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Host-Microbe-Metabolite Interaction in Intestinal Health

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A special issue of Metabolites (ISSN 2218-1989). This special issue belongs to the section "Nutrition and Metabolism".

Deadline for manuscript submissions: closed (15 January 2022) | Viewed by 39325

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Special Issue Editors

Prof. Dr. Yiorgos Apidianakis

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Guest Editor

Department of Biological Sciences, University of Cyprus, 2109 Aglatzia, Cyprus
Interests: genetics; microbes; intestinal environment; inflammation; intestinal cancer predisposition; mucosal disease prevention

Dr. Agapios Agapiou

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Guest Editor

Department of Chemistry, University of Cyprus, P.O. Box 20537, Nicosia 1678, Cyprus
Interests: metabolomics (volatolomics); hyphenated gas chromatography-mass spectrometry; analytical systems/platforms; preconcentration techniques; chemometrics; inflammatory markers; non-invasive monitoring

Special Issue Information

Dear Colleagues,

The gut is primarily a metabolic organ and our strongest and biggest interface with the environment. Intestine-bearing animals such as worms, insects, and humans function in a tripartite metabolic interaction with their intestinal microbes and dietary ingredients. This host–microbe–diet interaction works in all possible combinations, and it is important to study in concert, because a microbe or metabolite beneficial for a host at a specific age may be detrimental for another host and another stage of life. Therefore, not only commonalities in intestinal metabolites and microbes of the individuals within a population, but also inter-individual and longitudinal (aging and experience-driven) differences are important to find. Human, mouse, and arthropod gut microbiota confer examples of complex ecosystems containing bacteria, the corresponding bacterial infecting viruses, the bacteriophages, as well as fungi and parasites. Dietary patterns typical for each species are known, but are variable in nature.

This Special Issue aims to highlight the mechanistic interaction of hosts with their intestinal microbes and the metabolites of the luminal content in accordance with dietary and lifestyle patterns. Gut-derived metabolites and dietary habits, as well as probiotics and prebiotics, can shape and be shaped by microbiota and the genetics, lifestyle, demographics, and medical history of the host. An overview of the recent advances in the multifactorial and longitudinal host–microbe-metabolite interactions focusing either on specific metabolites and microbes or more broadly into metabolomic and metagenomic profiles could shed light on intestinal health and disease. Non-invasive analytical tools and chemical monitoring methods for highlighting potential inflammatory and disease markers are welcome.

Prof. Dr. Yiorgos Apidianakis
Dr. Agapios Agapiou
Guest Editors

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Keywords

bacteria
fungi
viruses
microbiome
metabolite
fatty acids
volatiles
chemical profiles
inflammation
cancer

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Published Papers (9 papers)

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Research

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24 pages, 8514 KiB

Open AccessArticle

The Sterol Transporter Npc2c Controls Intestinal Stem Cell Mitosis and Host–Microbiome Interactions in Drosophila

by Constantina Neophytou, Euripides Soteriou and Chrysoula Pitsouli

Metabolites 2023, 13(10), 1084; https://doi.org/10.3390/metabo13101084 - 16 Oct 2023

Cited by 1 | Viewed by 2374

Abstract

Cholesterol is necessary for all cells to function. The intracellular cholesterol transporters Npc1 and Npc2 control sterol trafficking and their malfunction leads to Neimann–Pick Type C disease, a rare disorder affecting the nervous system and the intestine. Unlike humans that encode single Npc1 and Npc2 transporters, flies encompass two Npc1 (Npc1a-1b) and eight Npc2 (Npc2a-2h) members, and most of the Npc2 family genes remain unexplored. Here, we focus on the intestinal function of Npc2c in the adult. We find that Npc2c is necessary for intestinal stem cell (ISC) mitosis, maintenance of the ISC lineage, survival upon pathogenic infection, as well as tumor growth. Impaired mitosis of Npc2c-silenced midguts is accompanied by reduced expression of Cyclin genes, and genes encoding ISC regulators, such as Delta, unpaired1 and Socs36E. ISC-specific Npc2c silencing induces Attacin-A expression, a phenotype reminiscent of Gram-negative bacteria overabundance. Metagenomic analysis of Npc2c-depleted midguts indicates intestinal dysbiosis, whereby decreased commensal complexity is accompanied by increased gamma-proteobacteria. ISC-specific Npc2c silencing also results in increased cholesterol aggregation. Interestingly, administration of the non-steroidal ecdysone receptor agonist, RH5849, rescues mitosis of Npc2c-silenced midguts and increases expression of the ecdysone response gene Broad, underscoring the role of Npc2c and sterols in ecdysone signaling. Assessment of additional Npc2 family members indicates potential redundant roles with Npc2c in ISC control and response to ecdysone signaling. Our results highlight a previously unidentified essential role of Npc2c in ISC mitosis, as well as an important role in ecdysone signaling and microbiome composition in the Drosophila midgut. Full article

