Biology subjects

Le Gall, M.

Publications and source records attributed to Le Gall, M..

9 recordsLinked to original sources

bioRxiv2026

Early Colonic and Microbial Responses Precede Hyperphagia in Short Bowel Syndrome: Insights from a Rat Model

BackgroundShort bowel syndrome (SBS) resulting from extensive small bowel resection is characterized by severe malabsorption and represents the leading cause of intestinal failure. Although spontaneous intestinal adaptation can partially restore nutrient absorption, the temporal coordination and hierarchy of the adaptive mechanisms involved--particularly those linking the gut microbiota, enteroendocrine function, hyperphagia, and intestinal remodeling-- remain incompletely understood. MethodsWe investigated the kinetics of spontaneous intestinal adaptation in a rat model mimicking type 2 SBS over a 28-day postoperative period. Body weight, food intake, gastrointestinal transit, fecal losses, intestinal morphology, enteroendocrine hormone secretion, hypothalamic neuropeptide expression, and gut microbiota composition were assessed longitudinally in SBS and SHAM-operated rats. ResultsExtensive small bowel resection induced marked early weight loss, accelerated intestinal transit, diarrhea, and increased fecal energy losses that persisted throughout the follow-up. Profound gut microbiota remodeling occurred as early as day 7, remained largely stable thereafter, and was characterized by reduced diversity and enrichment in Lactobacillaceae and Enterobacteriaceae. Early elongation of remaining colon and epithelial remodeling were observed, preceding the jejunal hyperplasia, which became evident from day 14 onward. Enteroendocrine adaptation was marked by an early increase in plasma peptide YY levels, whereas glucagon-like peptide-1 showed a modest response. Food intake was increased in SBS rats from day 7 onward, and hyperphagia developed gradually and reached a plateau by the end of the third postoperative week, in parallel with increased hypothalamic AgRP levels and reduced POMC levels. No significant improvement of intestinal transit and fecal energy losses was observed during the study period. ConclusionIntestinal adaptation to extensive resection follows a time-dependent sequence in which early gut microbiota remodeling and colonic adaptation precede hyperphagia and small intestinal remodeling. These findings highlight the gut microbiota and the colon as central components of the early post-resection adaptation and potential therapeutic targets in SBS.

pathology↗

bioRxiv2025

The protein-protein interaction landscape of Fanconi anemia protein A (FANCA) reveals its contributions to mRNA processes.

Fanconi Anemia (FA) is a rare inherited recessive disorder characterized by bone marrow failure, congenital abnormalities, and a predisposition to myeloid leukemia and some solid cancers. FA is caused by mutations in one of the 22 so-called FANC genes, with two thirds of FA patients being FANCA mutants. FANC proteins cooperate within the FANC/BRCA pathway, a DNA repair system essential for resolving DNA interstrand crosslinks (ICLs) in S-phase. The canonical understanding of FA pathogenesis involves genome instability and impaired cellular proliferation due to DNA damage accumulation and stress response overactivation. However, recent data shows FANCA has a function in ribosome biogenesis and translation, which prompts a reassessment of FANCAs role(s) in cellular physiology and FA pathogenesis. We reasoned that unveiling the multiple interactions of the FANCA protein would shed light on these potentially new FANCA functions. By combining immunoprecipitation and BioID approaches, in three different cell lines and with different in silico analysis methods, we constructed lists of FANCA interactome proteins of different levels of selectivity and assembled them into a novel multilayered FANCA protein-protein interaction (PPI) landscape. Strikingly, we find that FANCA associates with proteins involved in processes distinct from DNA repair, such as translation, ribosome biogenesis, mRNA splicing, nucleocytoplasmic transport, chromatin remodeling, and the TCA cycle. We then analyzed the protein content of polysome profiling fractions and found that FANCA loss may affect ribosomal protein stoichiometry within ribosomal subunits. Overall, our data expands FANCAs PPI network far beyond the previously reported interactions. Importantly, we confirm the biological significance of low-selectivity interactions and propose to re-evaluate their importance in proteomic studies. The study of previously unsuspected FANCA functions, such as translation, could provide new therapeutic targets in FA and therefore improve patient care.

