Biology subjects

Chassaing, B.

Publications and source records attributed to Chassaing, B..

25 records · Page 2Linked to original sources

bioRxiv2022

Obesity promotes Fumonisin B1 toxicity and induces hepatitis

Background and aimObesity is a major public health issue worldwide. Obesity is associated with chronic inflammation that contribute to long-term complications, including insulin resistance, type 2 diabetes and non-alcoholic fatty liver disease. We hypothesized that obesity may also influence the sensitivity to food contaminants, such as fumonisin B1 (FB1), a mycotoxin produced mainly by the Fusarium verticillioides. FB1, a common contaminant of corn, is the most abundant and best characterized member of the fumonisins family. This toxin provokes severe mycotoxicosis in animals, which leads to hepatotoxicity and alterations in the immune response and intestinal barrier permeability. We investigated here whether diet-induced obesity could modulate the sensitivity to oral FB1 exposure, with emphasis on gut health and hepatotoxicity. MethodsThe metabolic effects of FB1 were assessed in obese and non-obese male C57BL/6J mice. For 15 weeks, mice received a high-fat diet (HFD) or normal chow diet (CHOW). During the last three weeks, mice were exposed or not to FB1 (10 mg/kg body weight/day) through drinking water. ResultsAs expected, HFD feeding induced significant body weight gain, glucose intolerance, and hepatic steatosis. FB1-exposed mice displayed a higher sphinganine/sphingosine ratio, a well-known FB1 biomarker of exposure, due to inhibition of ceramide synthases activity by FB1. Combined exposure to HFD and FB1 resulted in body weight loss and a decrease in fasting blood glucose level. This co-exposition also induces gut dysbiosis, an increase in plasma FB1 level, a decrease in liver weight and hepatic steatosis. Moreover, plasma transaminase levels were significantly increased and associated with liver inflammation in HFD/FB1-treated mice. Liver gene expression analysis revealed that the combined exposure to HFD and FB1 was associated with reduced expression of genes involved in lipogenesis and increased expression of immune response and cell cycle-associated genes. ConclusionThese results suggest that, in the context of obesity, FB1 exposure promotes gut dysbiosis and severe liver inflammation. To our knowledge, this study provides the first example of obesity-induced hepatitis in response to a food contaminant.

pharmacology and toxicology↗

bioRxiv2021

The gut microbiome is associated with cocaine behavior and predicts addiction vulnerability in adult male rats

The gut-brain axis is a bi-directional communication system through which microbial communities in the gut interact with the nervous system, perhaps influencing neuropsychiatric disorders such as drug abuse. This study used behavioral data and biological samples from the Cocaine Biobank to test the hypothesis that the gut microbiota can predict and reflect susceptibility to cocaine reinforcement. Adult male heterogenous rats were catheterized and allowed to self-administer cocaine in short-access sessions (2 hr/day, 10 days, 0.5 mg/kg per intravenous infusion), followed by progressive ratio (PR) tests, long-access sessions (6 hr/day, 14 days), and alternating blocks of PR, long-access, and footshock testing. Fecal samples were collected at three time points and bacterial 16s rRNA genes were sequenced to profile the microbiota. As expected, cocaine-related behavior varied among subjects, such that a quartile split identified low and high responders on each measure, as well as an overall addiction index. Although beta diversity in the microbiota at baseline and after short access did not predict membership in high or low addiction quartiles, linear discriminant analysis (LDA) identified taxa that were more robustly represented in low or high responders. Beta diversity after long access was different among quartiles, as were several specific taxa. Investigation of baseline differences revealed that high relative abundance of Akkermansia muciniphila predicted future low response rates, whereas Ruminococcaceae predicted high response. This study is the first to report that microbiota variability reflects levels of cocaine intake and that microbial profiles might facilitate diagnosis and identify risk factors predictive of drug vulnerability. Significance StatementMicrobial organisms inhabiting the gut of animals appear to influence organismal function through various signaling pathways, ultimately affecting behavior and disease vulnerability. This experiment investigates links between gut bacteria and vulnerability to addiction-related behaviors in adult male rats. Not only did gut bacterial profiles change as a result of cocaine intake but also gut bacterial profiles before any exposure to cocaine predicted which animals would be high or low addiction-prone individuals. These results suggest that microbial profiles might facilitate diagnosis and identify risk factors predictive of drug addiction.

neuroscience↗

bioRxiv2020

Tolerogenic Dendritic Cells Shape a Transmissible Gut Microbiota that Protects from Metabolic Diseases

