AJP Gastrointestinal and Liver Physiology

Kaufmann, Benedikt; Seyfried, Nick; Hartmann, Daniel; Hartmann, Phillipp

doi: 10.1152/ajpgi.00017.2023pmid: 37129252

The use of probiotics, prebiotics and synbiotics has become an important therapy in numerous gastrointestinal diseases in recent years. Modifying the gut microbiota, this therapeutic approach helps to restore a healthy microbiome. Nonalcoholic fatty liver disease and alcohol-associated liver disease are among the leading causes of chronic liver disease worldwide. A disrupted intestinal barrier, microbial translocation and an altered gut microbiome metabolism, or metabolome, are crucial in the pathogenesis of these chronic liver diseases. As pro-, pre- and synbiotics modulate these targets, they were identified as possible new treatment options in liver disease. In this review, we highlight the current findings on clinical and mechanistic effects of this therapeutic approach in nonalcoholic fatty liver disease and alcohol-associated liver disease.

Salvi, Pooja S.; Shaughnessy, Matthew P.; Sumigray, Kaelyn D.; Cowles, Robert A.

doi: 10.1152/ajpgi.00113.2022pmid: 37158470

Regulation of small intestinal epithelial growth by endogenous and environmental factors is critical for intestinal homeostasis and recovery from insults. Depletion of the intestinal microbiome increases epithelial proliferation in small intestinal crypts, similar to the effects observed in animal models of serotonin potentiation. Based on prior evidence that the microbiome modulates serotonin activity, we hypothesized that microbial depletion-induced epithelial proliferation is dependent on host serotonin activity. A mouse model of antibiotic-induced microbial depletion (AIMD) was employed. Serotonin potentiation was achieved through either genetic knockout of the serotonin transporter (SERT) or pharmacologic SERT inhibition, and inhibition of serotonin synthesis was achieved with para-chlorophenylalanine. AIMD and serotonin potentiation increased intestinal villus height and crypt proliferation in an additive manner, but the epithelial proliferation observed after AIMD was blocked in the absence of endogenous serotonin. Using Lgr5-EGFP-reporter mice, we evaluated intestinal stem cell (ISC) quantity and proliferation. AIMD increased the number of ISCs per crypt and ISC proliferation compared to controls, and changes in ISC number and proliferation were dependent on the presence of host serotonin. Furthermore, western blotting demonstrated that AIMD reduced epithelial SERT protein expression compared to controls. In conclusion, host serotonin activity is necessary for microbial depletion-associated changes in villus height and ISC proliferation in crypts, and microbial depletion produces a functional serotonin-potentiated state through reduced SERT protein expression. These findings provide an understanding of how changes to the microbiome contribute to intestinal pathology and can be applied therapeutically.

Sodhi, Chhinder P.; Ahmad, Raheel; Fulton, William B.; Lopez, Carla M.; Eke, Benjamin O.; Scheese, Daniel; Duess, Johannes W.; Steinway, Steve N.; Raouf, Zachariah; Moore, Hannah; Tsuboi, Koichi; Sampah, Maame Efua; Jang, Hee-Seong; Buck, Rachael H.; Hill, David R.; Niemiro, Grace M.; Prindle, Thomas; Wang, Sanxia; Wang, Menghan;

Markey, Gary E.; Donohoe, Claire L.; McNamee, Eóin N.; Masterson, Joanne C.

