Recent Trends of Microbiota-Based Microbial Metabolites Metabolism in Liver Disease

Abstract

The gut microbiome and microbial metabolomic influences on liver diseases and their diagnosis, prognosis, and treatment are still controversial. Research studies have provocatively claimed that the gut microbiome, metabolomics understanding, and microbial metabolite screening are key approaches to understanding liver cancer and liver diseases. An advance of logical innovations in metabolomics profiling, the metabolome inclusion, challenges, and the reproducibility of the investigations at every stage are devoted to this domain to link the common molecules across multiple liver diseases, such as fatty liver, hepatitis, and cirrhosis. These molecules are not immediately recognizable because of the huge underlying and synthetic variety present inside the liver cellular metabolome. This review focuses on microenvironmental metabolic stimuli in the gut-liver axis. Microbial small-molecule profiling (i.e., semiquantitative monitoring, metabolic discrimination, target profiling, and untargeted profiling) in biological fluids has been incompletely addressed. Here, we have reviewed the differential expression of the metabolome of short-chain fatty acids (SCFAs), tryptophan, one-carbon metabolism and bile acid, and the gut microbiota effects are summarized and discussed. We further present proof-of-evidence for gut microbiota-based metabolomics that manipulates the host's gut or liver microbes, mechanosensitive metabolite reactions and potential metabolic pathways. We conclude with a forward-looking perspective on future attention to the “dark matter” of the gut microbiota and microbial metabolomics.

Introduction

The gut microbiome is a microbial ecosystem that has diverse effects on physiological metabolism, particularly microbial metabolic activity. The human gut microbiome is always changing. Many gastrointestinal metabolites are derived from dietary and environmental sources. Since a decade, the number of scientific publications on the gut microbiota has steadily increased. Gut microbiota-based metabolomics or metabolomics profiling examination has been proven to have the ability to screen and validate the metabolites' role in host and drug metabolism (1, 2). Clinical metabolomics profiling and chemical profiling from numerous host cells are used to evaluate a range of biological contexts at the level of metabolites or small molecules (low molecular weight, < 1500 Da) (3–7).

Clinical metabolomics has been advanced and placed as a division of systems biology. Gut microbiome-associated metabolites are directly connected with the liver via the portal vein. The gut microbiota directly yields the metabolome (full set of metabolites) and organic compounds (i.e., ethanol, acetaldehyde, ammonia, etc.). Metabolic compounds and bacterial products (pathogen-associated microbial metabolites) are frequently metabolized in liver cells (2, 8, 9).

The gut-liver pivot alludes to the multiple interactions between the intestinal microbiome and the liver, which can produce microbial metabolites. Microbial metabolic profiling acts as a therapeutic agent for specific liver diseases. These microbial profiling techniques play a significant role in heterogeneous liver diseases (10–12). At the point of planning an investigation and looking at proof, understanding the utility and impediments of both designated and untargeted metabolomics approaches are fundamental. Microbial metabolite evolution (additionally referred to as “clinical fluxomics”) can quantify and follow analytes through metabolic pathways (13, 14).

The metabolomics profiling in gut-microbiome and liver diseases have been rapidly growing since past decade. These data explain the importance of metabolomics research. The metabolome is inherently huge and complex. The non-targeted metabolome is more connected with the 16S rRNA microbiome composition than targeted metabolomics. This non-targeted metabolomics has identified novel metabolites in colorectal cancer (CRC) patients. High-throughput microbial community sequences have been studied (15, 16). Metabolites represent a functional change associated with genomic variation and differences in complex microbial communities. The microbial metabolites of SCFAs, such as butyrate, can influence gene expression, cell proliferation, and ultimately adenoma formation (17).

More interestingly, the microbial metabolic pathway-based human gut microbiome of monozygotic twins has been explained (18). Microbes such as Escherichia coli and Saccharomyces cerevisiae have 3,700 and 16,000 metabolites, respectively (19, 20).

Fundamental studies of various gut-organ axes are necessary in this domain. The metabotype (or metabolome) is basically different than the genotype. This metabotype designates what is happening in the cellular microenvironment. The genomics, transcriptomics, proteomics, metabolomics, and phenotype are now used in various areas in life science (21, 22). Untargeted and targeted metabolomics will transform what we source as medicine for every disease. Understanding of the microbiome and metabolome can be projected over the two decades.

Gut Microbiota and Short Chain Fatty Acids

Gut microbiota-derived SCFAs (i.e., acetate, propionate, and butyrate) were found in the human large intestine and are involved in microbial fermentation (23–25). Table 1 shows that gut bacterial genera are involved in the fermentation process of SCFAs, amino acids, organic acids, polar metabolites, and dietary polyphenols. SCFAs play an important role in nutrients and energy from the intestinal epithelium. SCFAs are used for the maintenance of intestinal homeostasis. Various studies have confirmed that SCFAs participate in the regulation of NAFLD by activating G-protein-coupled receptor (GPR) 41 or 43, which are expressed in various areas, such as adipose, liver, tissues, peripheral blood, and intestinal cells (47, 48). As per previous publications, intestinal gluconeogenesis (IGN) functions as a regulator of NAFLD via upregulation of hepatic insulin sensitivity and downregulation of hepatic glucose production (HGP) through the gut-brain-liver neural circuit (49, 50).