Excess of chronic contact between microbial motifs and intestinal immune cells are known to trigger a low-grade inflammation involved in many pathologies such as obesity and diabetes. The important skewing of intestinal adaptive immunity in the context of diet-induced obesity (DIO) is well described but how dendritic cells (DCs) participate to these changes is still poorly documented. To address this question, transgenic mice with enhanced DCs lifespan and immunogenicity (DChBcl-2 mice), are challenged with a high fat diet. Those mice display resistance to DIO and metabolic alterations. The DIO resistant phenotype is associated with healthier parameters of intestinal barrier function and lower intestinal inflammation. DChBcl-2 DIO-resistant mice demonstrate a particular increase in tolerogenic DC numbers and function which is associated with strong intestinal IgA, Th17 and T regulatory immune responses. Microbiota composition and function analyses reveal that the DChBcl-2 mice microbiota is characterized by a lower immunogenicity and an enhanced butyrate production. Cohousing experiments and fecal microbial transplantations are sufficient to transfer the DIO resistance status to WT mice demonstrating that maintenance of DCs tolerogenic ability sustains a microbiota able to drive DIO resistance. DCs tolerogenic function is revealed as a new potent target in metabolic diseases management.

immunology↗

bioRxiv2019

IL-22 induced cell extrusion and IL-18-induced pyroptosis prevent and cure rotavirus infection

Administration of bacterial flagellin elicits production of TLR5-mediated IL-22 and NLRC4-mediated IL-18 that act in concert to cure and prevent rotavirus (RV) infection. This study investigated the mechanism by which these cytokines act to impede this virus. Although IL-18 and IL-22 induce each others expression, we found that IL-18 and IL-22 both impeded RV independently of each other and did so by distinct mechanisms, in both cases via activation of their cognate receptors in intestinal epithelial cells (IEC). IL-22 drove IEC proliferation and migration toward villus tips, which resulted in increased extrusion of highly differentiated IEC that serve as the site of RV replication. In contrast, IL-18 induced pyroptotic death of RV-infected IEC thus directly interrupting the RV replication cycle, resulting in spewing of incompetent virus into the intestinal lumen and causing a rapid drop in levels of RV-infected IEC. Together, these actions resulted in rapid and complete expulsion of RV, even in hosts with severely compromised immune systems. These results suggest that IL-18/22 might be a means of treating viral infections that preferentially target short-lived epithelial cells.

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↗

bioRxiv2019

Specific targeting of intestinal Prevotella copri by a Listeria monocytogenes bacteriocin

Deciphering the specific function of every microorganism in microbial gut communities is a key issue to interrogate their role during infection. Here, we report the discovery of a Listeria bacteriocin, Lmo2776, that specifically targets the abundant gut commensal Prevotella copri and affects Listeria infection. Oral infection of conventional mice with a {Delta}lmo2776 mutant leads to a thinner intestinal mucus layer and higher Listeria loads both in the intestinal content and deeper tissues compared to WT Listeria, while no difference is observed in germ-free mice. This microbiota-dependent effect is phenocopied by precolonization of germ-free mice before Listeria infection, with P. copri, but not with other commensals. Together, these data unveil a role for Prevotella in controlling intestinal infection, highlighting that pathogens may selectively deplete microbiota to avoid excessive inflammation.

microbiology↗

bioRxiv2019

Gut microbiota influence B cell function in a TLR5-dependent manner

Toll-like receptor (TLR) 5-deficient mice display aberrantly low levels of flagellin-specific antibodies (Flic-IgA) secreted into the gut, combined with excess bacterial flagellin in the gut, and together these attributes define microbiome dysbiosis (T5-dysbiosis). How TLR5 signaling deficiency results in T5-dysbiosis is unclear. Here, we address the role of B cells in T-dysbiosis. We observed that B cells do not express TLR5, and that B cell transplantation from TLR5-/- mouse donors into B-cell deficient mice resulted in a slight reduction in Flic-IgA levels compared to B-cells from WT donors. Bone marrow transplants from WT and TLR5-/- donors into recipients of both genotypes confirmed that TLR5 signaling by non-hematopoietic cells is required for T5-dysbiosis. We observed TLR5 deficiency was associated with an expanded population of IgA+ B cells. TLR5-/- mice tended to have higher richness for the IgA gene hypervariable region (CDR3 gene) variants. Transplantation of microbiomes from TLR5-/- and WT microbiomes donors into germfree mice resulted in a higher proportion of IgA-secreting B cells, and higher overall fecal IgA and anti-Flic IgA for TLR5-/- microbiome recipients. This observation indicated that the TLR5-/- mouse microbiome elicits an anti-flagellin antibody response that requires TLR5 signaling. Together these results indicate that TLR5 signaling on epithelial cells influences B cell populations and antibody repertoire.

immunology↗