Bezafibrate improves mitochondrial function, blood-brain barrier integrity, and social deficits in models of 22q11.2 deletion syndrome.

Maintenance of blood-brain barrier (BBB) integrity is critical to optimal brain function, and its impairment has been linked to multiple neurological disorders. A notable feature of the BBB is its elevated mitochondrial content compared with peripheral endothelial cells, although the functional implications of this phenomenon are unclear. Here, we studied BBB mitochondrial function in the context of 22q11.

The gut microbiome shapes pharmacology and treatment outcomes for a key anti-inflammatory therapy.

Unlabelled: The human gut microbiome encodes a formidable metabolic repertoire that harvests nutrients from the diet, but these same pathways may also metabolize medications. Indeed, large screens have revealed extensive microbial metabolism of drugs , but the pharmacologic and clinical repercussions of microbiota-mediated metabolism remain to be discerned. As a proof-of-concept, we investigate how human gut microbes contribute to pharmacology and efficacy of a key anti-inflammatory drug, methotrexate (MTX).

Fibroblast lipid metabolism through ACSL4 regulates epithelial sensitivity to ferroptosis in IBD.

Increased reactive oxygen species (ROS) levels are a hallmark of inflammatory bowel disease (IBD) and constitute a major mechanism of epithelial cell death. Approaches to broadly inhibit ROS have had limited efficacy in treating IBD. Here we show that lipid peroxidation contributes to the pathophysiology of IBD by promoting ferroptosis, an iron-dependent form of programmed cell death.

Almond snacking modulates gut microbiome and metabolome in association with improved cardiometabolic and inflammatory markers.

Western-style dietary patterns have been linked with obesity and associated metabolic disorders and gut dysbiosis, whereas prudent dietary and snacking choices mitigate these predispositions. Using a multi-omics approach, we investigated how almond snacking counters gut imbalances linked to adiposity and an average American Diet (AAD). Fifteen adults with overweight or obesity underwent a randomized, crossover-controlled feeding trial comparing a 4-week AAD with a similar isocaloric diet supplemented with 42.

Phytochemical-Mediated Ah Receptor Activity Is Dependent on Dietary Context.

The aryl hydrocarbon receptor (AHR) is an important mediator of intestinal homeostasis. The AHR senses certain classes of phytochemicals, including many flavonoids and tryptophan metabolites generated in the intestinal tract. Several in vitro studies demonstrate the presence of AHR ligands in numerous plants commonly consumed by humans.

Microbiota and metabolite-based prediction tool for colonic polyposis with and without a known genetic driver.

Despite extensive investigations into the microbiome and metabolome changes associated with colon polyps and colorectal cancer (CRC), the microbiome and metabolome profiles of individuals with colonic polyposis, including those with (Gene-pos) and without (Gene-neg) a known genetic driver, remain comparatively unexplored. Using colon biopsies, polyps, and stool from patients with Gene-pos adenomatous polyposis ( = 9), Gene-neg adenomatous polyposis ( = 18), and serrated polyposis syndrome (SPS,  = 11), we demonstrated through 16S rRNA sequencing that the mucosa-associated microbiota in individuals with colonic polyposis is representative of the microbiota associated with small polyps, and that both Gene-pos and SPS cohorts exhibit differential microbiota populations relative to Gene-neg polyposis cohorts. Furthermore, we used these differential microbiota taxa to perform linear discriminant analysis to differentiate Gene-neg subjects from Gene-pos and from SPS subjects with an accuracy of 89% and 93% respectively.

A designed synthetic microbiota provides insight to community function in Clostridioides difficile resistance.

Clostridioides difficile, a major cause of antibiotic-associated diarrhea, is suppressed by the gut microbiome, but the precise mechanisms are not fully described. Through a meta-analysis of 12 human studies, we designed a synthetic fecal microbiota transplant (sFMT1) by reconstructing microbial networks negatively associated with C. difficile colonization.

Differential hepatic activation of mouse and human peroxisome proliferator-activated receptor-α by perfluorohexane sulfonate.

Exposure of perfluorohexane sulfonate (PFHxS) is associated with hepatomegaly and accumulation of lipids that may be mediated by nuclear receptors like peroxisome proliferator-activated receptor-α (PPARα), constitutive androstane receptor (CAR), or pregnane X receptor (PXR). This study tested the hypotheses that: (i) PFHxS causes changes in liver by activating PPARα, CAR, or PXR, and (ii) there is a species difference in PPARα activity by PFHxS. Wild-type, Ppara-null, and PPARA-humanized mice were fed either a control diet, or one containing 2.

Immunobiology of bile and cholangiocytes.

The biliary tract is now recognized as an immune organ, and within the biliary tract, both bile and cholangiocytes play a key role in maintaining immune defense and homeostasis. First, immunoreactive proteins such as secretory IgA provide local antimicrobial effects. Second, bile acids (BAs) protect the biliary tree from immune-related injury through receptor signaling, mainly via the membrane-bound receptor TGR5 on cholangiocytes.

microbiota model recapitulates and predicts individualised sensitivity to dietary emulsifier.

Background: Non-absorbed dietary emulsifiers, including carboxymethylcellulose (CMC), directly disturb intestinal microbiota, thereby promoting chronic intestinal inflammation in mice. A randomised controlled-feeding study (Functional Research on Emulsifiers in Humans, FRESH) found that CMC also detrimentally impacts intestinal microbiota in some, but not all, healthy individuals.

Objectives: This study aimed to establish an approach for predicting an individual's sensitivity to dietary emulsifiers via their baseline microbiota.

Chlorpyrifos modulates the mouse gut microbiota and metabolic activity.