(This article belongs to the Special Issue Host-Microbe-Metabolite Interaction in Intestinal Health)

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20 pages, 6684 KiB

Open AccessArticle

Fecal Microbiota and Associated Volatile Organic Compounds Distinguishing No-Adenoma from High-Risk Colon Adenoma Adults

by Kyriaki Katsaounou, Danae Yiannakou, Elpiniki Nikolaou, Cameron Brown, Paris Vogazianos, Aristos Aristodimou, Jianxiang Chi, Paul Costeas, Agapios Agapiou, Elisavet Frangou, George Tsiaoussis, George Potamitis, Athos Antoniades, Christos Shammas and Yiorgos Apidianakis

Metabolites 2023, 13(7), 819; https://doi.org/10.3390/metabo13070819 - 4 Jul 2023

Cited by 2 | Viewed by 2182

Abstract

Microbiota and the metabolites they produce within the large intestine interact with the host epithelia under the influence of a range of host-derived metabolic, immune, and homeostatic factors. This complex host–microbe interaction affects intestinal tumorigenesis, but established microbial or metabolite profiles predicting colorectal cancer (CRC) risk are missing. Here, we aimed to identify fecal bacteria, volatile organic compounds (VOC), and their associations that distinguish healthy (non-adenoma, NA) from CRC prone (high-risk adenoma, HRA) individuals. Analyzing fecal samples obtained from 117 participants ≥15 days past routine colonoscopy, we highlight the higher abundance of Proteobacteria and Parabacteroides distasonis, and the lower abundance of Lachnospiraceae species, Roseburia faecis, Blautia luti, Fusicatenibacter saccharivorans, Eubacterium rectale, and Phascolarctobacterium faecium in the samples of HRA individuals. Volatolomic analysis of samples from 28 participants revealed a higher concentration of five compounds in the feces of HRA individuals, isobutyric acid, methyl butyrate, methyl propionate, 2-hexanone, and 2-pentanone. We used binomial logistic regression modeling, revealing 68 and 96 fecal bacteria-VOC associations at the family and genus level, respectively, that distinguish NA from HRA endpoints. For example, isobutyric acid associations with Lachnospiraceae incertae sedis and Bacteroides genera exhibit positive and negative regression lines for NA and HRA endpoints, respectively. However, the same chemical associates with Coprococcus and Colinsella genera exhibit the reverse regression line trends. Thus, fecal microbiota and VOC profiles and their associations in NA versus HRA individuals indicate the significance of multiple levels of analysis towards the identification of testable CRC risk biomarkers. Full article

(This article belongs to the Special Issue Host-Microbe-Metabolite Interaction in Intestinal Health)

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19 pages, 5343 KiB

Open AccessArticle

Intestinal Immune Deficiency and Juvenile Hormone Signaling Mediate a Metabolic Trade-off in Adult Drosophila Females

by Gavriella Shianiou, Savvas Teloni and Yiorgos Apidianakis

Metabolites 2023, 13(3), 340; https://doi.org/10.3390/metabo13030340 - 24 Feb 2023

