Dietary protein source mediates colitis pathogenesis through bacterial modulation of bile acids.

Evidence-based dietary recommendations for individuals with inflammatory bowel diseases (IBD) are limited. Red meat consumption is associated with increased IBD incidence and relapse in patients, suggesting that switching to a plant-based diet may limit gut inflammation. However, the mechanisms underlying the differential effects of these diets remain poorly understood.

A Comprehensive Metabolomic and Microbial Analysis Following Dietary Amino Acid Reduction in Mice.

Nutritional metabolomics provides a comprehensive overview of the biochemical processes that are induced by dietary intake through the measurement of metabolite profiles in biological samples. However, there is a lack of deep phenotypic analysis that shows how dietary interventions influence the metabolic state across multiple physiologic sites. Dietary amino acids have emerged as important nutrients for physiology and pathophysiology given their ability to impact cell metabolism.

Metabolic regulation of the mitochondrial immune checkpoint.

Disrupting mitochondrial function in malignant cells is a promising strategy to enhance anticancer immunity. We have recently demonstrated that depriving colorectal cancer cells of serine results in mitochondrial dysfunction coupled with the cytosolic accumulation of mitochondrial DNA and consequent activation of CGAS- and STING-dependent tumor-targeting immune responses.

Serine Depletion Promotes Antitumor Immunity by Activating Mitochondrial DNA-Mediated cGAS-STING Signaling.

Serine is critical for supporting cancer metabolism, and depriving malignant cells of this nonessential amino acid exerts antineoplastic effects, in large part, through disrupting metabolic pathways. Given the intricate relationship between cancer metabolism and the immune system, the metabolic defects imposed by serine deprivation might impact tumor-targeting immunity. In this study, we demonstrated that restricting endogenous and exogenous sources of serine in colorectal cancer cells results in mitochondrial dysfunction, leading to mitochondrial DNA (mtDNA) accumulation in the cytosol and consequent cGAS-STING1-driven type I IFN secretion.

Over 30 years of STEP: The Pittsburgh experience with first-episode psychosis.

Aims: For over 30 years, combined research and treatment settings in the US have been critical to conceptualizing care for first-episode psychosis (FEP). Here we describe an early example of such a context, the Services for the Treatment of Early Psychosis (STEP) clinic, which is affiliated with the University of Pittsburgh.

Methods: We describe STEP's historical roots and establishment in the early 1990s; STEP's research and treatment contributions, alongside its growth and ongoing leadership.

Serine Supports Epithelial and Immune Cell Function in Colitis.

Inflammatory bowel diseases (IBD) are chronic inflammatory disorders of the gastrointestinal tract that are largely driven by immune cell activity, and mucosal healing is critical for remission. Serine is a nonessential amino acid that supports epithelial and immune cell metabolism and proliferation; however, whether these roles affect IBD pathogenesis is not well understood. Herein, the study showed that serine synthesis increased selectively in the epithelial cells of colons from patients with IBD and murine models of colitis.

A Pilot Controlled Feeding Trial Modifying Protein Intake in Healthy Subjects to Assess Adherence and the Metabolome.

Dietary protein has been shown to impact physiology and pathophysiology, including inflammation and cancer, effects believed to occur through host and microbe-mediated mechanisms. However, the majority of studies investigating this concept have been conducted in animal models, with less information on the optimal approach, tolerability and biologic effects of modifying protein intake in humans. The current study presents a longitudinal controlled feeding trial carried out in healthy humans to acutely modulate protein intake using individualized diets.

p53 engages the cGAS/STING cytosolic DNA sensing pathway for tumor suppression.

Tumor suppression by TP53 involves cell-autonomous and non-cell-autonomous mechanisms. TP53 can suppress tumor growth by modulating immune system functions; however, the mechanistic basis for this activity is not well understood. We report that p53 promotes the degradation of the DNA exonuclease TREX1, resulting in cytosolic dsDNA accumulation.

Modifying dietary amino acids in cancer patients.

Limiting nutrient utilization by cancer cells in order to disrupt their metabolism and suppress their growth represents a promising approach for anti-cancer therapy. Recently, studies demonstrating the anti-neoplastic effects of lowering amino acid (AA) availability have opened up an exciting and quickly growing field of study. Although intracellular synthesis can often provide the AAs necessary to support cancer cells, diet and the tumor microenvironment can also be important sources.

Microbes Contribute to Chemopreventive Efficacy, Intestinal Tumorigenesis, and the Metabolome.

Unlabelled: Bacteria are believed to play an important role in intestinal tumorigenesis and contribute to both gut luminal and circulating metabolites. Celecoxib, a selective cyclooxygenase-2 inhibitor, alters gut bacteria and metabolites in association with suppressing the development of intestinal polyps in mice. The current study sought to evaluate whether celecoxib exerts its chemopreventive effects, in part, through intestinal bacteria and metabolomic alterations.

Restored Ketosis Drives Anticancer Immunity in Colorectal Cancer.

Dietary interventions including alterations in the amount or type of specific macronutrients have been shown to mediate antineoplastic effects in preclinical tumor models, but the underlying mechanisms are only partially understood. In this issue of Cancer Research, Wei and colleagues demonstrate that restoring ketogenesis in the colorectal cancer microenvironment decreases the KLF5-dependent synthesis of CXCL12 by cancer-associated fibroblasts, ultimately enhancing tumor infiltration by immune effector cells and increasing the therapeutic efficacy of an immune checkpoint inhibitor specific for PD-1. These findings provide a novel, therapeutically actionable link between suppressed ketogenesis and immunoevasion in the colorectal cancer microenvironment.

Induction and evaluation of murine colitis induced by T cell transfer.

