Gut microbes and the liver circadian clock partition glucose and lipid metabolism.

Circadian rhythms govern glucose homeostasis, and their dysregulation leads to complex metabolic diseases. Gut microbes exhibit diurnal rhythms that influence host circadian networks and metabolic processes, yet underlying mechanisms remain elusive. Here, we showed hierarchical, bidirectional communication among the liver circadian clock, gut microbes, and glucose homeostasis in mice.

Gut microbiota as a transducer of dietary cues to regulate host circadian rhythms and metabolism.

Certain members of the gut microbiota exhibit diurnal variations in relative abundance and function to serve as non-canonical drivers of host circadian rhythms and metabolism. Also known as microbial oscillators, these microorganisms entrain upon non-photic cues, primarily dietary, to modulate host metabolism by providing input to both circadian clock-dependent and clock-independent host networks. Microbial oscillators are generally promoted by plant-based, low-fat (lean) diets, and most are abolished by low-fibre, high-sugar, high-fat (Western) diets.

Physiology of Electrolyte Transport in the Gut: Implications for Disease.

We now have an increased understanding of the genetics, cell biology, and physiology of electrolyte transport processes in the mammalian intestine, due to the availability of sophisticated methodologies ranging from genome wide association studies to CRISPR-CAS technology, stem cell-derived organoids, 3D microscopy, electron cryomicroscopy, single cell RNA sequencing, transgenic methodologies, and tools to manipulate cellular processes at a molecular level. This knowledge has simultaneously underscored the complexity of biological systems and the interdependence of multiple regulatory systems. In addition to the plethora of mammalian neurohumoral factors and their cross talk, advances in pyrosequencing and metagenomic analyses have highlighted the relevance of the microbiome to intestinal regulation.

The Yin and Yang of bile acid action on tight junctions in a model colonic epithelium.

Gastrointestinal epithelial barrier loss due to tight junction (TJ) dysfunction and bile acid-induced diarrhea are common in patients with inflammatory diseases. Although excess colonic bile acids are known to alter mucosal permeability, few studies have compared the effects of specific bile acids on TJ function. We report that the primary bile acid, chenodeoxycholic acid (CDCA), and its 7-dehydroxylated derivative, lithocholic acid (LCA) have opposite effects on epithelial integrity in human colonic T84 cells.

Chenodeoxycholic acid requires activation of EGFR, EPAC, and Ca2+ to stimulate CFTR-dependent Cl- secretion in human colonic T84 cells.

Bile acids are known to initiate intricate signaling events in a variety of tissues, primarily in the liver and gastrointestinal tract. Of the known bile acids, only the 7α-dihydroxy species, deoxycholic acid and chenodeoxycholic acid (CDCA), and their conjugates, activate processes that stimulate epithelial Cl secretion. We have previously published that CDCA acts in a rapid manner to stimulate colonic ion secretion via protein kinase A (PKA)-mediated activation of the dominant Cl channel, the cystic fibrosis transmembrane conductance regulator (CFTR) (Ao M, Sarathy J, Domingue J, Alrefai WA, and Rao MC.

Insights into the pathogenesis of ulcerative colitis from a murine model of stasis-induced dysbiosis, colonic metaplasia, and genetic susceptibility.

Gut dysbiosis, host genetics, and environmental triggers are implicated as causative factors in inflammatory bowel disease (IBD), yet mechanistic insights are lacking. Longitudinal analysis of ulcerative colitis (UC) patients following total colectomy with ileal anal anastomosis (IPAA) where >50% develop pouchitis offers a unique setting to examine cause vs. effect.

Lithocholic acid attenuates cAMP-dependent Cl- secretion in human colonic epithelial T84 cells.

Bile acids (BAs) play a complex role in colonic fluid secretion. We showed that dihydroxy BAs, but not the monohydroxy BA lithocholic acid (LCA), stimulate Cl(-) secretion in human colonic T84 cells (Ao M, Sarathy J, Domingue J, Alrefai WA, Rao MC. Am J Physiol Cell Physiol 305: C447-C456, 2013).

HEK-293 cells expressing the cystic fibrosis transmembrane conductance regulator (CFTR): a model for studying regulation of Cl- transport.

The Human Embryonic Kidney 293 cell line (HEK-293) readily lends itself to genetic manipulation and is a common tool for biologists to overexpress proteins of interest and study their function and molecular regulation. Although these cells have some limitations, such as an inability to form resistive monolayers necessary for studying transepithelial ion transport, they are nevertheless valuable in studying individual epithelial ion transporters. We report the use of HEK-293 cells to study the cystic fibrosis transmembrane conductance regulator (CFTR) Cl(-) channel.

Chenodeoxycholic acid stimulates Cl(-) secretion via cAMP signaling and increases cystic fibrosis transmembrane conductance regulator phosphorylation in T84 cells.

