Metabolites

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17 pages, 3245 KiB

Open AccessArticle

FOXO3 Expression in Macrophages Is Lowered by a High-Fat Diet and Regulates Colonic Inflammation and Tumorigenesis

by Rida Iftikhar, Harrison M. Penrose, Angelle N. King, Yunah Kim, Emmanuelle Ruiz, Emad Kandil, Heather L. Machado and Suzana D. Savkovic

Metabolites 2022, 12(3), 250; https://doi.org/10.3390/metabo12030250 - 16 Mar 2022

Cited by 8 | Viewed by 3339

Abstract

Obesity, characterized by augmented inflammation and tumorigenesis, is linked to genetic predispositions, such as FOXO3 polymorphisms. As obesity is associated with aberrant macrophages infiltrating different tissues, including the colon, we aimed to identify FOXO3-dependent transcriptomic changes in macrophages that drive obesity-mediated colonic inflammation [...] Read more.

Obesity, characterized by augmented inflammation and tumorigenesis, is linked to genetic predispositions, such as FOXO3 polymorphisms. As obesity is associated with aberrant macrophages infiltrating different tissues, including the colon, we aimed to identify FOXO3-dependent transcriptomic changes in macrophages that drive obesity-mediated colonic inflammation and tumorigenesis. We found that in mouse colon, high-fat-diet-(HFD)-related obesity led to diminished FOXO3 levels and increased macrophages. Transcriptomic analysis of mouse peritoneal FOXO3-deficient macrophages showed significant differentially expressed genes (DEGs; FDR < 0.05) similar to HFD obese colons. These DEG-related pathways, linked to mouse colonic inflammation and tumorigenesis, were similar to those in inflammatory bowel disease (IBD) and human colon cancer. Additionally, we identified a specific transcriptional signature for the macrophage-FOXO3 axis (MAC-FOXO3₈₂), which separated the transcriptome of affected tissue from control in both IBD (p = 5.2 × 10⁻⁸ and colon cancer (p = 1.9 × 10⁻¹¹), revealing its significance in human colonic pathobiologies. Further, we identified (heatmap) and validated (qPCR) DEGs specific to FOXO3-deficient macrophages with established roles both in IBD and colon cancer (IL-1B, CXCR2, S100A8, S100A9, and TREM1) and those with unexamined roles in these colonic pathobiologies (STRA6, SERPINH1, LAMB1, NFE2L3, OLR1, DNAJC28 and VSIG10). These findings establish an important understanding of how HFD obesity and related metabolites promote colonic pathobiologies. Full article

(This article belongs to the Special Issue Intestinal Epithelial Metabolism and Metabolites as Gatekeepers for Organismal Health)

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19 pages, 4164 KiB

Open AccessArticle

Cross-Talk between Probiotic Nissle 1917 and Human Colonic Epithelium Affects the Metabolite Composition and Demonstrates Host Antibacterial Effect

by Karol Dokladny, John K. Crane, Alex J. Kassicieh, James B. Kaper and Olga Kovbasnjuk

Metabolites 2021, 11(12), 841; https://doi.org/10.3390/metabo11120841 - 05 Dec 2021

Cited by 1 | Viewed by 2541

Abstract

Colonic epithelium–commensal interactions play a very important role in human health and disease development. Colonic mucus serves as an ecologic niche for a myriad of commensals and provides a physical barrier between the epithelium and luminal content, suggesting that communication between the host [...] Read more.

Colonic epithelium–commensal interactions play a very important role in human health and disease development. Colonic mucus serves as an ecologic niche for a myriad of commensals and provides a physical barrier between the epithelium and luminal content, suggesting that communication between the host and microbes occurs mainly by soluble factors. However, the composition of epithelia-derived metabolites and how the commensal flora influences them is less characterized. Here, we used mucus-producing human adult stem cell-derived colonoid monolayers exposed apically to probiotic E. coli strain Nissle 1917 to characterize the host–microbial communication via small molecules. We measured the metabolites in the media from host and bacterial monocultures and from bacteria-colonoid co-cultures. We found that colonoids secrete amino acids, organic acids, nucleosides, and polyamines, apically and basolaterally. The metabolites from host-bacteria co-cultures markedly differ from those of host cells grown alone or bacteria grown alone. Nissle 1917 affects the composition of apical and basolateral metabolites. Importantly, spermine, secreted apically by colonoids, shows antibacterial properties, and inhibits the growth of several bacterial strains. Our data demonstrate the existence of a cross-talk between luminal bacteria and human intestinal epithelium via metabolites, which might affect the numbers of physiologic processes including the composition of commensal flora via bactericidal effects. Full article