The organophosphate chlorpyrifos is a commonly used pesticide for fruits and vegetables despite its association with neurotoxicity in humans. While some studies suggest that organophosphates may impact the gut microbiota, no studies to date have investigated the direct effect of chlorpyrifos on the gut microbiota with doses that approximate environmentally relevant dietary concentrations (EPA chronic reference dose: 0.3 µg/kg/day in humans and EPA acute reference dose: 5 µg/kg/day in humans).

Sphingosine Kinase 2 Regulates Aryl Hydrocarbon Receptor Nuclear Translocation and Target Gene Activation.

Sphingolipids play vital roles in metabolism and regulation. Previously, the aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor, was reported to directly regulate ceramide synthesis genes by binding to their promoters. Herein, sphingosine kinase 2 (SPHK2), responsible for producing sphingosine-1-phosphate (S1P), was found to interact with AHR through LXXLL motifs, influencing AHR nuclear localization.

Modulation of Ceramide-Induced Apoptosis in Enteric Neurons by Aryl Hydrocarbon Receptor Signaling: Unveiling a New Pathway beyond ER Stress.

2,3,7,8-tetrachlorodibenzo--dioxin (TCDD), a persistent organic pollutant and a potent aryl hydrocarbon receptor (AHR) ligand, causes delayed intestinal motility and affects the survival of enteric neurons. In this study, we investigated the specific signaling pathways and molecular targets involved in TCDD-induced enteric neurotoxicity. Immortalized fetal enteric neuronal (IM-FEN) cells treated with 10 nM TCDD exhibited cytotoxicity and caspase 3/7 activation, indicating apoptosis.

Effects of Early Life Exposures to the Aryl Hydrocarbon Receptor Ligand TCDF on Gut Microbiota and Host Metabolic Homeostasis in C57BL/6J Mice.

Background: Exposure to persistent organic pollutants (POPs) and disruptions in the gastrointestinal microbiota have been positively correlated with a predisposition to factors such as obesity, metabolic syndrome, and type 2 diabetes; however, it is unclear how the microbiome contributes to this relationship.

Objective: This study aimed to explore the association between early life exposure to a potent aryl hydrocarbon receptor (AHR) agonist and persistent disruptions in the microbiota, leading to impaired metabolic homeostasis later in life.

Methods: This study used metagenomics, nuclear magnetic resonance (NMR)- and mass spectrometry (MS)-based metabolomics, and biochemical assays to analyze the gut microbiome composition and function, as well as the physiological and metabolic effects of early life exposure to 2,3,7,8-tetrachlorodibenzofuran (TCDF) in conventional, germ-free (GF), and -null mice.

Activation of Peroxisome Proliferator-Activated Receptor-β/δ (PPARβ/δ) in Keratinocytes by Endogenous Fatty Acids.

Nuclear hormone receptors exist in dynamic equilibrium between transcriptionally active and inactive complexes dependent on interactions with ligands, proteins, and chromatin. The present studies examined the hypothesis that endogenous ligands activate peroxisome proliferator-activated receptor-β/δ (PPARβ/δ) in keratinocytes. The phorbol ester treatment or HRAS infection of primary keratinocytes increased fatty acids that were associated with enhanced PPARβ/δ activity.

Changes in the type 2 diabetes gut mycobiome associate with metformin treatment across populations.

Unlabelled: The human gut teems with a diverse ecosystem of microbes, yet non-bacterial portions of that community are overlooked in studies of metabolic diseases firmly linked to gut bacteria. Type 2 diabetes mellitus (T2D) is associated with compositional shifts in the gut bacterial microbiome and the mycobiome, the fungal portion of the microbiome. However, whether T2D and/or metformin treatment underpins fungal community changes is unresolved.

Surgery for Crohn's Disease Is Associated With a Dysbiotic Microbiome and Metabolome: Results From Two Prospective Cohorts.

Background & Aims: Crohn's disease is associated with alterations in the gut microbiome and metabolome described as dysbiosis. We characterized the microbial and metabolic consequences of ileal resection, the most common Crohn's disease surgery.

Methods: Patients with and without intestinal resection were identified from the Diet to Induce Remission in Crohn's Disease and Study of a Prospective Adult Research Cohort with Inflammatory Bowel Disease studies.

Dietary fiber guar gum-induced shift in gut microbiota metabolism and intestinal immune activity enhances susceptibility to colonic inflammation.

With an increasing interest in dietary fibers (DFs) to promote intestinal health and the growth of beneficial gut bacteria, there is a continued rise in the incorporation of refined DFs in processed foods. It is still unclear how refined fibers, such as guar gum, affect the gut microbiota activity and pathogenesis of inflammatory bowel disease (IBD). Our study elucidated the effect and underlying mechanisms of guar gum, a fermentable DF (FDF) commonly present in a wide range of processed foods, on colitis development.

The underappreciated diversity of bile acid modifications.

The repertoire of modifications to bile acids and related steroidal lipids by host and microbial metabolism remains incompletely characterized. To address this knowledge gap, we created a reusable resource of tandem mass spectrometry (MS/MS) spectra by filtering 1.2 billion publicly available MS/MS spectra for bile-acid-selective ion patterns.

Immune cell-intrinsic Ah receptor facilitates the expression of antimicrobial REG3G in the small intestine.

The intestinal epithelial layer is susceptible to damage by chemical, physiological and mechanical stress. While it is essential to maintain the integrity of epithelium, the biochemical pathways that contribute to the barrier function have not been completely investigated. Here we demonstrate an aryl hydrocarbon receptor (AHR)-dependent mechanism facilitating the production of the antimicrobial peptide AMP regenerating islet-derived protein 3 gamma (REG3G), which is essential for intestinal homeostasis.