Cited by 5 | Viewed by 2820

Abstract

A trade-off hypothesis pertains to the biased allocation of limited resources between two of the most important fitness traits, reproduction and survival to infection. This quid pro quo manifests itself within animals prioritizing their energetic needs according to genetic circuits balancing metabolism, germline activity and immune response. Key evidence supporting this hypothesis includes dipteran fecundity being compromised by systemic immunity, and female systemic immunity being compromised by mating. Here, we reveal a local trade-off taking place in the female Drosophila midgut upon immune challenge. Genetic manipulation of intestinal motility, permeability, regeneration and three key midgut immune pathways provides evidence of an antagonism between specific aspects of intestinal defense and fecundity. That is, juvenile hormone (JH)-controlled egg laying, lipid droplet utilization and insulin receptor expression are specifically compromised by the immune deficiency (Imd) and the dual oxidase (Duox) signaling in the midgut epithelium. Moreover, antimicrobial peptide (AMP) expression under the control of the Imd pathway is inhibited upon mating and JH signaling in the midgut. Local JH signaling is further implicated in midgut dysplasia, inducing stem cell-like clusters and gut permeability. Thus, midgut JH signaling compromises host defense to infection by reducing Imd-controlled AMP expression and by inducing dysplasia, while midgut signaling through the Imd and Duox pathways compromises JH-guided metabolism and fecundity. Full article

(This article belongs to the Special Issue Host-Microbe-Metabolite Interaction in Intestinal Health)

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24 pages, 4495 KiB

Open AccessArticle

Dietary Stimuli, Intestinal Bacteria and Peptide Hormones Regulate Female Drosophila Defecation Rate

by Katerina Kotronarou, Anna Charalambous, Amalia Evangelou, Olympiada Georgiou, Andri Demetriou and Yiorgos Apidianakis

Metabolites 2023, 13(2), 264; https://doi.org/10.3390/metabo13020264 - 12 Feb 2023

Cited by 2 | Viewed by 3147

Abstract

Peptide hormones control Drosophila gut motility, but the intestinal stimuli and the gene networks coordinating this trait remain poorly defined. Here, we customized an assay to quantify female Drosophila defecation rate as a proxy of intestinal motility. We found that bacterial infection with the human opportunistic bacterial pathogen Pseudomonas aeruginosa (strain PA14) increases defecation rate in wild-type female flies, and we identified specific bacteria of the fly microbiota able to increase defecation rate. In contrast, dietary stress, imposed by either water-only feeding or high ethanol consumption, decreased defecation rate and the expression of enteroendocrine-produced hormones in the fly midgut, such as Diuretic hormone 31 (Dh31). The decrease in defecation due to dietary stress was proportional to the impact of each stressor on fly survival. Furthermore, we exploited the Drosophila Genetic Reference Panel wild type strain collection and identified strains displaying high and low defecation rates. We calculated the narrow-sense heritability of defecation rate to be 91%, indicating that the genetic variance observed using our assay is mostly additive and polygenic in nature. Accordingly, we performed a genome-wide association (GWA) analysis revealing 17 candidate genes linked to defecation rate. Downregulation of four of them (Pmp70, CG11307, meso18E and mub) in either the midgut enteroendocrine cells or in neurons reduced defecation rate and altered the midgut expression of Dh31, that in turn regulates defecation rate via signaling to the visceral muscle. Hence, microbial and dietary stimuli, and Dh31-controlling genes, regulate defecation rate involving signaling within and among neuronal, enteroendocrine, and visceral muscle cells. Full article

(This article belongs to the Special Issue Host-Microbe-Metabolite Interaction in Intestinal Health)

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21 pages, 7303 KiB

Open AccessArticle

Proteobacteria and Firmicutes Secreted Factors Exert Distinct Effects on Pseudomonas aeruginosa Infection under Normoxia or Mild Hypoxia

by Anna Charalambous, Evangelos Grivogiannis, Irene Dieronitou, Christina Michael, Laurence Rahme and Yiorgos Apidianakis

Metabolites 2022, 12(5), 449; https://doi.org/10.3390/metabo12050449 - 17 May 2022