(This article belongs to the Special Issue Intestinal Epithelial Metabolism and Metabolites as Gatekeepers for Organismal Health)

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Review

Jump to: Research

12 pages, 1096 KiB

Open AccessReview

Diurnal Interplay between Epithelium Physiology and Gut Microbiota as a Metronome for Orchestrating Immune and Metabolic Homeostasis

by Juan Jose Martínez-García, Dominique Rainteau, Lydie Humbert, Antonin Lamaziere, Philippe Lesnik and Mathias Chamaillard

Metabolites 2022, 12(5), 390; https://doi.org/10.3390/metabo12050390 - 26 Apr 2022

Cited by 2 | Viewed by 2459

Abstract

The behavior and physiology of most organisms are temporally coordinated and aligned with geophysical time by a complex interplay between the master and peripheral clocks. Disruption of such rhythmic physiological activities that are hierarchically organized has been linked to a greater risk of [...] Read more.

The behavior and physiology of most organisms are temporally coordinated and aligned with geophysical time by a complex interplay between the master and peripheral clocks. Disruption of such rhythmic physiological activities that are hierarchically organized has been linked to a greater risk of developing diseases ranging from cancer to metabolic syndrome. Herein, we summarize the molecular clockwork that is employed by intestinal epithelial cells to anticipate environmental changes such as rhythmic food intake and potentially dangerous environmental stress. We also discuss recent discoveries contributing to our understanding of how a proper rhythm of intestinal stem cells may achieve coherence for the maintenance of tissue integrity. Emerging evidence indicates that the circadian oscillations in the composition of the microbiota may operate as an important metronome for the proper preservation of intestinal physiology and more. Furthermore, in this review, we outline how epigenetic clocks that are based on DNA methylation levels may extensively rewire the clock-controlled functions of the intestinal epithelium that are believed to become arrhythmic during aging. Full article

(This article belongs to the Special Issue Intestinal Epithelial Metabolism and Metabolites as Gatekeepers for Organismal Health)

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21 pages, 3382 KiB

Open AccessReview

The Intestinal Barrier—Shielding the Body from Nano- and Microparticles in Our Diet

by Marlene Schwarzfischer and Gerhard Rogler

Metabolites 2022, 12(3), 223; https://doi.org/10.3390/metabo12030223 - 02 Mar 2022

Cited by 16 | Viewed by 5737

Abstract

Nano- and microparticles are an implicit part of the human diet. They are unknowingly ingested with our food that contains them as additives or pollutants. However, their impact on human health is not yet understood and controversially discussed. The intestinal epithelial barrier shields [...] Read more.

Nano- and microparticles are an implicit part of the human diet. They are unknowingly ingested with our food that contains them as additives or pollutants. However, their impact on human health is not yet understood and controversially discussed. The intestinal epithelial barrier shields our body against exogenous influences, such as commensal bacteria, pathogens, and body-foreign particles and, therefore, protects our body integrity. Breakdown of the intestinal epithelial barrier and aberrant immune responses are key events in the pathogenesis of inflammatory bowel disease (IBD). Epithelial lesions might enable systemic translocation of nano- and microparticles into the system, eventually triggering an excessive immune response. Thus, IBD patients could be particularly vulnerable to adverse health effects caused by the ingestion of synthetic particles with food. The food-additive titanium dioxide (TiO₂) serves as a coloring agent in food products and is omnipresent in the Western diet. TiO₂ nanoparticles exacerbate intestinal inflammation by activation of innate and adaptive immune response. Because of serious safety concerns, the use of TiO₂ as a food additive was recently banned from food production within the European Union. Due to environmental pollution, plastic has entered the human food chain, and plastic microparticles have been evidenced in the drinking water and comestible goods. The impact of plastic ingestion and its resulting consequences on human health is currently the subject of intense research. Focusing on TiO₂ and plastic particles in the human diet and their impact on epithelial integrity, gut homeostasis, and intestinal inflammation, this review is addressing contemporary hot topics which are currently attracting a lot of public attention. Full article