genetics↗

bioRxiv2024

The colon is an extra-pancreatic source of glucagon: demonstration in a mouse model of pancreatectomy

Glucagon is considered as a pancreas-specific hormone. However, an extra-pancreatic source of glucagon, which secretion is inappropriately induced by oral glucose, has been suspected for years in patients with diabetes. In a mouse model of subtotal pancreatectomy, we recapitulated the abnormal secretion of glucagon in response to oral glucose observed in pancreatectomised patients and excluded the remaining pancreas as the source of glucagon. We showed that the colon can produce and secrete glucagon. Subtotal pancreatectomy resulted in an increased expression of PCSK2 protease in the colon that favors the maturation of proglucagon into glucagon over other glucagon-related peptides normally produced by enteroendocrine cells. These results identify a mechanism that could contribute to abnormal glucagon production and poor glycemic control in pancreatectomized diabetic subjects. Moreover, our findings may pave the road to new therapeutic strategies to counteract poor glucose control for patients with diabetes.

physiology↗

bioRxiv2024

T-cell acute lymphoblastic leukemia progression is supported by inflammatory molecules including Hepatocyte Growth factor

BackgroundT-cell acute lymphoblastic leukemia (T-ALL) is a malignant hematological disorder characterized by an increased proliferation of immature T lymphocytes precursors. T-ALL treatment includes chemotherapy with strong side effects, and patients that undergo relapse display poor prognosis. Although cell-intrinsic oncogenic pathways are well-studied, the tumor microenvironment, like inflammatory cellular and molecular components is less explored in T-ALL. We sought to determine the composition of the inflammatory microenvironment induced by T-ALL, and its role in T-ALL progression. MethodsTwo mouse T-ALL cell models were injected into immunocompetent mice. We used anti-Ly6G, and clodronate liposomes to suppress neutrophils and phagocytes, respectively. 5- (N-ethylcarboxamido)adenosine (NECA), an agonist of adenosine receptors was used to decrease inflammatory molecules secretion. FindingsWe show that T-ALLs enhance blood neutrophils and resident monocytes, accompanied with a plasmatic acute secretion of inflammatory molecules. Depleting neutrophils or resident monocytes does not modulate plasmatic inflammatory molecule secretion and mice survival. However, inhibiting the secretion of inflammatory molecules by microenvironment with NECA diminishes T-ALL progression enhancing mouse survival. We uncovered Hepatocyte Growth Factor (HGF), T-ALL-driven and the most decreased molecule with NECA, as a potential therapeutic target in T-ALL. InterpretationAltogether, we identified a signature of inflammatory molecules that can potentially be involved in T-ALL evolution and uncovered HGF as a new potential therapeutic target. FundingsThe work was supported by CEA, Inserm, Universite Paris-Saclay and Universite Paris-Cite, la Recherche contre le Cancer (ARC) and Hope of Princess Manon charity. The LSHL team is labellised by Ligue Nationale Contre le Cancer. Research in contextO_ST_ABSEvidence before this studyC_ST_ABST-cell acute lymphoblastic leukemia (T-ALL) is an aggressive and lethal hematologic malignancy accounting for about 15% of pediatric and 25% of adult ALL. T-ALL originates from a block of differentiation and uncontrolled proliferation of immature T cells. Current chemotherapies provide an overall 5 years survival higher than 90% in children and of about 50% in adults. Both pediatric and adult relapses have a very poor outcome with resistance to treatment. Therefore, the identification of molecular targets and the development of new specific therapies are major goals to improve treatment success, and one way to reach this goal is to have a better understanding the dialog between T-ALL cells and their microenvironment. Cellular and molecular actors in the microenvironment have been identified to impact several types of leukemia. Recently, the supportive role of myeloid cells has been described in T-ALL. Moreover, interactions between receptors and ligands such as DL1, IL-18, IL-7, IGF1 and CXCL12 sustain proliferation, survival or initiation of T-ALL. However, the composition and the contribution of the inflammatory microenvironment that may broadly help T-ALL progression still remains poorly explored. Added value of this studyThe study, utilizing NOTCH1 and TAL1/LMO1-driven mouse T-ALL models, reveals that T-ALL induces an inflammatory microenvironment characterized by increased levels of blood neutrophils, resident monocytes, and plasmatic inflammatory molecules. Targeting molecular microenvironment with the non-selective adenosine receptor agonist NECA drastically decreases T-ALL progression and prolongs mice survival. This study further identifies hepatocyte growth factor (HGF), a known regulator of proliferation and migration of tumor cells, as a putative supportive and targetable factor in T-ALL. Implications of all the available evidenceIn this study, evidence linking T-ALL and inflammatory microenvironment is provided. These data extend our understanding of the biological function of inflammatory microenvironment in T-ALL progression, and open to the targeting of the inflammatory microenvironment, and more specifically HGF/cMet signaling in T-ALL. Such targeted therapeutic approach could be added to current treatments to improve patient outcome.

