Bile Salt Hydrolases: At the Crossroads of Microbiota and Human Health

The gut microbiota has been increasingly linked to metabolic health and disease over the last few decades. Several factors have been suggested to be involved in lipid metabolism and metabolic responses. One mediator that has gained great interest as a clinically important enzyme is bile salt hydrolase (BSH). BSH enzymes are widely distributed in human gastrointestinal microbial communities and are believed to play key roles in both microbial and host physiology. In this review, we discuss the current evidence related to the role of BSHs in health and provide useful insights that may pave the way for new therapeutic targets in human diseases

Microbial reduction of cholesterol to coprostanol: An old concept and new insights

The gut microbiota plays a key role in cholesterol metabolism, mainly through the reduction of cholesterol to coprostanol. The latter sterol exhibits distinct physicochemical properties linked to its limited absorption in the gut. Few bacteria were reported to reduce cholesterol into coprostanol. Three microbial pathways of coprostanol production were described based on the analysis of reaction intermediates. However, these metabolic pathways and their associated genes remain poorly studied. In this review, we shed light on the microbial metabolic pathways related to coprostanol synthesis. Moreover, we highlight current strategies and future directions to better characterize these microbial enzymes and pathways

From animal models to gut-on-chip: the challenging journey to capture inter-individual variability in chronic digestive disorders

ABSTRACTChronic digestive disorders are of increasing incidence worldwide with expensive treatments and no available cure. Available therapeutic schemes mainly rely on symptom relief, with large degrees of variability in patients’ response to such treatments, underlining the need for new therapeutic strategies. There are strong indications that the gut microbiota’s contribution seems to be a key modulator of disease activity and patients’ treatment responses. Hence, efforts have been devoted to understanding host–microbe interactions and the mechanisms underpinning such variability. Animal models, being the gold standard, provide valuable mechanistic insights into host–microbe interactions. However, they are not exempt from limitations prompting the development of alternative methods. Emerging microfluidic technologies and gut-on-chip models were shown to mirror the main features of gut physiology and disease state, reflect microbiota modification, and include functional readouts for studying host responses. In this commentary, we discuss the relevance of animal models in understanding host–microbe interactions and how gut-on-chip technology holds promises for addressing patient variability in responses to chronic digestive disease treatment

Design of clinical trials evaluating cathepsin C inhibition in inflammatory bowel diseases

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Glyphosate and glyphosate-based herbicide exposure during the peripartum period affects maternal brain plasticity, maternal behaviour and microbiome

International audienceGlyphosate is found in a large array of non‐selective herbicides such as Roundup® (Monsanto, Creve Coeur, MO, USA) and is by far the most widely used herbicide. Recent work in rodent models suggests that glyphosate‐based herbicides during development can affect neuronal communication and result in altered behaviours, albeit through undefined mechanisms of action. To our knowledge, no study has investigated the effects glyphosate or its formulation in herbicide on maternal behaviour and physiology. In the present study, relatively low doses of glyphosate (5 mg kg‐1 d‐1), Roundup® (5 mg kg‐1 d‐1 glyphosate equivalent), or vehicle were administered by ingestion to Sprague‐Dawley rats from gestational day (GD) 10 to postpartum day (PD)22. The treatments significantly altered licking behaviour toward pups between PD2 and PD6. We also show in the dams at PD22 that Roundup exposure affected the maturation of doublecortin‐immunoreactive new neurones in the dorsal dentate gyrus of the hippocampus of the mother. In addition, the expression of synaptophysin was up‐regulated by glyphosate in the dorsal and ventral dentate gyrus and CA3 regions of the hippocampus, and down‐regulated in the cingulate gyrus. Although a direct effect of glyphosate alone or its formulation on the central nervous system is currently not clear, we show that gut microbiota is significantly altered by the exposure to the pesticides, with significant alteration of the phyla Bacteroidetes and Firmicutes. This is the first study to provide evidence that glyphosate alone or in formulation (Roundup) differentially affects maternal behaviour and modulates neuroplasticity and gut microbiota in the mother

Serine protease inhibitors and human wellbeing interplay: new insights for old friends

