Biology subjects

Jobin, C.

Publications and source records attributed to Jobin, C..

8 recordsLinked to original sources

bioRxiv2026

Effects of Polyunsaturated Fatty Acids and Selenoneine on Growth and Lipidomic Profiles in Patient-Derived Prostate Cancer Organoids

Prostate cancer (PCa) is the second most frequent cancer in men and represents a major public health issue worldwide. To complement current therapeutic approaches, our work aims to understand the impact of nutritional interventions on PCa evolution. Recent studies showed that supplementation with omega-3 fatty acids reduces tumour growth in PCa mouse models. Several beneficial effects were observed, particularly on the gut microbiome, suggesting indirect effects on tumours, and whether these fatty acids have a direct molecular impact on the prostate remains elusive. Here, we hypothesized that the prostate directly takes up dietary fatty acids to reprogram metabolism, which could contribute to the beneficial effects on cancer treatment. To test this hypothesis, five series of patient-derived organoids (PDOs), with paired lines originating from normal and tumour samples, were treated with omega-3 and omega-6 fatty acids. While heterogeneity was observed in growth capacities of PDO lines, omega-3 supplementation overall decreased PDO growth, with a stronger decrease in PCa lines. This effect was stronger when co-treated with selenoneine, a nutrient enriched in some marine foods with high omega-3 content. Lipidomic experiments were then performed, revealing that PDOs can take up fatty acids, both omega-3 and omega-6. Furthermore, PDOs could metabolize omega-3 fatty acids into downstream metabolites, even if high inter-patient heterogeneity was observed. Altogether, this study, using PDOs as a working model to study the human prostate, provides a better understanding of the molecular impacts of fatty acid supplementation on prostate and PCa biology for the development of future nutritional interventions.

cancer biology↗

bioRxiv2025

A defined bacterial consortium and spatial transcriptomics highlight the complex interaction between Campylobacter jejuni and the murine intestine

The intestinal microbiota influences host susceptibility to Campylobacter jejuni (C. jejuni) infection. However, the interaction between specific intestinal bacteria and the C. jejuni-mediated host response is unclear. We established a defined consortium of bacteria to delineate C. jejuni-induced host responses. Three groups of germ-free (GF) Il10-/- mice were used in this study: 1) mice colonized with a defined consortium of 13 bacterial isolates (C13) representing the four most prominent phyla in the mouse gut. 2) C13 plus C. jejuni 81-176 and 3) GF alone. The C13 + C. jejuni group induced significant intestinal inflammation and inflammatory mRNA gene expression compared to mice colonized with C13. 16S rRNA gene sequencing revealed an increased relative abundance of Escherichia and Paraclostridium in C13 + C. jejuni. Fluorescence in situ hybridization (FISH) and RNAscope integrated with spatial transcriptomics provided a high-resolution map of infection-induced gene expression, revealing localized immune responses and epithelial remodeling in defined colonic regions. Region-specific analysis further demonstrated that tissue-associated C. jejuni differentially modulates host gene expression compared to tissue-associated Enterobacteriaceae. Collectively, these findings demonstrate the potential of defined microbial consortia and spatially resolved transcriptomics to dissect the complex interplay between host, microbiota, and pathogens during enteric infection.

microbiology↗

bioRxiv2025

Cooperation Between Genotoxic Bacteria Accelerates Tumorigenesis in a Mouse Model of Colon Carcinogenesis

To identify causal links between gut microbes and tumorigenesis, we colonized groups of germ-free colon tumor-susceptible mice (ApcMin/+;Il10-/-) with 15 cultured human fecal microbiotas from healthy individuals, as well as patients with inflammatory bowel disease and colorectal cancer. The number of colonic tumors in ApcMin/+;Il10-/- mice varied by donor microbiota but not by the health status of the donor. In vitro screens of host cell proliferation, genotoxicity, and inflammation in bacteria-mammalian cell cocultures revealed that genotoxicity best predicted tumorigenic microbes in vivo with genotoxic microbes present in all tested individuals. The genotoxic subset of strains from each donor induced more tumors than the complete community - even when the complete community was not tumorigenic. Combining genotoxic microbes from multiple sources increased tumor number and decreased the time to tumor onset. Together these results suggest that most individuals harbor genotoxic bacterial strains and the balance of genotoxic to protective strains determines the timing and severity of tumorigenesis in vivo.

