oral-gavage-neonatal-mouse-pups-functional-assessment-gut-barrier

Oral Gavage in Neonatal Mouse Pups and Functional Assessment of Gut Barrier Integrity Using Ussing Chambers

Growing evidence underscores the importance of the first 1,000 days of life in shaping the gut-microbiome axis. This early-life window is critical in the ...

Université Paris Cité

IHU Infiny

Numerous studies of knockout mice find impacts on microbiota composition that influence host phenotype. However, such differences can vanish when KO mice are compared directly to WT littermates, suggesting these differences do not reflect the genetic deletion per se but microbiota composition drifting over generations. Hence, our hypothesis that absence of di/tri-peptide transporter PepT1 altered microbiota composition resulting in resistance to colitis compelled scrutiny. In this study, we used PepT1 and WT founder mice bred separately for multiple generations. Such mice were then bred to each other to generate F1 PepT1 and WT littermates, which were then bred within their genotype to generate F2, F3, and F4, offspring. Here we report that founder PepT1 mice were, relative to their WT counterparts, resistant to DSS colitis. Such resistance was associated with alterations in gut microbiota, which, when transplanted to germfree mice, was sufficient to transfer resistance to colitis. Such differences were not observed when comparing F1 PepT1 to F1 WT littermates but rather, returned gradually over subsequent generations such that, relative to their F4 WT controls, F4 PepT1 displayed microbiota composition and colitis-resistant phenotype nearly identical to the founder PepT1 mice. Our findings indicate a role for PepT1 in influencing microbiota composition and, consequently, proneness to colitis and cancer. Overall, our study indicates that littermate-controlled experiments can be insufficient for assessing microbiota-dependent phenotypes and prevent a full comprehension of genotype-driven phenomena. Rather, impact of a single genetic alteration on microbiota and host phenotype may take generations to manifest.

Impact of PepT1 deletion on microbiota composition and colitis requires multiple generations.

[Gut microbiota and miRNA: A couple of star actors in idiopathic juvenile arthritis?].

To assess the associations between exposure to food additive emulsifiers and risk of cardiovascular disease (CVD).

Food additive emulsifiers and risk of cardiovascular disease in the NutriNet-Santé cohort: prospective cohort study.

Emulsifiers are widely used food additives in industrially processed foods to improve texture and enhance shelf-life. Experimental research suggests deleterious effects of emulsifiers on the intestinal microbiota and the metabolome, leading to chronic inflammation and increasing susceptibility to carcinogenesis. However, human epidemiological evidence investigating their association with cancer is nonexistent. This study aimed to assess associations between food additive emulsifiers and cancer risk in a large population-based prospective cohort.

Food additive emulsifiers and cancer risk: Results from the French prospective NutriNet-Santé cohort.

Experimental studies have suggested potential detrimental effects of emulsifiers on gut microbiota, inflammation, and metabolic perturbations. We aimed to investigate the associations between exposures to food additive emulsifiers and the risk of type 2 diabetes in a large prospective cohort of French adults.

Food additive emulsifiers and the risk of type 2 diabetes: analysis of data from the NutriNet-Santé prospective cohort study.

Inflammatory bowel diseases (IBD) etiology is multifactorial. Luminal microRNAs (miRNAs) have been suspected to play a role in the promotion of chronic inflammation, but the extent to which fecal miRNAs are interacting with the intestinal ecosystem in a way that contribute to diseases, including IBD, remains unknown. Here, fecal let-7b and miR-21 were found elevated, associated with inflammation, and correlating with multiple bacteria in IBD patients and IL-10 mice, model of spontaneous colitis. Using an  microbiota modeling system, we revealed that these two miRNAs can directly modify the composition and function of complex human microbiota, increasing their proinflammatory potential.  investigations revealed that luminal increase of let-7b drastically alters the intestinal microbiota and enhances macrophages' associated proinflammatory cytokines (TNF, IL-6, and IL-1β). Such proinflammatory effects are resilient and dependent on the bacterial presence. Moreover, we identified that besides impairing the intestinal barrier function, miR-21 increases myeloperoxidase and antimicrobial peptides secretion, causing intestinal dysbiosis. More importantly,  inhibition of let-7b and miR-21 with anti-miRNAs significantly improved the intestinal mucosal barrier function and promoted a healthier host-microbiota interaction in the intestinal lining, which altogether conferred protection against colitis. In summary, we provide evidence of the functional significance of fecal miRNAs in host-microbiota communication, highlighting their therapeutic potential in intestinal inflammation and dysbiosis-related conditions, such as IBD.

Fecal let-7b and miR-21 directly modulate the intestinal microbiota, driving chronic inflammation.

Metabolic syndrome (MetS) is a cluster of several human conditions including abdominal obesity, hypertension, dyslipidemia, and hyperglycemia, all of which are risk factors of type 2 diabetes, cardiovascular disease, and metabolic dysfunction-associated steatotic liver disease (MASLD). Dietary pattern is a well-recognized MetS risk factor, but additional changes related to the modern Western life-style may also contribute to MetS. Here we hypothesize that the disappearance of amoebas in the gut plays a role in the emergence of MetS in association with dietary changes. Four groups of C57B/6J mice fed with a high-fat diet (HFD) or a normal diet (ND) were colonized or not with , a commensal amoeba. Seventy days after inoculation, cecal microbiota, and bile acid compositions were analyzed by high-throughput sequencing of 16S rDNA and mass spectrometry, respectively. Cytokine concentrations were measured in the gut, liver, and mesenteric fat looking for low-grade inflammation. The impact of HFD on liver metabolic dysfunction was explored by Oil Red O staining, triglycerides, cholesterol concentrations, and the expression of genes involved in β-oxidation and lipogenesis. Colonization with E. muris had a beneficial impact, with a reduction in dysbiosis, lower levels of fecal secondary bile acids, and an improvement in hepatic steatosis, arguing for a protective role of commensal amoebas in MetS and more specifically HFD-associated MASLD.

 mitigates metabolic consequences of high-fat diet in mice.

There is growing evidence that micro-RNAs (miRNAs) are key players in the regulation of gut health. In this issue of Cell Metabolism, Li et al. uncovered that the dietary fiber stachyose can modulate the luminal miRNA load of the intestinal tracts by binding to HSP90β, thereby altering the gut's microbial composition.

Article	Year
Impact of PepT1 deletion on microbiota composition and colitis requires multiple generations. NPJ biofilms and microbiomes\| PubMed ID: 32694535	2020
[Gut microbiota and miRNA: A couple of star actors in idiopathic juvenile arthritis?]. Medecine sciences : M/S\| PubMed ID: 37219348	2023
Food additive emulsifiers and risk of cardiovascular disease in the NutriNet-Santé cohort: prospective cohort study. BMJ (Clinical research ed.)\| PubMed ID: 37673430	2023
Food additive emulsifiers and cancer risk: Results from the French prospective NutriNet-Santé cohort. PLoS medicine\| PubMed ID: 38349899	2024
Food additive emulsifiers and the risk of type 2 diabetes: analysis of data from the NutriNet-Santé prospective cohort study. The lancet. Diabetes & endocrinology\| PubMed ID: 38663950	2024
Fecal let-7b and miR-21 directly modulate the intestinal microbiota, driving chronic inflammation. Gut microbes\| PubMed ID: 39224018	2024
mitigates metabolic consequences of high-fat diet in mice. Gut microbes\| PubMed ID: 39396247	2024
Challenges and hopes of gastrointestinal miRNA regulation: The example of stachyose. Cell metabolism\| PubMed ID: 39908984	2025

Emilie Viennois

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