Effects of 1-week sacral nerve stimulation on the rectal intestinal epithelial barrier and neuromuscular transmission in a porcine model

International audienceSacral nerve stimulation (SNS) is a validated treatment for fecal incontinence, although the mechanism of action remains unknown. Short-term effects of SNS on the intestinal epithelial barrier (IEB) have been reported previously. The aim of our study was to assess the impact of a 1-week SNS on the IEB in a preclinical model

Luminal contents from the gut of colicky infants induce visceral hypersensitivity in mice

International audienceBackground: The pathophysiology of infantile colic is poorly understood, though various studies report gut microbiota dysbiosis in colicky infants. We aimed to test the hypothesis that colic-related dysbiosis is associated with visceral hypersensitivity triggered by an altered luminal milieu. Methods: Fecal samples from seven colicky and seven non-colicky infants were studied. Fecal supernatants (FS) were infused into the colons of C57/Bl6 mice (n=10/ specimen). Visceral sensitivity was subsequently assessed in the animals by recording their abdominal muscle response to colorectal distension (CRD) by electromyography (EMG). Serine and cysteine protease activities were assessed in FS with specific substrates. Infant fecal microbiota composition was analyzed by DNA extraction and 16S rRNA gene pyrosequencing. Key Results: FS from colicky infants triggered higher EMG activity than FS from non-colicky infants in response to both the largest CRD volumes and overall, as assessed by the area under the curve of the EMG across all CRD volumes. Infant crying time strongly correlated with mouse EMG activity. Microbiota richness and phylogenetic diversity were increased in the colicky group, without showing prominent microbial composition alterations. Only Bacteroides vulgatus and Bilophila wadsworthia were increased in the colicky group. Bacteroides vulgatus abundance positively correlated with visceral sensitivity. No differences were found in protease activities. Conclusions & Inferences: Luminal contents from colicky infants trigger visceral hypersensitivity, which may explain the excessive crying behavior of these infants. Additional studies are required to determine the nature of the compounds involved, their mechanism of action, and the potential implications of intestinal microbiota in their generation

Bile acid receptors as targets for drug development

The intracellular nuclear receptor farnesoid X receptor and the transmembrane G protein-coupled receptor TGR5 respond to bile acids by activating transcriptional networks and/or signalling cascades. These cascades affect the expression of a great number of target genes relevant for bile acid, cholesterol, lipid and carbohydrate metabolism, as well as genes involved in inflammation, fibrosis and carcinogenesis. Pregnane X receptor, vitamin D receptor and constitutive androstane receptor are additional nuclear receptors that respond to bile acids, albeit to a more restricted set of species of bile acids. Recognition of dedicated bile acid receptors prompted the development of semi-synthetic bile acid analogues and nonsteroidal compounds that target these receptors. These agents hold promise to become a new class of drugs for the treatment of chronic liver disease, hepatocellular cancer and extrahepatic inflammatory and metabolic diseases. This Review discusses the relevant bile acid receptors, the new drugs that target bile acid signalling and their possible applications

Neuroplasticity and dysfunction after gastrointestinal inflammation

The gastrointestinal tract is innervated by several distinct populations of neurons, whose cell bodies either reside within (intrinsic) or outside (extrinsic) the gastrointestinal wall. Normally, most individuals are unaware of the continuous, complicated functions of these neurons. However, for patients with gastrointestinal disorders, such as IBD and IBS, altered gastrointestinal motility, discomfort and pain are common, debilitating symptoms. Although bouts of intestinal inflammation underlie the symptoms associated with IBD, increasing preclinical and clinical evidence indicates that infection and inflammation are also key risk factors for the development of other gastrointestinal disorders. Notably, a strong correlation exists between prior exposure to gut infection and symptom occurrence in IBS. This Review discusses the evidence for neuroplasticity (structural, synaptic or intrinsic changes that alter neuronal function) affecting gastrointestinal function. Such changes are evident during inflammation and, in many cases, long after healing of the damaged tissues, when the nervous system fails to reset back to normal. Neuroplasticity within distinct populations of neurons has a fundamental role in the aberrant motility, secretion and sensation associated with common clinical gastrointestinal disorders. To find appropriate therapeutic treatments for these disorders, the extent and time course of neuroplasticity must be fully appreciated.Stuart M. Brierley and David R. Linde