microbiology↗

bioRxiv2024

Metabolic immaturity of newborns and breast milk bile acids are the central determinants of heightened neonatal vulnerability to norovirus diarrhea

Noroviruses are the leading global cause of acute gastroenteritis, responsible for 685 million annual cases. While all age groups are susceptible to noroviruses, children are vulnerable to more severe infections than adults, underscored by 200 million pediatric cases and up to 200,000 deaths in children annually. Understanding the basis for the increased vulnerability of young hosts is critical to developing effective treatments. The pathogenic outcome of any enteric virus infection is governed by a complex interplay between the virus, intestinal microbiota, and host immune factors. A central mediator in these complex relationships are host- and microbiota-derived metabolites. Noroviruses bind a specific class of metabolites, bile acids, which are produced by the host and then modified by commensal bacterial enzymes. Paradoxically, bile acids can have both proviral and antiviral roles during norovirus infections. Considering these opposing effects, the microbiota-regulated balance of the bile acid pool may be a key determinant of the pathogenic outcome of a norovirus infection. The bile acid pool in newborns is unique due to immaturity of host metabolic pathways and developing gut microbiota, which could underlie the vulnerability of these hosts to severe norovirus infections. Supporting this concept, we demonstrate herein that microbiota and their bile acid metabolites protect from severe norovirus diarrhea whereas host-derived bile acids promote disease. Remarkably, we also report that maternal bile acid metabolism determines neonatal susceptibility to norovirus diarrhea during breastfeeding by delivering proviral bile acids to the newborn. Finally, directed targeting of maternal and neonatal bile acid metabolism can protect the neonatal host from norovirus disease. Altogether, these data support the conclusion that metabolic immaturity in newborns and ingestion of proviral maternal metabolites in breast milk are the central determinants of heightened neonatal vulnerability to norovirus disease.

microbiology↗

bioRxiv2022

Hematopoietic-specific heterozygous loss of Dnmt3a exacerbates colitis-associated colon cancer

Clonal hematopoiesis (CH) is defined as clonal expansion of mutant hematopoietic stem cells absent diagnosis of a hematologic malignancy. Presence of CH in solid tumor patients, including colon cancer, correlates with shorter survival. We hypothesized that bone marrow-derived cells with heterozygous loss-of-function mutations of DNMT3A, the most common genetic alteration in CH, contribute to the pathogenesis of colon cancer. In a mouse model that combines colitis-associated colon cancer with experimental CH driven by Dnmt3a+/{Delta}, we found higher tumor penetrance and increased tumor burden compared to controls. Histopathological analysis revealed accentuated colonic epithelium injury, dysplasia and adenocarcinoma formation. Transcriptome profiling of colon tumors identified enrichment of gene signatures associated with carcinogenesis, including angiogenesis. Treatment with the angiogenesis inhibitor axitinib eliminated the colon tumor-promoting effect of experimental CH driven by Dnmt3a haploinsufficiency. This study provides conceptually novel insights into non-tumor-cell-autonomous effect of hematopoietic alterations on colon carcinogenesis and identifies potential therapeutic strategies. SUMMARYA pre-clinical mouse model demonstrates that genetic alterations in the blood system characteristic of clonal hematopoiesis (CH) contribute to an aggressive solid tumor phenotype. It further identifies cancer angiogenesis as a potential therapeutic target to mitigate adverse CH effects.