cancer biology↗

bioRxiv2024

Development of rat organoids to study intestinal adaptations after Roux-en-Y Gastric Bypass

Organoids from intestinal regions have proven to be useful tools to study intestinal epithelial responses to different conditions. Roux-en-Y gastric bypass (RYGB) has been associated with important intestinal adaptations, but the mechanisms underlying these changes are still poorly understood. Organoids could therefore be used to better decipher the intestinal adaptations associated with this surgery. Rat is a common model to assess RYGB responses in vivo, but surprisingly, very few studies managed to develop organoids from rat small intestine. The primary objective of this study was to establish a protocol for cultivating organoids derived from the small intestine of healthy rats. The second objective of this study focuses on the development of organoids from the small intestine of rats subjected to RYGB to evaluate whether phenotypic or gene expression differences emerge. We successfully devised a functional protocol for developing organoids from fresh or frozen rat small intestine tissues. The obtained organoids exhibit significant variability, making interpretation challenging. Variability is observed in size, shape, and the number of organoids developed from the same sample, but also gene expression, depending on samples prepared on different days or from fresh or frozen tissues. This protocol was then applied to the small intestine of RYGB or sham-operated rats. However, we did not detect any major difference in size between intestinal organoids derived from Sham rats and those from RYGB rats. The expression of several genes (peptide transporters, amino acid transporters, genes specific to certain types of intestinal cells, etc.) was also assessed, and inter-experiment variability was higher than any effect due to the operation on the rat the intestinal tissue was originating. In conclusion, this study has established a functional protocol to grow small intestine organoids in rats. Initial results suggest that in our experimental conditions, organoids obtained from rats subjected to RYGB do not differ from those obtained from Sham rats. However, increasing the sample size and improving reproducibility between experiments will be essential to confirm these findings.

physiology↗

bioRxiv2024

RNA G-quadruplex dynamic steers the crosstalk between protein synthesis and energy metabolism

Cancer cells rely on mitochondria for their bioenergetic supply and macromolecule synthesis. Central to mitochondrial function is the regulation of mitochondrial protein synthesis, which primarily depends on the cytoplasmic translation of nuclear-encoded mitochondrial mRNAs whose protein products are imported into mitochondria. Despite the growing evidence that mitochondrial protein synthesis contributes to the onset and progression of cancer, and can thus offer new opportunities for cancer therapy, knowledge of the underlying molecular mechanisms remains limited. Here, we show that RNA G-quadruplexes (RG4s) regulate mitochondrial function by modulating cytoplasmic mRNA translation of nuclear-encoded mitochondrial proteins. Our data support a model whereby the RG4 folding dynamics, under the control of oncogenic signaling and modulated by small molecule ligands or RG4-binding proteins, modifies mitochondria-localized cytoplasmic protein synthesis. Ultimately, this impairs mitochondrial functions, affecting energy metabolism and consequently cancer cell proliferation.

cancer biology↗

bioRxiv2021

Loss of intestinal ChREBP impairs absorption of dietary sugars and prevents glycemic excursion curves