doi: 10.1152/ajpgi.00184.2022pmid: 37129237

MicroRNAs (miRNAs) are a class of small endogenous RNA molecules between 18 to 25 nucleotides long. The primary function of miRNAs is in the posttranscriptional regulation of mRNA targets through RNA interference culminating in mRNA degradation or translational repression. MiRNAs are fundamental in physiological and pathological processes such as, cell proliferation, differentiation, apoptosis, and inflammation. Among this includes the uncovered potential of miRNAs in overall esophageal disease with a focus on the clinicopathologic allergic disease eosinophilic esophagitis (EoE), gastroesophageal reflux disease (GERD) and the tumorigenic continuum from Barrett's esophagus towards esophageal adenocarcinoma (EAC). Although these pathologies are distinct from one another, they share pathophysiological elements such as an intense inflammatory milieu, esophageal dysfunction, and, as presented in this review, an overlap in miRNA expression which contributes to overall esophageal disease. The overlap in the dysregulated miRNA transcriptome of these pathologies highlights the key role miRNAs play in contributing to esophageal disease progression. Owing to this notable dysregulation, there is an attractive utility for miRNAs as less-invasive diagnostic and prognostic biomarkers in esophageal diseases which already require invasive endoscopies and biopsy retrieval. In this review, miRNAs within EoE, GERD, BE, EAC and esophageal achalasia are discussed, as well as reviewing a core set of miRNAs shared in the disease progression among some of these pathologies, as well as the potential utility of targeting miRNAs as therapeutic options in overall esophageal disease.

Wiklendt, Lukasz; Mohd Rosli, Reizal; Kumar, Raghu; Paskaranandavadivel, Niranchan; Bampton, Peter A.; Maslen, Lyn; Costa, Marcello; Brookes, Simon J.; O’Grady, Greg; Dinning, Phil G.

doi: 10.1152/ajpgi.00114.2022pmid: 37162180

Patients with irritable bowel syndrome (IBS) have recurrent lower abdominal pain, associated with altered bowel habit (diarrhea and/or constipation). As bowel habit is altered, abnormalities in colonic motility are likely to contribute, however, characterization of colonic motor patterns in IBS patients remains poor. Utilizing fiber-optic manometry, we aimed to characterize distal colonic postprandial colon motility in diarrhea predominant IBS. Methods: After an overnight fast, a 72 sensor (spaced at 1cm intervals) manometry catheter was colonoscopically placed to the proximal colon, in 13 patients with IBS-D and 12 healthy adults. Recordings were taken for two hours pre and post a 700kCal meal. Data were analyzed with our two developed automated techniques. Results: In both healthy adults and patients with IBS-D the dominant frequencies of pressure waves throughout the colon are between 2-4 cycles per minute (cpm) and the power of these frequencies increased significantly after a meal. While these pressure waves formed propagating contractions in both groups, the post-prandial propagating contraction increase was significantly smaller in patients compared to healthy adults. In healthy adults during the meal period, retrograde propagation between 2-8 cpm was significantly greater than antegrade propagation at the same frequencies. This difference was not observed in IBS-D.Conclusion: IBS-D patients show reduced prevalence of the retrograde cyclic motor pattern post-prandially compared to the marked prevalence in healthy adults. We hypothesize that this reduction may allow premature rectal filling, leading to postprandial urgency and diarrhea.

Gupta, Kapish

doi: 10.1152/ajpgi.00165.2022pmid: 37192193

Hepatocytes produce bile components and secrete them into a lumen, known as a bile canaliculus, that is formed by the apical membranes of adjoining hepatocytes. Bile canaliculi merge to form tubular structures that subsequently connect to the canal of Hering and larger intra- and extrahepatic bile ducts formed by cholangiocytes, which modify bile and enable flow through to the small intestine. The major functional requirements for bile canaliculi are maintenance of canalicular shape to preserve the blood-bile barrier and regulation of bile flow. These functional requirements are mediated by functional modules, primarily transporters, the cytoskeleton, cell-cell junctions, and mechanosensing proteins. I propose here that bile canaliculi behave as robust machines whereby the functional modules act in a coordinated manner to perform the multistep task of maintaining canalicular shape and bile flow. Cholestasis, the general term for aberrant bile flow, stems from drug/toxin-induced or genetic dysregulation of one or more of the protein components in the functional modules. Here, I discuss the interactions between components of the various functional modules in bile canaliculi and describe how these functional modules regulate canalicular morphology and function. I use this framework to provide a perspective on recent studies of bile canalicular dynamics.