Biology subjects

Michaud, M.

Publications and source records attributed to Michaud, M..

11 recordsLinked to original sources

bioRxiv2026

Microbial-associated acylated putrescines as immunomodulatory molecules in inflammatory bowel diseases

The gut microbiota regulates intestinal immunity through metabolite production, yet most disease-associated metabolites remain functionally uncharacterized. In inflammatory bowel diseases (IBD), where the microbial metabolome is profoundly altered, we identify N-acyl putrescines as microbiome-associated metabolites enriched across two independent cohorts. N-oleoylputrescine (NOP) emerges as the primary immunomodulatory candidate, inducing robust transcriptional responses in dendritic cells and colonic organoids. Enterocloster species harboring nonribosomal peptide synthetase gene clusters synthesize NOP, confirmed by isotope-tracing in vitro and germ-free mouse colonization in vivo. NOP suppresses core IBD inflammatory pathways in mouse dendritic cells and human monocytes, reducing signatures of histologic inflammation and therapy non-response. NOP dampens inflammation in four colitis models, decreases myeloid cell NF-{kappa}B activation, and suppresses type 1 immune responses through a T cell-intrinsic mechanism. That NOP accumulates in IBD despite its anti-inflammatory properties reveals a holobiont defense strategy: the gut microbiota deploys immunomodulatory metabolites as a compensatory response to restore homeostasis.

immunology↗

bioRxiv2026

In vivo analyses reveal rapid and permissive lipid transport between the ER and mitochondria

Interorganelle lipid transport is essential for mitochondrial membrane biogenesis and function, yet its kinetics and substrate selectivity remain poorly understood in vivo. Here, we developed two complementary approaches to quantify lipid trafficking from the endoplasmic reticulum (ER) to mitochondria in yeast. Metabolic labeling combined with organelle fractionation revealed that newly synthesized phospholipids rapidly accumulate in mitochondria, with 20-35% of newly synthesized molecules detected in mitochondrial fractions within minutes of synthesis. To directly quantify lipid flux, we established a synthetic transport assay based on the production of heterologous galactolipids absent from yeast. This approach revealed an ER-to-mitochondria transport flux of approximately 2.6 x 105 lipid molecules per cell per minute. Remarkably, galactolipids were transported with high efficiency despite their absence from fungal membranes, indicating limited substrate selectivity of ER-mitochondria lipid transport pathways. Together, these complementary assays provide quantitative tools to investigate intracellular lipid transport and reveal the rapid and permissive nature of lipid exchange between the ER and mitochondria. SummaryUsing complementary metabolic labeling and synthetic lipid reporter assays, we quantitatively measured ER-mitochondria lipid transport in yeast. Our results reveal rapid lipid exchange, high transport fluxes and limited substrate selectivity, indicating that mitochondrial lipid trafficking efficiently accommodates structurally diverse membrane lipids.

Cell Biology↗

bioRxiv2026

Spatial multi-omics of multiple myeloma uncovers niche-dependent pro-myeloma and immunosuppressive signaling in the bone marrow and extramedullary lesions

Multiple myeloma (MM) is a plasma cell malignancy shaped by dynamic interactions between MM cells and non-malignant cells in the immune microenvironment. To spatially profile the influence of cellular context on MM and immune cell expression, we developed a multimodal framework integrating 10x Genomics Visium HD, 10x Genomics Xenium, and clinically annotated single-cell RNA (scRNA-seq) sequencing datasets. Visium HD enabled unbiased, whole transcriptome, spatial discovery at 16 {micro}m resolution, Xenium provided orthogonal validation at single-cell resolution, and scRNA-seq extended findings by mapping spatial labels and leveraging the greater sequencing depth. We developed a custom framework for cell type annotation within Visium HD spatial bins. Our approach enabled identification of plasma cell-dense niches enriched for non-canonical Wnt signaling, associated with gene expression supporting cell adhesion mediated drug resistance, inferior progression-free survival, and extramedullary lesions. Immune cells within these neighborhoods exhibited suppressed transcriptional states, including increased inhibitory receptor expression such as LAG3. Utilizing the niche-driven transcriptional states in MM and immune cells, we were able to develop a 15-gene signature independently predictive of progression free survival (HR = 2.00, p < 0.0001). Collectively, this study demonstrates the potential of integrated spatial and single-cell transcriptomics to define niche-specific programs supporting MM progression.

cancer biology↗

bioRxiv2026

Soft tissue morphology of the vomeronasal organ in Lontra canadensis and its osteological correlate: Implications for the evolution of the caniform accessory olfactory system