cancer biology↗

bioRxiv2020

Microbiota Accelerates Age-Related CpG island Methylation in Colonic Mucosa

DNA methylation is an epigenetic mark that is altered in cancer and aging tissues. The effects of extrinsic factors on DNA methylation remain incompletely understood. Microbial dysbiosis is a hallmark of colorectal cancer, and infections have been linked to aberrant DNA methylation in cancers of the GI tract. To determine the microbiotas impact on DNA methylation, we studied the methylomes of colorectal mucosa in germ-free (no microbiota) and specific-pathogen-free (controlled microbiota) mice, as well as in Il-10 KO mice (Il10-/-) which are prone to inflammation and tumorigenesis in the presence of microbiota. The presence of microbiota was associated with changes in 5% of the methylome and Il10-/- mice showed alterations in 4.1% of the methylome. These changes were slightly more often hypo than hypermethylation and affected preferentially CpG sites located in gene bodies and intergenic regions. Mice with both Il-10 KO and microbiota showed much more pronounced alterations, affecting 18% of the methylome. When looking specifically at CpG island methylation alterations, a hallmark of aging and cancer, 0.4% were changed by the microbiota, 0.4% were changed by Il10-/-, while 4% were changed by both simultaneously. These effects are comparable to what is typically seen when comparing colon cancer to normal. We next compared these methylation changes to those seen in aging, and after exposure to the colon carcinogen Azoxymethane (AOM). Aging was associated with alterations in 18% of the methylome, and aging changes were accelerated in the Il10-/- /SPF mice. By contrast, AOM induced profound hypomethylation that was distinct from the effects of aging or of the microbiota. CpG sites modified by the microbiota were over-represented among DNA methylation changes in colorectal cancer. Thus, the microbiota affects the DNA methylome of colorectal mucosa in patterns reminiscent of what is observed in aging and in colorectal cancer.

microbiology↗

bioRxiv2019

Bacterial Hyperswarming as a Protective Response to Intestinal Stress

Bacterial swarming, a collective movement on a surface, has rarely been associated with human pathophysiology. Here, we report for the first time that bacterial swarmers are associated with protection against intestinal inflammation. We show that bacterial swarmers are highly predictive of intestinal stress in mice and humans. We isolated a novel Enterobacter swarming strain, SM3, from mouse feces. SM3 and other known commensal swarmers contrast to their respective swarming-deficient, but swimming-competent isogenic strains abrogated intestinal inflammation in mice. Treatment of colitic mice with SM3, but not its mutants, enriched beneficial fecal anaerobes belonging to the family, Bacteroidales S24-7. We observed SM3 swarming associated pathways in the in vivo fecal metatranscriptomes. In vitro growth of S24-7 was enriched in presence of SM3 or its mutants conjecturing that bacterial swarming in vivo might influence SM3s access to S24-7 in the intestines. Overall, our work identifies a new paradigm in which intestinal stress allows for the emergence of swarming bacteria, which can counterintuitively heal intestinal inflammation.

microbiology↗

bioRxiv2019

Yersiniabactin producing AIEC promote inflammation-associated fibrosis in gnotobiotic Il10-/- mice

Fibrosis is a significant complication of intestinal disorders associated with microbial dysbiosis and pathobiont expansion, notably Crohns disease (CD). Mechanisms that favor fibrosis are not well understood and therapeutic strategies are limited. Here we demonstrate that colitis susceptible Il10-deficient mice develop inflammation-associated fibrosis when mono-associated with adherent/invasive Escherichia coli (AIEC) that harbor the yersiniabactin (Ybt) pathogenicity island. Inactivation of Ybt siderophore production in AIEC nearly abrogated fibrosis development in inflamed mice. In contrast, inactivation of Ybt import through its cognate receptor FyuA enhanced fibrosis severity. This corresponded with increased colonic expression of profibrogenic genes prior to the development of histological disease, therefore suggesting causality. FyuA-deficient AIEC also exhibited greater localization within sub-epithelial tissues and fibrotic lesions that was dependent on Ybt biosynthesis and corresponded with increased fibroblast activation in vitro. Together, these findings suggest that Ybt establishes a pro-fibrotic environment in the host in the absence of binding to its cognate receptor and indicates a direct link between intestinal AIEC and the induction of inflammation-associated fibrosis.

microbiology↗