Serine Protease Inhibitors (Serpins) control tightly regulated physiological processes and their dysfunction is associated to various diseases. Thus, increasing interest is given to these proteins as new therapeutic targets. Several studies provided functional and structural data about human serpins. By comparison, only little knowledge regarding bacterial serpins exists. Through the emergence of metagenomic studies, many bacterial serpins were identified from numerous ecological niches including the human gut microbiota. The origin, distribution and function of these proteins remain to be established. In this report, we shed light on the key role of human and bacterial serpins in health and disease. Moreover, we analyze their function, phylogeny and ecological distribution. This review highlights the potential use of bacterial serpins to set out new therapeutic approaches

The Nexus of Diet, Gut Microbiota and Inflammatory Bowel Diseases in Dogs

Canine inflammatory bowel diseases (IBD) are of increasing interest in veterinary medicine. They refer to complex and debilitating conditions of dogs’ gastrointestinal tract. Although little evidence for causal inferences is currently available, it is believed that IBD pathophysiology entails intricate interactions between environmental factors, the intestinal immune system, and the microbial communities that colonize the gut. To better understand the mechanisms underlying these disorders, leveraging factors associated with the development of these diseases is imperative. Of these factors, emerging evidence supports the role of dietary patterns as key players influencing the composition and function of gut microbes, with subsequent effects on health and disease. In this review, we particularly focus on addressing IBD in dogs and discuss how specific nutrients may elicit or relieve gut inflammation. Gaining mechanistic insights into such interplay and the underpinning mechanisms is key to inferring dietary recommendations, and setting up new and promising therapeutics

SP-1, a Serine Protease from the Gut Microbiota, Influences Colitis and Drives Intestinal Dysbiosis in Mice

Increased protease activity has been linked to the pathogenesis of IBD. While most studies have been focusing on host proteases in gut inflammation, it remains unclear how to address the potential contribution of their bacterial counterparts. In the present study, we report a functional characterization of a newly identified serine protease, SP-1, from the human gut microbiota. The serine protease repertoire of gut Clostridium was first explored, and the specificity of SP-1 was analyzed using a combinatorial chemistry method. Combining in vitro analyses and a mouse model of colitis, we show that oral administration of recombinant bacteria secreting SP-1 (i) compromises the epithelial barrier, (ii) alters the microbial community, and (ii) exacerbates colitis. These findings suggest that gut microbial protease activity may constitute a valuable contributor to IBD and could, therefore, represent a promising target for the treatment of the disease

Characterization of Two <i>Parabacteroides distasonis</i> Candidate Strains as New Live Biotherapeutics against Obesity

The gut microbiota is now considered as a key player in the development of metabolic dysfunction. Therefore, targeting gut microbiota dysbiosis has emerged as a new therapeutic strategy, notably through the use of live gut microbiota-derived biotherapeutics. We previously highlighted the anti-inflammatory abilities of two Parabacteroides distasonis strains. We herein evaluate their potential anti-obesity abilities and show that the two strains induced the secretion of the incretin glucagon-like peptide 1 in vitro and limited weight gain and adiposity in obese mice. These beneficial effects are associated with reduced inflammation in adipose tissue and the improvement of lipid and bile acid metabolism markers. P. distasonis supplementation also modified the Actinomycetota, Bacillota and Bacteroidota taxa of the mice gut microbiota. These results provide better insight into the capacity of P. distasonis to positively influence host metabolism and to be used as novel source of live biotherapeutics in the treatment and prevention of metabolic-related diseases

Gut Serpinome: Emerging Evidence in IBD

International audienceInflammatory bowel diseases (IBD) are incurable disorders whose prevalence and global socioeconomic impact are increasing. While the role of host genetics and immunity is well documented, that of gut microbiota dysbiosis is increasingly being studied. However, the molecular basis of the dialogue between the gut microbiota and the host remains poorly understood. Increased activity of serine proteases is demonstrated in IBD patients and may contribute to the onset and the maintenance of the disease. The intestinal proteolytic balance is the result of an equilibrium between the proteases and their corresponding inhibitors. Interestingly, the serine protease inhibitors (serpins) encoded by the host are well reported; in contrast, those from the gut microbiota remain poorly studied. In this review, we provide a concise analysis of the roles of serine protease in IBD physiopathology and we focus on the serpins from the gut microbiota (gut serpinome) and their relevance as a promising therapeutic approach