Cited by 7 | Viewed by 3316

Abstract

Microbiota may alter a pathogen’s virulence potential at polymicrobial infection sites. Here, we developed a multi-modal Drosophila assay, amenable to the assessment of human bacterial interactions using fly survival or midgut regeneration as a readout, under normoxia or mild hypoxia. Deploying a matrix of 12 by 33 one-to-one Drosophila co-infections via feeding, we classified bacterial interactions as neutral, synergistic, or antagonistic, based on fly survival. Twenty six percent of these interactions were antagonistic, mainly occurring between Proteobacteria. Specifically, Pseudomonas aeruginosa infection was antagonized by various Klebsiella strains, Acinetobacter baumannii, and Escherichia coli. We validated these interactions in a second screen of 7 by 34 one-to-one Drosophila co-infections based on assessments of midgut regeneration, and in bacterial co-culture test tube assays, where antagonistic interactions depended on secreted factors produced upon high sugar availability. Moreover, Enterococci interacted synergistically with P. aeruginosa in flies and in test tubes, enhancing the virulence and pyocyanin production by P. aeruginosa. However, neither lactic acid bacteria nor their severely hypoxic culture supernatants provided a survival benefit upon P. aeruginosa infection of flies or mice, respectively. We propose that at normoxic or mildly hypoxic sites, Firmicutes may exacerbate, whereas Proteobacteria secreted factors may ameliorate, P. aeruginosa infections. Full article

(This article belongs to the Special Issue Host-Microbe-Metabolite Interaction in Intestinal Health)

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17 pages, 2834 KiB

Open AccessArticle

Concentrations of Fecal Bile Acids in Participants with Functional Gut Disorders and Healthy Controls

by Shanalee C. James, Karl Fraser, Wayne Young, Phoebe E. Heenan, Richard B. Gearry, Jacqueline I. Keenan, Nicholas J. Talley, Susan A. Joyce, Warren C. McNabb and Nicole C. Roy

Metabolites 2021, 11(9), 612; https://doi.org/10.3390/metabo11090612 - 9 Sep 2021

Cited by 17 | Viewed by 4467

Abstract

Bile acids are metabolites involved in nutrient absorption and signaling with levels influenced by dietary intake, metabolic processes, and the gut microbiome. We aimed to quantify 23 bile acids in fecal samples to ascertain if concentrations differed between healthy participants and those with functional gut disorders. Fecal bile acids were measured using liquid chromatography-mass spectrometry (LC-MS) in the COMFORT (The Christchurch IBS cohort to investigate mechanisms for gut relief and improved transit) cohort of 250 participants with Rome IV IBS (IBS-constipation (C), IBS-diarrhea (D), IBS-mixed (M)), functional gut disorders (functional constipation (FC), functional diarrhea (FD)) and healthy controls (FC n = 35, FD n = 13, IBS-C n = 24, IBS-D n = 52, IBS-M n = 29, and control n = 97). Dietary information was recorded to ascertain three-day dietary intake before fecal samples were collected. Fecal bile acid concentrations, predominantly primary bile acids, were significantly different between all functional gut disorder participants and healthy controls (CDCA p = 0.011, CA p = 0.003) and between constipation (FC + IBS-C) and diarrhea (FD + IBS-D) groups (CDCA p = 0.001, CA p = 0.0002). Comparison of bile acids between all functional groups showed four metabolites were significantly different, although analysis of combined groups (FC + IBS-C vs. FD + IBS-D) showed that 10 metabolites were significantly different. The bile acid profiles of FD individuals were similar to those with IBS-D, and likewise, those with FC were similar to IBS-C. Individuals with a diarrhea phenotype (FD + IBS-D) had higher concentrations of bile acids compared to those with constipation (FC + IBS-C). Bile acid metabolites distinguish between individuals with functional gut disorders and healthy controls but are similar in constipation (or diarrhea) whether classified as IBS or not. Full article

(This article belongs to the Special Issue Host-Microbe-Metabolite Interaction in Intestinal Health)

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20 pages, 6329 KiB

Open AccessArticle

A Metabolic Model of Intestinal Secretions: The Link between Human Microbiota and Colorectal Cancer Progression

by Pejman Salahshouri, Modjtaba Emadi-Baygi, Mahdi Jalili, Faiz M. Khan, Olaf Wolkenhauer and Ali Salehzadeh-Yazdi

Metabolites 2021, 11(7), 456; https://doi.org/10.3390/metabo11070456 - 15 Jul 2021

