Biology subjects

Sansonetti, P.

Publications and source records attributed to Sansonetti, P..

5 recordsLinked to original sources

bioRxiv2025

Strain-level translocation and enrichment mechanisms of oral bacteria in the lower gastrointestinal tract of stunted children

Emerging evidence suggests that ectopic colonization of oral bacteria in the lower digestive tract may exacerbate gastrointestinal disorders. Nevertheless, it remains unclear whether bacteria of oral origin are continuously translocating from the oral cavity to the lower gastrointestinal tract or are locally adapted and persist in their respective niches. We investigated strain translocation dynamics in 44 healthy and stunted children from Bangui, Central African Republic. Using cross-sectional shotgun metagenomic sequencing of saliva, gastric, duodenal and fecal samples, and isolation and whole genome sequencing of 87 Streptococcus salivarius isolates, we showed translocation of members of the genera Streptococcus, Veillonella, Rothia and Haemophilus. Fecal isolates were more closely related to oral isolates from the same individuals than those from other individuals. Additionally, saliva showed higher S. salivarius nucleotide diversity compared to other compartments, suggesting a source-sink dynamic in which S. salivarius populations are continuously seeded from the oral cavity without durably establishing in the lower gastrointestinal tract. Last, we showed that overrepresentation of oral bacteria in the duodenum of stunted children is due to increased biomass, while in the colon it is linked to depletion of overall biomass, including in butyrate-producing strains. Our study quantifies mechanisms of oral-to-gut translocation and enrichment of oral taxa, providing key insights into microbiota disruption in stunted children.

microbiology↗

bioRxiv2023

Spatially-resolved metabolomic identifies colibactin-specific principles of reprogrammed lipid metabolism to promote cancer progression.

Intratumoral bacteria locally contribute to cellular and molecular tumor heterogeneity that support cancer stemness through poorly understood mechanisms. This study aims to explore how Colibactin-producing Escherichia coli (CoPEC) flexibly alters the tumor microenvironment in right-sided colorectal cancer (CRC). Metabolomic and transcriptomic spatial profiling uncovered that CoPEC colonization establishes a high-glycerophospholipid microenvironment within the tumor that is conducive to exhaustion of infiltrated CD8+ T cell and has a lowered prognostic value in right-sided CRC. Mechanistically, the accumulation of lipid droplets in infected cancer cells relied on the production of colibactin as a measure to limit genotoxic stress and supply with sufficient energy for sustaining cell survival and lowering tumor immunogenicity. Specifically, a heightened phosphatidylcholine remodeling of CoPEC-infected cancer cells by the enzyme of the Lands cycle coincided with a lowered accumulation of proapoptotic ceramide and lysophosphatidylcholine. Consequently, a reduced infiltration of CD8+ T lymphocytes that produce the cytotoxic cytokines IFN-{gamma} was found where invading bacteria have been geolocated. By contrast, such an immunosuppressive dysmetabolic process was not observed when human colon cancer cells were infected with the mutant strain that did not produce colibactin (11G5{delta}ClbQ). This work revealed an unexpected property of CoPEC on lipid overload within tumors that could locally provide an inflammatory environment leading to immunosuppressive mechanisms and tumor expansion. This may pave the way for improving chemoresistance and subsequently outcome of CRC patients who are colonized by CoPEC.

cancer biology↗

bioRxiv2023

The oncogenic role of Streptococcus gallolyticus subsp. gallolyticus is linked to activation of multiple cancer-related signaling pathways