High levels of chenodeoxycholic acid (CDCA) and deoxycholic acid stimulate Cl(-) secretion in mammalian colonic epithelia. While different second messengers have been implicated in this action, the specific signaling pathway has not been fully delineated. Using human colon carcinoma T84 cells, we elucidated this cascade assessing Cl(-) transport by measuring I(-) efflux and short-circuit current (Isc).

Prolactin and dexamethasone regulate second messenger-stimulated cl(-) secretion in mammary epithelia.

Mammary gland ion transport is essential for lactation and is regulated by prolactin and glucocorticoids. This study delineates the roles of prolactin receptors (PRLR) and long-term prolactin and dexamethasone (P-D)-mediation of [Ca(2+)](i) and Cl(-) transport in HC-11 cells. P-D (24 h) suppressed ATP-induced [Ca(2+)](i).

Kate Bárány: a life of science, teaching, and service.

We celebrate the lives of Michael and Kate Bárány in this issue of the Journal of Muscle Research and Cell Motility. Kate and Michael died within weeks of each other in 2011. Joe Chalovich has written about Michael and we write about Kate.

Calcitonin receptor-mediated CFTR activation in human intestinal epithelial cells.

High levels of calcitonin (CT) observed in medullary thyroid carcinoma and other CT-secreting tumours cause severe diarrhoea. Previous studies have suggested that CT induces active chloride secretion. However, the involvement of CT receptor (CTR) and the molecular mechanisms underlying the modulation of intestinal electrolyte secreting intestinal epithelial cells have not been investigated.

Lubiprostone activates Cl- secretion via cAMP signaling and increases membrane CFTR in the human colon carcinoma cell line, T84.

Background: Lubiprostone, used clinically (b.i.d.

Ion transport in the small intestine.

Purpose Of Review: The 2009 review on small intestinal ion transport, in this series, focused on recent advances in duodenal bicarbonate secretion, the importance of scaffolding proteins and the pathophysiology of inflammation-associated diarrhea. The current review focuses on advances in ion-coupled solute transport, the dynamic role of the paracellular pathway in transepithelial-fluid transport and of elucidating the cellular basis of diarrheas associated with enteric infections.

Recent Findings: In understanding the cellular pathophysiology underlying diarrheal diseases, there is increased focus on the role of altering Na absorptive mechanisms as well as the role of the paracellular pathway.

Specific immunomodulatory and secretory activities of stevioside and steviol in intestinal cells.

Stevioside, isolated from Stevia rebaudiana, is a commercial sweetener. It was previously demonstrated that stevioside attenuates NF-kappaB-dependent TNF-alpha and IL-1beta synthesis in LPS-stimulated monocytes. The present study examined the effects of stevioside and its metabolite, steviol, on human colon carcinoma cell lines.

Role of protein kinase C-delta in the age-dependent secretagogue action of bile acids in mammalian colon.

The role of specific PKC isoforms in the regulation of epithelial Cl(-) secretion by Ca(2+)-dependent secretagogues remains controversial. In the developing rabbit distal colon, the bile acid taurodeoxycholate (TDC) acts via intracellular calcium to stimulate Cl(-) transport in adult, but not in young, animals, whereas the PKC activator phorbol dibutyrate (PDB) stimulates Cl(-) transport at all ages. We tested the hypothesis that specific PKC isoforms account for the age-specific effects of TDC.

Epidermal growth factor stimulates chloride transport in primary cultures of weanling and adult rabbit colonocytes.

Objectives: We have shown that Ca2+-dependent regulation of Cl- secretion in the mammalian colon exhibits age dependence. Because epidermal growth factor (EGF) has a well-established role in growth and can increase intracellular calcium [Ca2+]i, it is conceivable that its developmental influence may extend to the regulation of intestinal ion transport. In this study, we examined the role of EGF in the regulation of Cl- transport in the developing rabbit distal colon.

Inhibitory effects of choleretic hydroxyacetophenones on ileal bile acid transport in rats.

The effects of the choleretic and cholesterol lowering compound, 2,4,6-trihydroxyacetophenone (THA) and its analog, 2,6-dihydroxyacetophenone (DHA), on ileal bile acid absorption were investigated in rats. THA inhibited taurocholate (TC) uptake into ileal brush-border membrane vesicles (BBMV), showing a maximum inhibition of 50%, whereas DHA completely inhibited TC uptake into ileal BBMV. THA exhibited competitive inhibition with a Ki of 9.

Weanling, but not adult, rabbit colon absorbs bile acids: flux is linked to expression of putative bile acid transporters.

Intestinal handling of bile acids is age dependent; adult, but not newborn, ileum absorbs bile acids, and adult, but not weanling or newborn, distal colon secretes Cl(-) in response to bile acids. Bile acid transport involving the apical Na(+)-dependent bile acid transporter (Asbt) and lipid-binding protein (LBP) is well characterized in the ileum, but little is known about colonic bile acid transport. We investigated colonic bile acid transport and the nature of the underlying transporters and receptors.