Increased sugar consumption is a risk factor for features of the metabolic syndrome including obesity, hypertriglyceridemia, insulin resistance, diabetes, and nonalcoholic fatty liver disease. The gut epithelium, which plays a central role in dietary sugar digestion, absorption and metabolism has emerged a key actor of metabolic disorders. While the transcription factor ChREBP (Carbohydrate response element binding protein) has been established as a key player of the adaptive reprograming of cellular metabolism in various tissues upon glucose or fructose challenge, its specific contribution to the regulation of blood glucose upon dietary sugar intake was not previously addressed. We demonstrate here that ChREBP is abundantly expressed in the proximal gut epithelium, where carbohydrate digestion and absorption primarily occur and in particular L cells, which produce the glucoincretin GLP-1. The inducible deletion of ChREBP specifically in the mouse gut epithelium (Ch{Delta}GUT mice) resulted in the reduction of early glycemic excursion upon oral glucose load. Surprisingly, despite being associated with reduced GLP-1 production, loss of gut ChREBP activity significantly dampened glucose transepithelial flux, and thereby delayed glucose distribution to peripheral tissues. Among the underlying mechanisms, we unveil that Ch{Delta}GUT mice show an impaired expression of key intestinal hexose (glucose, galactose, fructose) transporters and metabolic enzymes as well as brush border dissacharidases. In agreement, intestinal ChREBP deficiency was accompanied by a precocious intolerance to both high-lactose and high-sucrose diets concomitant with mild galactose and severe fructose malabsorption syndromes. Altogether, our study demonstrates that, by transcriptionally orchestrating local digestion and absorption of dietary sugars, ChREBP activity in the mouse gut epithelium controls glucose appearance rate into systemic circulation and prevents against intolerance to mono- and disaccharides.

physiology↗

bioRxiv2021

The Autophagy Receptor TAX1BP1 (T6BP) is a novel player in antigen presentation by MHC-II molecules.

CD4+ T lymphocytes play a major role in the establishment and maintenance of immunity. They are activated by antigenic peptides derived from extracellular or newly synthesized (endogenous) proteins presented on the surface of antigen presenting cells (APCs) by the MHC-II molecules. The pathways leading to endogenous MHC-II presentation remain poorly characterized. We demonstrate here that the autophagy receptor, T6BP, influences both autophagy-dependent and -independent endogenous presentation of HIV- and HCMV-derived peptides. By studying the immunopeptidome of MHC-II molecules, we show that T6BP affects both the quantity and quality of peptides presented. T6BP silencing induces the mislocalization of the MHC-II-loading compartments and a rapid degradation of the invariant chain (CD74) without altering the expression and internalization kinetics of MHC-II molecules. We determined the interactome of T6BP, identified calnexin as a T6BP partner and show that CANX cytosolic tail is required for this interaction. Remarkably, calnexin silencing replicates the functional consequences of T6BP silencing: decreased CD4+ T cell activation and exacerbated CD74 degradation. Altogether, we unravel T6BP as a key player of the MHC-II-restricted endogenous presentation pathway and we propose one potential mechanism of action.

immunology↗

bioRxiv2020

USP9X deubiquitinase couples the pluripotency network and cell metabolism to regulate ESC differentiation potential

Embryonic stem cells (ESC) have the unique ability to differentiate into all three germ cell layers. ESC transition through different states of pluripotency in response to growth factor signals and environmental cues before becoming terminally differentiated. Here, we demonstrated, by a multi-omic strategy, that the deubiquitinase USP9X regulates the developmental potential of ESC, and their transition from a naive to a more developmentally advance, or primed, state of pluripotency. We show that USP9X facilitates developmental gene expression and induces modifications of the mitochondrial bioenergetics, including decreased routing of pyruvate towards its oxidation and reduced respiration. In addition, USP9X binds to the pluripotency factor ESRRB, regulates its abundance and the transcriptional levels of a subset of its target genes. Finally, under permissive culture conditions, depletion of Usp9X accelerates cell differentiation in all cell lineages. We thus identified a new regulator of naive pluripotency and show that USP9X couples ESRRB pluripotency transcriptional network and cellular metabolism, both of which are important for ESC fate and pluripotency.

cell biology↗