Inflammatory bowel diseases (IBD) involve repetitive bouts of inflammation in the intestinal tract and can result in severe morbidity for patients. Moreover, long-standing IBD increases the risk for developing intestinal neoplasia. Although several factors including immune cell activity, microbiota and diet have been implicated in IBD pathogenesis, it is still considered a disease of idiopathic origin.

Targeting Serine in Cancer: Is Two Better Than One?

Several recent preclinical studies have demonstrated that simultaneously blocking exogenous and endogenous sources of serine in malignant cells mediates superior anticancer effects as compared with limiting either source alone. Here, we critically summarize key developments in targeting serine to treat cancer and discuss persisting challenges for implementing such a therapeutic approach in patients.

GLUT5 is a determinant of dietary fructose-mediated exacerbation of experimental colitis.

The Western diet has been suggested to contribute to the rising incidence of inflammatory bowel diseases. This has led to the hypothesis that fructose, a component of the Western diet, could play a role in the pathogenesis of inflammatory bowel diseases. A high-fructose diet is known to exacerbate experimental colitis.

Anti-tumor effects of an ID antagonist with no observed acquired resistance.

ID proteins are helix-loop-helix (HLH) transcriptional regulators frequently overexpressed in cancer. ID proteins inhibit basic-HLH transcription factors often blocking differentiation and sustaining proliferation. A small-molecule, AGX51, targets ID proteins for degradation and impairs ocular neovascularization in mouse models.

Induction of colitis-associated neoplasia in mice using azoxymethane and dextran sodium sulfate.

Long-standing inflammatory bowel diseases (IBD) increase the risk for the development of colorectal cancer (CRC). This increase is due in large part to chronic intestinal inflammation which exposes the epithelium to pro-carcinogenic factors. Moreover, enhanced mucosal proliferation associated with repetitive wound healing events following an inflammatory episode, further enhance this pro-tumorigenic environment.

Performing Colonoscopic-Guided Pinch Biopsies in Mice and Evaluating Subsequent Tissue Changes.

Understanding the tissue and cellular changes that occur in the acute injury response as well as during the wound healing process is of paramount importance when studying diseases of the gastrointestinal (GI) tract. The murine colonic pinch biopsy model is a useful tool to define these processes. Additionally, the interplay between gut luminal content (e.

Exogenous and Endogenous Sources of Serine Contribute to Colon Cancer Metabolism, Growth, and Resistance to 5-Fluorouracil.

Serine is a nonessential amino acid generated by the sequential actions of phosphoglycerate dehydrogenase (PHGDH), phosphoserine aminotransferase (PSAT1), and phosphoserine phosphatase (PSPH). Increased serine biosynthesis occurs in several cancers and supports tumor growth. In addition, cancer cells can harness exogenous serine to enhance their metabolism and proliferation.

Dietary interventions to prevent high-fructose diet-associated worsening of colitis and colitis-associated tumorigenesis in mice.

Diet is believed to be an important factor in the pathogenesis of inflammatory bowel disease. High consumption of dietary fructose has been shown to exacerbate experimental colitis, an effect mediated through the gut microbiota. This study evaluated whether dietary alterations could attenuate the detrimental effects of a high-fructose diet (HFrD) in experimental colitis.

Thalamic, Amygdalar, and hippocampal nuclei morphology and their trajectories in first episode psychosis: A preliminary longitudinal study.

The thalamus, amygdala, and hippocampus play important pathophysiologic roles in psychosis. Few studies have prospectively examined subcortical nuclei in relation to predicting clinical outcomes after a first-episode of psychosis (FEP). Here, we examined volumetric differences and trajectories among subcortical nuclei in FEP patients and their associations with illness severity.

Dietary Fructose Alters the Composition, Localization, and Metabolism of Gut Microbiota in Association With Worsening Colitis.

Background & Aims: The incidence of inflammatory bowel diseases has increased over the last half century, suggesting a role for dietary factors. Fructose consumption has increased in recent years. Recently, a high fructose diet (HFrD) was shown to enhance dextran sodium sulfate (DSS)-induced colitis in mice.

Visual Cortical Alterations and their Association with Negative Symptoms in Antipsychotic-Naïve First Episode Psychosis.

Visual perceptual and processing deficits are common in schizophrenia and possibly point towards visual pathway alterations. However, no studies have examined visual cortical morphology in first-episode psychosis (FEP). In an antipsychotic-naïve FEP population, we investigated primary visual (V1), association area (V2), and motion perception (V5/MT) morphology compared to controls.

Drugging cancer metabolism: Expectations vs. reality.

As compared to their normal counterparts, neoplastic cells exhibit a variety of metabolic changes that reflect not only genetic and epigenetic defects underlying malignant transformation, but also the nutritional and immunobiological conditions of the tumor microenvironment. Such alterations, including the so-called Warburg effect (an increase in glucose uptake largely feeding anabolic and antioxidant metabolism), have attracted considerable attention as potential targets for the development of novel anticancer therapeutics. However, very few drugs specifically conceived to target bioenergetic cancer metabolism are currently approved by regulatory agencies for use in humans.

Trajectory of neurological examination abnormalities in antipsychotic-naïve first-episode psychosis population: a 1 year follow-up study.

Background: Neurological Examination Abnormalities (NES) are quantified by measuring subtle, partially localizable (cerebello-thalamo-prefrontal cortical circuit) and heritable neurological signs comprising sensory integration, motor coordination and complex motor sequencing that are associated with first-episode psychosis (FEP). A few studies have evaluated NES longitudinally and as a predictor for diagnostic and response classification, but these studies have been confounded, underpowered and divergent. We examined (1) baseline and longitudinal NES differences between diagnostic and year 1 response groups; (2) if NES predicts diagnostic and response groups and (3) relationships between clinical variables and NES measures in antipsychotic-naïve FEP.