scindens and close relatives in stool of CRC subjects (n = 1,034). Using two gnotobiotic mouse models of CRC, we demonstrate that colonization with 7DH+ bacteria (C. scindens or Extibacter muris) increased colonic tumor loads. This work provides clear evidence for the causal role of microbiome-derived DCA production in CRC under detrimental dietary conditions, opening avenues for future preventive strategies.

microbiology↗

bioRxiv2022

A physiologically based model of bile acid metabolism in mice

Bile acid (BA) metabolism is a complex system that includes a wide variety of primary and secondary, as well as conjugated and unconjugated BAs that undergo continuous enterohepatic circulation (EHC). Alterations in both composition and dynamics of BAs have been associated with various diseases. However, a mechanistic understanding of the relationship between altered BA metabolism and related diseases is lacking. Computational modeling may support functional analyses of the physiological processes involved in the EHC of BAs along the gut-liver axis. In this study, we developed a physiologically-based model of murine BA metabolism describing synthesis, conjugation, microbial transformations, systemic distribution, excretion and EHC of BAs at the whole-body level. For model development, BA metabolism of specific pathogen-free (SPF) mice was characterized in vivo by measuring BA levels and composition in various organs, expression of transporters along the gut and cecal microbiota composition. We found significantly different BA levels between male and female mice that could only be explained by adjusted expression of the hepatic enzymes and transporters in the model. Of note, this finding was in agreement with experimental observations. The model for SPF mice could also describe equivalent experimental data in germ-free mice by specifically switching of microbial activity in the intestine. The here presented model can therefore facilitate and guide functional analyses of BA metabolism in mice, e.g., the effect of pathophysiological alterations on BA metabolism and translation of results from mouse studies to a clinically relevant context through cross-species extrapolation.

systems biology↗

bioRxiv2022

Bacteriophages targeting protective commensals impair resistance against Salmonella Typhimurium infection in gnotobiotic mice

Gut microbial communities protect the host against a variety of major human gastrointestinal pathogens. Bacteriophages (phages) are ubiquitous in nature and frequently ingested via food and drinking water. Moreover, they are an attractive tool for microbiome engineering due to the lack of known serious adverse effects on the host. However, the functional role of phages within the gastrointestinal microbiome remain poorly understood. Here, we investigated the effects of microbiota-directed phages on infection with the human enteric pathogen Salmonella enterica serovar Typhimurium (S. Tm), using a gnotobiotic mouse model (OMM12) for colonization resistance (CR). We show that phage cocktails targeting Escherichia coli and Enterococcus faecalis acted in a strain-specific manner. They transiently reduced the population density of their respective target before establishing coexistence for up to 9 days. Infection susceptibility to S. Tm was markedly increased at an early time point after phage challenge. Surprisingly, OMM12 mice were more susceptible 7 days after a single phage inoculation, when the targeted bacterial populations were back to pre-phage administration density. The presence of phages that dynamically modulates the density of protective members of the gut microbiota provides opportunities for invasion of bacterial pathogens.

microbiology↗