Phosphocreatine Rescues Intestinal Epithelial Metabolic Dysfunction Related to Creatine Kinase Loss and Is Protective in Murine Colitis.

Background & Aims: Inflammatory bowel disease is associated with intestinal energetic derangements, including reduced creatine kinase (CK) expression. CK is critical to cellular energetics, catalyzing bidirectional transfer of high-energy phosphate between creatine and ATP, and phosphocreatine (PCr) and ADP. However, the impact of CK loss on intestinal epithelial cells (IECs) remains unclear.

Regulation of Epithelial HIF by Probiotic .

The gastrointestinal tract is home to trillions of microorganisms that interact with their host in profound ways, including regulation of immune, endocrine, and neurological functions. One mechanism by which these microbes interact with their eukaryotic host is through the generation of short-chain fatty acids (SCFAs), which are metabolized by the intestinal epithelium creating a state of "physiologic hypoxia". This hypoxia, in turn, results in stabilization and activation of hypoxia-inducible factor (HIF), a transcription factor family shown to support gut barrier function and homeostasis, in the intestinal epithelium.

Chlorination of epithelial tight junction proteins by neutrophil myeloperoxidase promotes barrier dysfunction and mucosal inflammation.

Neutrophils (polymorphonuclear leukocytes, PMNs) comprise a major component of the immune cell infiltrate during acute mucosal inflammation and have an important role in molding the inflammatory tissue environment. While PMNs are essential to clearance of invading microbes, the major PMN antimicrobial enzyme myeloperoxidase (MPO) can also promote bystander tissue damage. We hypothesized that blocking MPO would attenuate acute colitis and prevent the development of chronic colitis by limiting bystander tissue damage.

Epithelial heme oxygenase-1 enhances colonic tumorigenesis by inhibiting ferroptosis.

Colorectal cancer has been linked to chronic colitis and red meat consumption, which can increase colonic iron and heme. Heme oxygenase-1 ( ) metabolizes heme and releases ferrous iron, but its role in colonic tumorigenesis is not well-described. Recent studies suggest that ferroptosis, the iron-dependent form of cell death, protects against colonic tumorigenesis.

Integrating major ion geochemistry, stable isotopes (O, H) and radioactive isotopes (Rn, C, Cl, H) to understand the interaction between catchment waters and an intermittent river.

Determining the locations and sources of baseflow and the transit times of water is important for understanding catchment behaviour and functioning. Major ion geochemistry, stable isotopes (O and H), and radioisotopes (Rn, H, C, and Cl) were used to investigate the sources and transit times of water in the upper catchment of the intermittent Avoca River in southeast Australia. Rn activities and Cl concentrations implied the presence of baseflow inputs and the distribution was mainly controlled by local topography.

The TNF Mouse as a Model of Intestinal Fibrosis.

Crohn disease (CD) is a highly morbid chronic inflammatory disease. Although many patients with CD also develop fibrostenosing complications, there are no medical therapies for intestinal fibrosis. This is due, in part, to a lack of high-fidelity biomimetic models to enhance understanding and drug development, which highlights the need for developing in vivo models of inflammatory bowel disease-related intestinal fibrosis.

The hypoxic tissue microenvironment as a driver of mucosal inflammatory resolution.

On the backdrop of all acute inflammatory processes lies the activation of the resolution response. Recent years have witnessed an emerging interest in defining molecular factors that influence the resolution of inflammation. A keystone feature of the mucosal inflammatory microenvironment is hypoxia.

The TNF mouse as a model of intestinal fibrosis.

Background & Aims: Crohn's disease (CD) is a highly morbid chronic inflammatory disease. The majority of CD patients also develop fibrostenosing complications. Despite this, there are no medical therapies for intestinal fibrosis.

Essential role for epithelial HIF-mediated xenophagy in control of Salmonella infection and dissemination.

The intestinal mucosa exists in a state of "physiologic hypoxia," where oxygen tensions are markedly lower than those in other tissues. Intestinal epithelial cells (IECs) have evolved to maintain homeostasis in this austere environment through oxygen-sensitive transcription factors, including hypoxia-inducible factors (HIFs). Using an unbiased chromatin immunoprecipitation (ChIP) screen for HIF-1 targets, we identify autophagy as a major pathway induced by hypoxia in IECs.

Hypoxia-inducible factor as a bridge between healthy barrier function, wound healing, and fibrosis.

The healthy mammalian intestine is lined by a single layer of epithelial cells. These cells provide a selectively permeable barrier to luminal contents and normally do so in an efficient and effective manner. Barrier function in the healthy mucosa is provided via several mechanisms including epithelial junctional complexes, mucus production, as well as mucosal-derived antimicrobial proteins.

Contact-dependent, polarized acidification response during neutrophil-epithelial interactions.

Neutrophil (PMN) infiltration during active inflammation imprints changes in the local tissue environment. Such responses are often accompanied by significant extracellular acidosis that result in predictable transcriptional responses. In this study, we explore the mechanisms involved in inflammatory acidification as a result of PMN-intestinal epithelial cell (IEC) interactions.

Modulation of surface CD11c expression tracks plasticity in murine intestinal tissue eosinophils.

Intestinal eosinophils are implicated in the inflammatory pathology of eosinophilic gastrointestinal diseases and inflammatory bowel diseases. Eosinophils also contribute to intestinal immunologic and tissue homeostasis and host defense. Recent studies in allergic airway disease suggest functional subphenotypes of eosinophils may underly their pathogenic versus protective roles.