(This article belongs to the Special Issue Intestinal Epithelial Metabolism and Metabolites as Gatekeepers for Organismal Health)

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20 pages, 778 KiB

Open AccessReview

Lipid Metabolism Interplay in CRC—An Update

by Dana Krauß, Ourania Fari and Maria Sibilia

Metabolites 2022, 12(3), 213; https://doi.org/10.3390/metabo12030213 - 26 Feb 2022

Cited by 8 | Viewed by 3367

Abstract

Colorectal cancer (CRC) to date still ranks as one of the deadliest cancer entities globally, and despite recent advances, the incidence in young adolescents is dramatically increasing. Lipid metabolism has recently received increased attention as a crucial element for multiple aspects of carcinogenesis [...] Read more.

Colorectal cancer (CRC) to date still ranks as one of the deadliest cancer entities globally, and despite recent advances, the incidence in young adolescents is dramatically increasing. Lipid metabolism has recently received increased attention as a crucial element for multiple aspects of carcinogenesis and our knowledge of the underlying mechanisms is steadily growing. However, the mechanism how fatty acid metabolism contributes to CRC is still not understood in detail. In this review, we aim to summarize our vastly growing comprehension and the accompanied complexity of cellular fatty acid metabolism in CRC by describing inputs and outputs of intracellular free fatty acid pools and how these contribute to cancer initiation, disease progression and metastasis. We highlight how different lipid pathways can contribute to the aggressiveness of tumors and affect the prognosis of patients. Furthermore, we focus on the role of lipid metabolism in cell communication and interplay within the tumor microenvironment (TME) and beyond. Understanding these interactions in depth might lead to the discovery of novel markers and new therapeutic interventions for CRC. Finally, we discuss the crucial role of fatty acid metabolism as new targetable gatekeeper in colorectal cancer. Full article

(This article belongs to the Special Issue Intestinal Epithelial Metabolism and Metabolites as Gatekeepers for Organismal Health)

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18 pages, 1373 KiB

Open AccessReview

Microenvironmental Metabolites in the Intestine: Messengers between Health and Disease

by Antonio Enrico Zaurito and Markus Tschurtschenthaler

Metabolites 2022, 12(1), 46; https://doi.org/10.3390/metabo12010046 - 07 Jan 2022

Cited by 5 | Viewed by 2379

Abstract

The intestinal mucosa is a highly absorptive organ and simultaneously constitutes the physical barrier between the host and a complex outer ecosystem. Intestinal epithelial cells (IECs) represent a special node that receives signals from the host and the environment and translates them into [...] Read more.

The intestinal mucosa is a highly absorptive organ and simultaneously constitutes the physical barrier between the host and a complex outer ecosystem. Intestinal epithelial cells (IECs) represent a special node that receives signals from the host and the environment and translates them into corresponding responses. Specific molecular communication systems such as metabolites are known to transmit information across the intestinal boundary. The gut microbiota or food-derived metabolites are extrinsic factors that influence the homeostasis of the intestinal epithelium, while mitochondrial and host-derived cellular metabolites determine the identity, fitness, and regenerative capacity of IECs. Little is known, however, about the role of intrinsic and extrinsic metabolites of IECs in the initiation and progression of pathological processes such as inflammatory bowel disease and colorectal cancer as well as about their impact on intestinal immunity. In this review, we will highlight the most recent contributions on the modulatory effects of intestinal metabolites in gut pathophysiology, with a particular focus on metabolites in promoting intestinal inflammation or colorectal tumorigenesis. In addition, we will provide a perspective on the role of newly identified oncometabolites from the commensal and opportunistic microbiota in shaping response and resistance to antitumor therapy. Full article

(This article belongs to the Special Issue Intestinal Epithelial Metabolism and Metabolites as Gatekeepers for Organismal Health)

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20 pages, 2100 KiB

Open AccessReview

Targeting the Gut in Obesity: Signals from the Inner Surface

by Natalia Petersen, Thomas U. Greiner, Lola Torz, Angie Bookout, Marina Kjærgaard Gerstenberg, Carlos M. Castorena and Rune Ehrenreich Kuhre

Metabolites 2022, 12(1), 39; https://doi.org/10.3390/metabo12010039 - 05 Jan 2022

Cited by 3 | Viewed by 2921

Abstract

Obesity is caused by prolonged energy surplus. Current anti-obesity medications are mostly centralized around the energy input part of the energy balance equation by increasing satiety and reducing appetite. Our gastrointestinal tract is a key organ for regulation of food intake and supplies [...] Read more.