The olfactory system plays a critical role in mammalian environmental perception, with some clades relying on an expanded accessory olfactory (vomeronasal) system (VNS) to detect larger, non-volatile odorants. Mammals make extensive use of this system for social communication between conspecifics. Recent studies have begun to investigate how the VNS changes in response to or as part of ecological transitions. Several studies have identified trends of VNS-associated gene loss or regression in secondarily aquatic mammals. However, continuing discussion on genotype-phenotype correlation within the VNS means that greater effort should be made to investigate the morphology of the VNS in species where it remains poorly understood. Here, we use skeletal and soft-tissue data to demonstrate that the vomeronasal groove, an established osteological correlate for the VNO in bats and primates, is also a valid indicator for its presence in Caniformia. Additionally, we confirm the presence of the VNO in the secondarily aquatic North American river otter (Lontra canadensis) and compare its morphology with that of two close-related species, the semi-aquatic American mink (Neogale vison) and the terrestrial long-tailed weasel (Neogale frenata). This study expands the valid taxonomic scope of the vomeronasal grooves proxy as an osteological correlate, confirms the presence of the VNO in the previously undescribed system of the North American river otter, and highlights the complexity of the mammalian accessory olfactory system.

evolutionary biology↗

bioRxiv2025

Brain size reduction in dogs was already established at least by the Late Neolithic of western Europe, 5,000 years ago

The timing and causes of brain size reduction in domestic dogs remain uncertain. Using endocasts volume as a proxy for brain size, this study provides a first insight into long-term brain size evolution in the wolf-dog lineage. We compared endocranial volumes of 185 modern and 22 prehistoric wolves and dogs ranging from Western Europe to Australia, and spanning the Pleniglacial (35 Ky BP) to the Late Neolithic (5 Ky BP). Our results reveal that Pleistocene so called "protodogs" show no brain size reduction compared to coeval Pleistocene wolves. Instead, we observed a slightly larger relative endocranial volume in the 35,000-year-old protodog from Goyet, which could suggest increased behavioural flexibility in the presence of humans. This hypothesis needs to be tested further. In contrast, Late Neolithic dogs show a drastic 46% brain size reduction with an endocranial volumes comparable to modern small terrier and toy breeds. The anxious and wary temperaments of these Late Neolithic dogs, induced by the brain tissue reorganization associated with such a size reduction, could have served an alerting purpose, among the many other potential roles dogs could have played within this Late Neolithic socio-ecosystems.

zoology↗

bioRxiv2025

Acetoacetate suppresses colon cancer via an MR1-MAIT axis

Colorectal cancer (CRC) is a leading cause of cancer mortality and additional preventative, and therapeutic strategies are urgently needed. Ketogenic diets have mixed effects on tumorigenesis and compliance is challenging. Exogenous ketones, {beta}-hydroxybutyrate ({beta}HB) or acetoacetate (AcAc), offer an alternative approach. While {beta}HB has been investigated, the anti-cancer effects of AcAc are poorly defined. Here, we show that orally administering ethyl AcAc (EAA) suppresses tumor growth in several pre-clinical CRC models. Single-cell RNA sequencing, flow cytometry, and genetic and antibody-mediated depletion studies reveal that EAA selectively expands and activates cytotoxic mucosal-associated invariant T (MAIT) cells in an MHC class I-related protein 1 (MR1)-dependent manner. EAA increases MR1 expression by tumor monocytes, which is recapitulated in human cell cultures, where AcAc and 5-amino-6-D-ribitylaminouracil (5-A-RU) induce MAIT cell expansion and tumor killing. Mechanistically, AcAc converts to methylglyoxal, combining with microbially-derived 5-A-RU to generate 5-(2-oxopropylideneamino)-6-D-ribitylaminouracil (5-OP-RU), a potent MR1 ligand. These findings identify an AcAc-MR1-MAIT cell axis as a potential immunotherapy approach for CRC therapy.

immunology↗

bioRxiv2024

DGTS overproduced in seed plants is excluded from plastid membranes and promotes endomembrane expansion

Plants and algae must adapt to environmental changes, facing various stresses that negatively impact their growth and development. One common stress is phosphate (Pi) deficiency, which is often in limiting quantity in the environment. In response to Pi deficiency, these organisms increase Pi uptake and remobilize intracellular Pi. Phospholipids are degraded to provide Pi and replaced by non-phosphorous lipids, such as glycolipids or betaine lipids. During the evolution, seed plants lost their capacity to synthesize betaine lipid. By expressing BTA1 genes, involved in the synthesis of diacylglyceryl-N,N,N-trimethyl-homoserine (DGTS), from different species, our work shows that DGTS can be produced in seed plants. In Arabidopsis, expressing BTA1 under a phosphate starvation-inducible promoter resulted in limited DGTS production without having any impact on plant growth or lipid remodeling. In transient expression systems in Nicotiana benthamiana, leaves were able to accumulate DGTS up to 20 % of their glycerolipid content at a slight expense of galactolipid and phospholipid production. At the subcellular level, we showed that DGTS is absent from plastid and seems to be enriched in endomembrane, driving an ER membrane proliferation. Finally, DGTS synthesis pathway seems to compete with PC synthesis via the Kennedy pathway but does not seem to be derived from PC diacylglycerol backbone and therefore does not interfere with the eukaryotic pathway involved in galactolipid synthesis.

