Biology subjects

Barreau, F.

Publications and source records attributed to Barreau, F..

5 recordsLinked to original sources

bioRxiv2025

Colitis-primed circulating T cells drive small intestinal barrier function through Nod2, microbiota and myosin light chain kinase-dependent mechanisms

Inflammatory bowel diseases (IBD), including Crohns disease (CD) and ulcerative colitis (UC), are characterized by intestinal inflammation and barrier dysfunction. While disruption of the intestinal barrier contributes to the pathogenesis of IBD, yet how colonic inflammation alters small intestinal homeostasis remains poorly defined. Here, we demonstrate that three models of colitis, including 2,4,6-Trinitrobenzenesulfonic acid (TNBS), Dextran Sulfate Sodium (DSS), and oxazolone, induce paracellular barrier dysfunction in the small intestine, with model-specific immune profiles. Th1/Th17-skewed responses (TNBS and DSS) were associated with microbiota-dependent upregulation of myosin light chain kinase (MLCK), ROR{gamma}t CD4 T cell expansion, and elevated expression of Nod2, which was not observed under Th2-dominant (oxazolone) conditions. Inhibition of MLCK restored barrier function and suppressed inflammation in a CD4 T cell-dependent manner. Using Nod2-deficient and 2939insC mutant mice, we showed Nod2 as a critical regulator of small intestinal permeability during colitis. Bone marrow chimeras revealed compartment-specific roles of Nod2, with non-hematopoietic Nod2 sufficient to preserve epithelial integrity, while hematopoietic Nod2 expression is required to limit cytokine-mediated inflammation. Moreover, MLCK inhibition ameliorated intestinal lesions only in mice with Nod2 deficiency in the hematopoietic compartment. Finally, microbiota transfer experiments ruled out a causal role for dysbiosis in driving small intestinal permeability defects in Nod2-deficient mice. These findings uncover a Nod2-MLCK-CD4 T cell axis linking colonic inflammation to small intestinal barrier dysfunction and highlight distinct immune-epithelial-microbial mechanisms shaping intestinal homeostasis during colitis. Graphical AbstractCirculating ROR{gamma}t Foxp3- CD4 T cells from mice with TNBS- or DSS-induced colitis increase small intestinal permeability by promoting cytokine secretion that enhances MLCK activity. This effect is attenuated by Nod2 activation. Specifically, Nod2 expression in hematopoietic cells reduces cytokine secretion and permeability, while activation of Nod2 in non-hematopoietic cells alone is sufficient to prevent increased permeability by directly regulating MLCK activity, independently of cytokine influence. Moreover, the absence of Nod2 is associated with inflammatory lesions in the small intestine of TNBS-treated mice.

immunology↗

bioRxiv2024

Deleterious imprinting of perinatal exposure to nano-polystyrene on inflammatory bowel diseases

The tremendous and exponential production of plastics as well as its poor recycling leads to massive release in the environment questioning their outcomes on human health. Plastics are degraded into micro-plastic (MPL) and nano-plastic (NPL) that undergo weathering. MPL and NPL enter the human food chain via contaminated food, when animals are bred or vegetables grew on in plastic polluted environment and through the degradation of plastics food packaging. Ingested MPL or NPL can pass through epithelial barrier. This study focuses on consequences of oral perinatal exposure to polystyrene 50nm pristine or weathered (w) on intestinal disorders onset in offspring. Mouse were forced fed daily with 1.25mg of PS50 or PS50w starting at 15 days of gestation until pups weaned (Post Natal Day PND21). Oral tolerance protocol was induced at PND15 (nutritional switch) with ovalbumin (OVA) whereas DSS-induced colitis was performed in PND63 offspring. PS50 nor PS50w perinatal exposure did impair tolerance or immunization to OVA at PND15 in male or females. However, PS50 and PS50w perinatal exposure significantly worsened macroscopic score of DSS-induced colitis in both sexes. Perinatal exposure to PS50w appeared to be even more deleterious than PS50 for colitis exacerbation in males. In conclusion, early life exposure to PS50 or PS50w has long-lasting consequences on gut physiology by increasing the colonic severity of colitis while it does not modify oral tolerance establishment in early life. Those preliminary results questioned the kinetic of perinatal PS50 and PS50w exposure outcome over the life course and introduce the notion of imprinting. HighlightsO_LIPerinatal exposure to PS50 or PS50w does not affect oral tolerance establishment nor immune response to immunisation at PND15 C_LIO_LIPerinatal exposure to PS50 or PS50w have long lasting consequences on intestinal inflammation and colitis. PS50w in male has even more deleterious outcomes. C_LIO_LIRestricted exposure to PS50 or PS50w during perinatal has a deleterious imprinting on adult offspring intestinal health C_LI Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=82 SRC="FIGDIR/small/629591v1_ufig1.gif" ALT="Figure 1"> View larger version (22K): org.highwire.dtl.DTLVardef@13bae52org.highwire.dtl.DTLVardef@131b42eorg.highwire.dtl.DTLVardef@2c7317org.highwire.dtl.DTLVardef@380df8_HPS_FORMAT_FIGEXP M_FIG C_FIG Environmental implicationThe use of plastics in daily products leads to ubiquitous contamination of the environment and subsequently of food chains. Plastics persist for long periods in the environment where, submitted to climate, they fragment into nanoplastic particles (NPL). Indeed, these NPL are weathered due to their exposure to UV light, thermal, chemical, physical and biological stresses. Thus, human populations are exposed to pristine (NPLp) and weathered NPL (NPLw) in their daily lives, with unknown effect on intestinal health, including the diseases development like adverse Food Reactions (AFR) or Inflammatory Bowel Diseases (IBD). Given that these pathologies could originate in perinatal development and that pregnant and breastfeeding women are exposed to NPL on a daily basis, this study explores the impact of perinatally exposure to pristine or weathered polystyrene nanoplastics on the gut development and susceptibility.