Obesity is caused by prolonged energy surplus. Current anti-obesity medications are mostly centralized around the energy input part of the energy balance equation by increasing satiety and reducing appetite. Our gastrointestinal tract is a key organ for regulation of food intake and supplies a tremendous number of circulating signals that modulate the activity of appetite-regulating areas of the brain by either direct interaction or through the vagus nerve. Intestinally derived messengers are manifold and include absorbed nutrients, microbial metabolites, gut hormones and other enterokines, collectively comprising a fine-tuned signalling system to the brain. After a meal, nutrients directly interact with appetite-inhibiting areas of the brain and induce satiety. However, overall feeding behaviour also depends on secretion of gut hormones produced by highly specialized and sensitive enteroendocrine cells. Moreover, circulating microbial metabolites and their interactions with enteroendocrine cells further contribute to the regulation of feeding patterns. Current therapies exploiting the appetite-regulating properties of the gut are based on chemically modified versions of the gut hormone, glucagon-like peptide-1 (GLP-1) or on inhibitors of the primary GLP-1 inactivating enzyme, dipeptidyl peptidase-4 (DPP-4). The effectiveness of these approaches shows that that the gut is a promising target for therapeutic interventions to achieve significant weigh loss. We believe that increasing understanding of the functionality of the intestinal epithelium and new delivery systems will help develop selective and safe gut-based therapeutic strategies for improved obesity treatment in the future. Here, we provide an overview of the major homeostatic appetite-regulating signals generated by the intestinal epithelial cells and how these signals may be harnessed to treat obesity by pharmacological means. Full article

(This article belongs to the Special Issue Intestinal Epithelial Metabolism and Metabolites as Gatekeepers for Organismal Health)

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18 pages, 1850 KiB

Open AccessReview

A Novel Pathway of Flavonoids Protecting against Inflammatory Bowel Disease: Modulating Enteroendocrine System

by Mingrui Li and Benno Weigmann

Metabolites 2022, 12(1), 31; https://doi.org/10.3390/metabo12010031 - 01 Jan 2022

Cited by 16 | Viewed by 3277

Abstract

Inflammatory bowel disease (IBD) is a comprehensive term for chronic or relapsing inflammatory diseases occurring in the intestinal tract, generally including Crohn’s disease (CD) and ulcerative colitis (UC). Presently, the pathogenesis of IBD is unknown, yet multiple factors have been reported to be [...] Read more.

Inflammatory bowel disease (IBD) is a comprehensive term for chronic or relapsing inflammatory diseases occurring in the intestinal tract, generally including Crohn’s disease (CD) and ulcerative colitis (UC). Presently, the pathogenesis of IBD is unknown, yet multiple factors have been reported to be related with the development of IBD. Flavonoids are phytochemicals with biological activity, which are ubiquitously distributed in edible plants, such as fruits and vegetables. Recent studies have demonstrated impressively that flavonoids have anti-IBD effects through multiple mechanisms. These include anti-inflammatory and antioxidant actions; the preservation of the epithelial barrier integrity, the intestinal immunomodulatory property, and the shaping microbiota composition and function. In addition, a few studies have shown the impact of flavonoids on enterohormones release; nonetheless, there is hardly any work showing the link between flavonoids, enterohormones release and IBD. So far, the interaction between flavonoids, enterohormones and IBD is elucidated for the first time in this review. Furthermore, the inference can be drawn that flavonoids may protect against IBD through modulating enterohormones, such as glucagon-like peptide 1 (GLP-1), GLP-2, dipeptidyl peptidase-4 inhibitors (DPP-4 inhibitors), ghrelin and cholecystokinin (CCK). In conclusion, this manuscript explores a possible mechanism of flavonoids protecting against IBD. Full article

(This article belongs to the Special Issue Intestinal Epithelial Metabolism and Metabolites as Gatekeepers for Organismal Health)

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