CMBEAR: Python-Based Recharge Estimator Using the Chloride Mass Balance Method in Australia.

The chloride mass balance (CMB) method is widely used to estimate long-term rates of groundwater recharge. In regions where surface water runoff is negligible, recharge can be estimated using measurements of chloride concentrations of groundwater and precipitation, and an estimate of long-term average rainfall. This paper presents the Chloride Mass Balance Estimator of Australian Recharge (CMBEAR), a Jupyter (Python) Notebook that is set up to rapidly apply the CMB method using gridded maps of chloride deposition rates across the Australian continent.

Disruption of monocyte-macrophage differentiation and trafficking by a heme analog during active inflammation.

Heme metabolism is a key regulator of inflammatory responses. Cobalt protoporphyrin IX (CoPP) is a heme analog and mimic that potently activates the NRF2/heme oxygenase-1 (HO-1) pathway, especially in monocytes and macrophages. We investigated the influence of CoPP on inflammatory responses using a murine model of colitis.

Sources and cycling of nitrogen revealed by stable isotopes in a highly populated large temperate coastal embayment.

The identification of nitrogen sources and cycling processes is critical to the management of nitrogen pollution. Here, we used both stable (δN-NO, δO-NO, δN-NH) and radiogenic (Rn) isotopes together with nitrogen concentrations to evaluate the relative importance of point (i.e.

Using geochemistry to identify and quantify the sources, distribution, and fluxes of baseflow to an intermittent river impacted by climate change: The upper Wimmera River, southeast Australia.

Documenting the distribution, sources and fluxes of baseflow discharge into rivers is important for their management and for maintaining ecosystem health. This study uses major ion geochemistry, Rn, and H to differentiate between the input of low-salinity near-river waters (bank storage and return waters and/or interflow) and regional groundwater in an intermittent river from southeast Australia that is undergoing long-term changes in flow resulting from climate change. Baseflow discharge calculated by Rn mass balance was up to 1.

In vitro Monitoring of Extracellular pH in Real-Time.

Early accumulation of neutrophils (PMN) is a hallmark of acute intestinal inflammation. This acute inflammation is either resolved or progresses to chronic inflammation. Without efficient PMN clearance at sites of infiltration, PMN can accumulate and contribute to chronic inflammatory conditions, including the intestinal diseases ulcerative colitis (UC) and Crohn's Disease (CD).

Lung neutrophils on a paleo diet: lean, mean inflammatory machines.

Sites of acute inflammation become austere environments for the procurement of energy. The combination of oxygen depletion (hypoxia) and decreased glucose availability requires surprising metabolic adaptability. In this issue of the JCI, Watts et al.

Mucosal acidosis elicits a unique molecular signature in epithelia and intestinal tissue mediated by GPR31-induced CREB phosphorylation.

Metabolic changes associated with tissue inflammation result in significant extracellular acidosis (EA). Within mucosal tissues, intestinal epithelial cells (IEC) have evolved adaptive strategies to cope with EA through the up-regulation of SLC26A3 to promote pH homeostasis. We hypothesized that EA significantly alters IEC gene expression as an adaptive mechanism to counteract inflammation.

Microbial-derived indoles inhibit neutrophil myeloperoxidase to diminish bystander tissue damage.

During episodes of acute inflammation, polymorphonuclear leukocytes (PMNs) are actively recruited to sites of inflammation or injury where they provide anti-microbial and wound-healing functions. One enzyme crucial for fulfilling these functions is myeloperoxidase (MPO), which generates hypochlorous acid from Cl and hydrogen peroxide. The potential exists, however, that uncontrolled the extracellular generation of hypochlorous acid by MPO can cause bystander tissue damage and inhibit the healing response.

Bile acids modulate colonic MAdCAM-1 expression in a murine model of combined cholestasis and colitis.

Primary sclerosing cholangitis (PSC) is a progressive fibrosing cholestatic liver disease that is strongly associated with inflammatory bowel disease (IBD). PSC-associated IBD (PSC-IBD) displays a unique phenotype characterized by right-side predominant colon inflammation and increased risk of colorectal cancer compared to non-PSC-IBD. The frequent association and unique phenotype of PSC-IBD suggest distinctive underlying disease mechanisms from other chronic liver diseases or IBD alone.

The HIF target ATG9A is essential for epithelial barrier function and tight junction biogenesis.

Intestinal epithelial cells (IECs) exist in a metabolic state of low oxygen tension termed "physiologic hypoxia." An important factor in maintaining intestinal homeostasis is the transcription factor hypoxia-inducible factor (HIF), which is stabilized under hypoxic conditions and mediates IEC homeostatic responses to low oxygen tension. To identify HIF transcriptional targets in IEC, chromatin immunoprecipitation (ChIP) was performed in Caco-2 IECs using HIF-1α- or HIF-2α-specific antibodies.

The spatial extent and timescales of bank infiltration and return flows in an upland river system: Implications for water quality and volumes.

The temporary storage of river water in riverbanks and its subsequent return to the river is an important part of the hydrological cycle. Detailed multi-year head and electrical conductivity (EC) variations document the spatial and temporal scales of bank infiltration and return flows in the Ovens catchment, southeast Australia. The study represents one of only a few that has integrated geochemical data and hydraulic heads over several hydrological cycles in a catchment unimpacted by groundwater extraction.