Cited by 9 | Viewed by 5319

Abstract

The human gut microbiota plays a dual key role in maintaining human health or inducing disorders, for example, obesity, type 2 diabetes, and cancers such as colorectal cancer (CRC). High-throughput data analysis, such as metagenomics and metabolomics, have shown the diverse effects of alterations in dynamic bacterial populations on the initiation and progression of colorectal cancer. However, it is well established that microbiome and human cells constantly influence each other, so it is not appropriate to study them independently. Genome-scale metabolic modeling is a well-established mathematical framework that describes the dynamic behavior of these two axes at the system level. In this study, we created community microbiome models of three conditions during colorectal cancer progression, including carcinoma, adenoma and health status, and showed how changes in the microbial population influence intestinal secretions. Conclusively, our findings showed that alterations in the gut microbiome might provoke mutations and transform adenomas into carcinomas. These alterations include the secretion of mutagenic metabolites such as H₂S, NO compounds, spermidine and TMA (trimethylamine), as well as the reduction of butyrate. Furthermore, we found that the colorectal cancer microbiome can promote inflammation, cancer progression (e.g., angiogenesis) and cancer prevention (e.g., apoptosis) by increasing and decreasing certain metabolites such as histamine, glutamine and pyruvate. Thus, modulating the gut microbiome could be a promising strategy for the prevention and treatment of CRC. Full article

(This article belongs to the Special Issue Host-Microbe-Metabolite Interaction in Intestinal Health)

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Review

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26 pages, 1774 KiB

Open AccessReview

Colon Cancer: From Epidemiology to Prevention

by Kyriaki Katsaounou, Elpiniki Nicolaou, Paris Vogazianos, Cameron Brown, Marios Stavrou, Savvas Teloni, Pantelis Hatzis, Agapios Agapiou, Elisavet Fragkou, Georgios Tsiaoussis, George Potamitis, Apostolos Zaravinos, Chrysafis Andreou, Athos Antoniades, Christos Shiammas and Yiorgos Apidianakis

Metabolites 2022, 12(6), 499; https://doi.org/10.3390/metabo12060499 - 30 May 2022

Cited by 22 | Viewed by 9463

Abstract

Colorectal cancer (CRC) is one of the most prevalent cancers affecting humans, with a complex genetic and environmental aetiology. Unlike cancers with known environmental, heritable, or sex-linked causes, sporadic CRC is hard to foresee and has no molecular biomarkers of risk in clinical use. One in twenty CRC cases presents with an established heritable component. The remaining cases are sporadic and associated with partially obscure genetic, epigenetic, regenerative, microbiological, dietary, and lifestyle factors. To tackle this complexity, we should improve the practice of colonoscopy, which is recommended uniformly beyond a certain age, to include an assessment of biomarkers indicative of individual CRC risk. Ideally, such biomarkers will be causal to the disease and potentially modifiable upon dietary or therapeutic interventions. Multi-omics analysis, including transcriptional, epigenetic as well as metagenomic, and metabolomic profiles, are urgently required to provide data for risk analyses. The aim of this article is to provide a perspective on the multifactorial derailment of homeostasis leading to the initiation of CRC, which may be explored via multi-omics and Gut-on-Chip analysis to identify much-needed predictive biomarkers. Full article

(This article belongs to the Special Issue Host-Microbe-Metabolite Interaction in Intestinal Health)

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15 pages, 1844 KiB

Open AccessReview

How Gut Microbes Nurture Intestinal Stem Cells: A Drosophila Perspective

by Constantina Neophytou and Chrysoula Pitsouli

Metabolites 2022, 12(2), 169; https://doi.org/10.3390/metabo12020169 - 10 Feb 2022

Cited by 10 | Viewed by 4291

Abstract

Host-microbiota interactions are key modulators of host physiology and behavior. Accumulating evidence suggests that the complex interplay between microbiota, diet and the intestine controls host health. Great emphasis has been given on how gut microbes have evolved to harvest energy from the diet to control energy balance, host metabolism and fitness. In addition, many metabolites essential for intestinal homeostasis are mainly derived from gut microbiota and can alleviate nutritional imbalances. However, due to the high complexity of the system, the molecular mechanisms that control host-microbiota mutualism, as well as whether and how microbiota affects host intestinal stem cells (ISCs) remain elusive. Drosophila encompasses a low complexity intestinal microbiome and has recently emerged as a system that might uncover evolutionarily conserved mechanisms of microbiota-derived nutrient ISC regulation. Here, we review recent studies using the Drosophila model that directly link microbiota-derived metabolites and ISC function. This research field provides exciting perspectives for putative future treatments of ISC-related diseases based on monitoring and manipulating intestinal microbiota. Full article

(This article belongs to the Special Issue Host-Microbe-Metabolite Interaction in Intestinal Health)

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