plant biology↗

bioRxiv2024

Single-cell analysis of pediatric acute myeloid leukemia samples uncovers treatment-resistant stem and mast cells

Pediatric acute myeloid leukemia (pAML) is a heterogeneous malignancy driven by diverse cytogenetic mutations. While risk stratification improved by identifying cytogenetic lesions, prognostication remains inadequate with 30% of standard-risk patients experiencing relapse within 5 years. Single-cell RNA sequencing (scRNAseq) enabled the interrogation of malignant cell heterogeneity in pAML and characterization of the immune microenvironment. Herein we report the largest pAML scRNAseq analysis to date with 708,285 cells from 164 bone marrow biopsies of 95 patients and 11 healthy controls. We uncovered treatment-resistant (TR) subtypes of pAML specific to RUNX1-RUNX1T1, FLT3-ITD, and CBFB-MYH11 patients. The enrichment of TR subtype gene signatures on the TARGET pAML data supported an association with significantly poor outcomes. Intriguingly, in addition to leukemic stem cells, we identified mast cell-like pAML associated with treatment resistance and poor outcomes. Together, immature and mature pAML subtypes are promising biomarkers for identifying patients at increased risk of relapse within cytogenetic categories.

cancer biology↗

bioRxiv2024

AtVPS13M1 is involved in lipid remodeling in low phosphate and is located at the mitochondria surface in plants

VPS13 are conserved lipid transporters with multiple subcellular localizations playing key roles in many fundamental cellular processes. While the localization and function of VPS13 have been extensively investigated in yeast and animals, little is known about their counterparts in plants, particularly regarding their role in stress response. In this study, we characterized AtVPS13M1, one of the four VPS13 paralogs of the flowering plant Arabidopsis thaliana. We show that AtVPS13M1 binds and transports glycerolipids with a low specificity in vitro. AtVPS13M1 interferes with phospholipids degradation in response to phosphate starvation, a nutrient stress that triggers a massive remodeling of membrane lipids. AtVPS13M1 is mainly expressed in young dividing and vascular tissues. Finally, we show that AtVPS13M1 is mainly located at the surface of mitochondria in leaves. Overall, our work highlights the conserved role in lipid transport of VPS13 in plants, reveals their importance in nutrient stress response and opens important perspectives for the understanding of lipid remodeling mechanisms and for the characterization of this protein family in plants.

cell biology↗

bioRxiv2024

The Vps13-like protein BLTP2 is pro-survival and regulates phosphatidylethanolamine levels in the plasma membrane to maintain its fluidity and function

Lipid transport proteins (LTPs) facilitate nonvesicular lipid exchange between cellular compartments and have critical roles in lipid homeostasis1. A new family of bridge-like LTPs (BLTPs) is thought to form lipid-transporting conduits between organelles2. One, BLTP2, is conserved across species but its function is not known. Here, we show that BLTP2 and its homolog directly regulate plasma membrane (PM) fluidity by increasing the phosphatidylethanolamine (PE) level in the PM. BLTP2 localizes to endoplasmic reticulum (ER)-PM contact sites3 4, 5, suggesting it transports PE from the ER to the PM. We find BLTP2 works in parallel with another pathway that regulates intracellular PE distribution and PM fluidity6, 7. BLTP2 expression correlates with breast cancer aggressiveness8-10. We found BLTP2 facilitates growth of a human cancer cell line and sustains its aggressiveness in an in vivo model of metastasis, suggesting maintenance of PM fluidity by BLTP2 may be critical for tumorigenesis in humans.

cell biology↗

bioRxiv2018

GenPipes: an open-source framework for distributed and scalable genomic analyses

With the decreasing cost of sequencing and the rapid developments in genomics technologies and protocols, the need for validated bioinformatics software that enables efficient large-scale data processing is growing. Here we present GenPipes, a flexible Python-based framework that facilitates the development and deployment of multi-step workflows optimized for High Performance Computing clusters and the cloud. GenPipes already implements 12 validated and scalable pipelines for various genomics applications, including RNA-Seq, ChIP-Seq, DNA-Seq, Methyl-Seq, Hi-C, capture Hi-C, metagenomics and PacBio long read assembly. The software is available under a GPLv3 open source license and is continuously updated to follow recent advances in genomics and bioinformatics. The framework has been already configured on several servers and a docker image is also available to facilitate additional installations. In summary, GenPipes offers genomic researchers a simple method to analyze different types of data, customizable to their needs and resources, as well as the flexibility to create their own workflows.

bioinformatics↗