Streptococcus gallolyticus subsp. gallolyticus (SGG), an opportunistic gram-positive pathogen responsible for septicemia and endocarditis in the elderly, is often associated with colon cancer (CRC). In this work, we investigated the oncogenic role of SGG strain UCN34 using the azoxymethane (AOM)-induced CRC model in vivo, organoid formation ex vivo and proteomic and phosphoproteomic analyses from murine colons. We showed that SGG UCN34 accelerates colon tumor development in the murine CRC model. Full proteome and phosphoproteome analysis of murine colons chronically colonized by SGG UCN34 or the closely related non-pathogenic S. gallolyticus subsp. macedonicus (SGM) revealed that 164 proteins and 725 phosphorylation sites were differentially regulated following colonization by SGG UCN34. Ingenuity Pathway Analysis (IPA) indicates a pro-tumoral shift specifically induced following colonization by SGG UCN34, as most proteins and phosphoproteins identified were associated with digestive cancer. Comprehensive analysis of the altered phosphoproteins using ROMA software revealed significantly elevated activities in several cancer hallmark pathways affecting tumoral cells and their microenvironment, i.e. MAPK (ERK, JNK and p38), mTOR and integrin/ILK/actin signaling, in SGG UCN34 colonized colon. Importantly, analysis of protein arrays of human colon tumors colonized with SGG showed up-regulation of PI3K/Akt/mTOR and MAPK pathways, providing clinical relevance to our findings. To test SGGs capacity to induce pre-cancerous transformation of the murine colonic epithelium, we grew ex vivo organoids which revealed unusual structures with compact morphology following exposure to SGG. Taken together, our results reveal that the oncogenic role of SGG UCN34 is associated with activation of multiple cancer-related signaling pathways. Author SummaryColorectal cancer is the third most common cause of cancer mortality worldwide. The colon is a very singular organ, colonized by a vast and complex community of microorganisms, known as the gut microbiota. Strong evidence supports a role of the microbiota in colon cancer development. Streptococcus gallolyticus subsp. gallolyticus (SGG), a gut commensal, was one of the first bacteria to be associated with colorectal cancer. A better understanding of the role of SGG in colon cancer development is critical to developing novel strategies to improve clinical diagnosis and treatment of this disease. Here, using a global proteomic analysis of mouse colonic tissue colonized by SGG, we show that over 90% of the proteins with altered levels are involved in cancer. SGG colonization promotes autocrine and paracrine pro-tumor signals contributing to transformation of the colonic epithelium but also modifying the stromal microenvironment, which in turn sustains tumor development. Importantly, two tumor hallmark pathways (PI3K/Akt/mTOR and MAPK) identified in our mouse model were also found in human colon tumor biopsies colonized by SGG, strengthening the clinical relevance to our study.

microbiology↗

bioRxiv2022

Neutrophils degranulate GAG-containing proteoglycofili, which block Shigella growth and degrade virulence factors

Summary paragraphNeutrophil degranulation plays a central role in their ability to kill pathogens but also to stimulate other immune cells1-3. Here we show that neutrophil degranulation, induced in hypoxia or upon Shigella infection in vitro and in vivo, leads to the release of polymers called neutrophil Proteoglycofili (PGF). PGF are mainly composed of granular proteins (myeloperoxidase, elastase, lactoferrin, cathelicidin, albumin) pre-stored in various types of granules, and chondroitin sulfate. PGF individual fibers have a diameter of 43.9 {+/-} 20.3 nm and. They secreted by viable neutrophils and do not contain DNA, as opposed to NETs which contains also granular proteins, chondroitin sulfate in addition to chromatin, released upon neutrophil disintegration and cell death. We demonstrated that PGF block the growth of Shigella and other bacteria and degrade Shigella virulence factors. The degradation of the chondroitin sulfate polymers with testes hyaluronidases destabilizes PGF ultrastructure and abolishes its antimicrobial activity. Our results provide novel insights in the neutrophil degranulation process and open new doors for the investigation of PGF contribution to cytokines concentration gradient formation and adaptive immune cells activation. Further investigations are required to better appreciate the importance of this "sterile blaster" in infectious or inflammatory diseases.

immunology↗

bioRxiv2019

Innate immune recognition of a bacterial MAMP leads to conditional activation of pro- or anti-inflammatory responses

Microbe-associated molecular patterns (MAMPs) are recognized by pattern recognition receptors (PRRs) of the innate immune system. Flagellin, the primary component of bacterial flagella, is recognized by membrane TLR5 and cytoplasmic NLRC4 receptors, which promote a vigorous pro-inflammatory response typically associated with bacterial infection. However, herein, we report that the nature of the flagellin-induced response is highly dependent on the physiological state of the tissue. Specifically, in the steady state, epithelial cell detection of flagellin orchestrates an anti-inflammatory response mediated by IL-33-dependent type 2 regulatory T cells while, in the context of injury, it induces a pro-inflammatory response mediated by myeloid cells, IL-18 and Th17 cells. Likewise, in the absence of infection, bacterial symbionts expressing high levels of flagellin induce a type 2 response. These data demonstrate that, depending on the inflammatory state of the milieu, MAMPs can function both as immunogens or tolerogens.

immunology↗