pathology↗

bioRxiv2023

Promoting intestinal healing by exclusive enteral nutrition with TGF-beta in a mouse model of colitis.

Background and aimsExclusive Enteral Nutrition (EEN) is the first line of treatment for pediatric Crohns disease (CD), but its mechanisms of action remain poorly understood. We studied EEN nutritional composition and TGF-{beta} effect in a mouse model of colitis, as well as the role of intestinal microbiota. MethodsMice were treated with Dextran Sulfate Sodium (DSS) during 5 days to induce colitis, until the inflammatory peak (day 7) or gut restitution (day 14). After DSS treatment, some of them received EEN formula such as Modulen IBD(R) (DM mice) or Infatrini Peptisorb(R) (DINF mice), with TGF-{beta} supplementation or neutralization, and clinical inflammation was evaluated. After sacrifice, macroscopic and microscopic inflammation were analyzed, as well as intestinal permeability (IP). The composition of mucosal colonic microbiota was analyzed and fecal microbiota transplantation was performed to evaluate its capacity to mediate anti-inflammatory and pro-regenerative effect. Colonic crypts from DSS and EEN mice were cultured as 3D organoids and cellular properties were analyzed. ResultsDSS mice developed colitis, as evidenced by the weight loss and clinical inflammation. It was accompanied by macroscopic inflammation such as colon thickness and edemas, and an elevated IP. In contrast, EEN mice with TGF-{beta} formula present faster weight recovery and decreased inflammatory parameters, with a normalized IP, suggesting gut restitution and functionality. These functional improvements were not obtained for EEN mice without TGF-{beta} formula. Moreover, EEN with Modulen IBD(R) (DM mice) modified the microbiota in comparison to DSS condition and attenuated inflammation. In addition, the organoids from DM mice colonic crypts treated had an enhanced survival, and re-epithelialization capacity. ConclusionsBoth EEN formula have anti-inflammatory properties, certainly by the nutritional composition. However, TGF-{beta} plays a significant role in intestinal restitution and restoring barrier function. These beneficial effects are partly mediated by the microbiota to maintain gut homeostasis.

physiology↗

bioRxiv2023

Deciphering the interplay between biology and physics: finite element method-implemented vertex organoid model raises the challenge

Understanding the intertwining of biology and mechanics in tissue architecture is a challenging issue, especially when it comes to the 3D tissue organization. Addressing this challenge requires both a biological model allowing multiscale observations from the cell to the tissue, and theoretical and computational approaches allowing the generation of a synthetic model, relevant to the biological model, and allowing access to the mechanical constraints experienced by the tissue. Here, using human colon epithelium monolayer organoid as biological model, and combining vertex and FEM approaches, we generated a comprehensive elastic finite element model of the human colon organoid and demonstrated its flexibility. This FEM model provides a basis for relating cell shape, tissue deformation, and strain at the cellular level due to imposed stresses. In conclusion, we demonstrated that the combination of vertex and FEM approaches allows for better modeling of the alteration of organoid morphology over time and better assessment of the mechanical cues involved in establishing the architecture of the human colon epithelium.

biophysics↗

bioRxiv2019

Nod2 protects remote small intestinal sites in case of colonic inflammation.

NOD2 mutations are key risk factors for Crohns disease (CD). NOD2 contributes to intestinal homeostasis by regulating innate and adaptive immunity together with intestinal epithelial function. However, the roles of NOD2 during gut inflammation is not known. We initially observed that NOD2 expression was increased in epithelial cells remote from inflamed areas in CD patients. To explore this finding, Nod2 mRNA expression, inflammation and gut permeability were examined in the small bowel of wild-type (WT), Nod2 knockout and Nod2 mutant mice after rectal instillation of 2,4,6-trinitrobenzene sulfonic acid (TNBS). In WT mice, Nod2 upregulation remote to rectal injury was associated with pro-inflammatory cytokine expression, recirculating CD4+ T-cells, increased paracellular permeability and myosin like chain kinase activity. Nod2 knockout or mutation led to duodenitis and ileitis demonstrating the remote protective role of Nod2. Bone morrow stem cell (BMSC) transplantations indicated that the small intestinal inflammation was due to NOD2 loss in both hematopoietic and non-hematopoietic compartments. As a whole, WT but not mutant NOD2 prevents disease extension at sites remote from the initial intestinal injury.

immunology↗