As shown in Table 1, the SCFAs acetate, propionate, hexanoate, pyruvate, lactate, succinate, and butyrate are significantly targeted IGNs, where glucose was de novo synthesized from the gut epithelium. Bacteria that belong to Clostridium, Eubacterium, Faecalibacterium, Roseburia, and Butyrivibriocrossotus has been producing butyrate through the reduction of two molecules of acetyl-CoA with synthesis of one molecule of ATP. These are most prominent butyrogenic bacteria groups. Studies reported the depletion of those bacteria in atherosclerosis. Butyrate is normally involved with preservation of the intestinal barrier function, tight junction proteins regulation and mucus layer maintenance. Here, glucose signaling to the brain via a GPR42-mediated neural circuit mechanism was widely initiated; therefore, glucose tolerance and insulin sensitivity were upregulated (51, 52). SCFAs are a product of bacterial fermentation of dietary fiber. According to protein sources, SCFAs can be formed by the gut microbiome (53). Figure 1 shows that the gut-liver axis is involved in SCFA alterations and their functional metabolism.

Figure 1

Additionally, GPR is initiated, and SCFAs mostly pass to the liver via the portal vein, where they can improve hepatic glycolipid homeostasis. This metabolic process initiation occurred via AMPK in a peroxisome proliferator-activated receptor (PPAR) γ-dependent manner (54). SCFAs travel across the blood–brain barrier (BBB) into the central nervous system (CNS) and can disturb neural development (neurogenesis, BBB permeability, microglia). The physiological process of gluconeogenesis, AMPK activity, and insulin sensitivity in the liver are significantly affected (52, 55). Finally, SCFAs are a significant signaling metabolome and are used for communication between host tissues and microbiota through the gut-brain-liver axis (56, 57).

Gut Microbiota and Tryptophan Catabolites

The amino acid tryptophan exists in common foods (i.e., bananas, chocolate, cheese, fish, milk, oats, wine, etc.). Tryptophan is a chemically complex amino acid that can undergo an extensive variety of transformations within its structure (58, 59). Tryptophan acts as an ideal molecule in bacterial catabolic activity. To support this concept, various signaling pathways in human cells result from tryptophan, including tryptamine and serotonin. Dietary tryptophan is involved in numerous intermediates within hosts. The kynurenine and serotonin pathways are directly transformed from tryptophan. Protein synthesis occurs through the conversion of gut microbes into indole derivative metabolites such as indole acetic acid (IAA), indole-3-propionic acid (IPA), and indole-3-aldehyde (IA) (58, 60).

The kynurenine pathway contains many metabolic intermediates, collectively termed “kynurenines” and the final product, nicotinamide adenine dinucleotide (NAD+) (61, 62). The metabolic reaction of tryptophan to kynurenine is chemically converted to either indoleamine 2,3-dioxygenase 1 (IDO1, involved in immune and gut epithelial cells) or tryptophan 2,3-dioxygenase (TDO, hepatocytes) (62). The gut microbiota is a known driver of IDO1 expression (63, 64) and IDO1 regulation has been shown to regulate microbial community composition (65). These enzymes are highly increased in many cancer cells. Kynurenine derivatives are produced with aryl hydrocarbion receptor (AhR) ligands that help to promote cellular migration and immune tolerance, thus driving cancer progression (62). The host synthesizes kynurenines with the help of gut microbiota that have a genomic capacity to yield many intermediate small molecules in metabolic pathways, such as Lactobacillus spp., and the pathogens Pseudomonas aeruginosa and Pseudomonas fluorescens, which produce these intermediates (66). We have listed in Table 2, Figure 2 the tryptophan metabolite-based microbiome and biological effects in human gut environments. Finally, kynurenine pathway intermediates significantly inhibited insulin synthesis, excretion, and signaling in rats. Increased levels of kynurenic acid and xanthurenic acid are found in type 2 diabetes mellitus (T2DM) patients (61).

Figure 2

Tryptamine and tryptophan catabolic chemical reactions are processed by gut microbial bacteria such as C. sporogenes and Ruminococcus gnavus (78, 79). Tryptamine acts as a β-arylamine neurotransmitter that can stimulate gut strength. In the gut microbial environment, tryptamine is known to induce the release of the neurotransmitter 5-hydroxytryptamine (5-HT) or serotonin via enterochromaffin cells, and it is involved in mucosal secretion and gut motility. 5-HT promotes gastrointestinal motility by acting on enteric nervous systems. However, the signaling molecule tryptamine affects the intestinal gut microbial composition, diversity, and metabolism in humans (80, 81). Here, ~90% of 5-HT or serotonin in the body is produced by enterochromaffin cells, which cannot cross the blood–brain barrier. The binding of 5-HT with specific 5-HT receptors produces various biological responses. In the central nervous system, 5-HT plays a central role in sleep, mood, appetite, behavior, and the maintenance of neurons and interstitial cells of Cajal within the gut myenteric plexus (80). In mice, Ruminococcus flavefaciens and Adlercreutzia equolifaciens reduced the beneficial properties of duloxetine. 5-HT is affected by the gut microbial composition, which acts as a gut microbial inhibitor (82, 83).

Gut Microbiota and One Carbon Metabolisms

The membrane metabolite of choline acts as a water-soluble compound. This is an essential nutrient for human and animal cellular metabolism. Choline can contribute to cellular outer membrane functions, neurotransmission roles, and methyl donors for various biosynthetic metabolic reactions (84). Endogenously, choline is formed. Choline is widely used by anaerobic gut microorganisms to generate trimethylamine (TMA) and acetaldehyde (85). The gut microbiota plays an ameliorative role in liver diseases. Liver diseases such as fatty liver, hepatitis, and cirrhosis are related to bile acid secretion disorder and metabolic syndrome (56, 86, 87). Table 3 lists the more important metabolites in the human gut microbiome.

TMA is present across the host gut and can be processed to trimethylamine-N-oxide (TMAO) in the liver cellular microenvironment through flavin-containing monooxygenases 1 and 3 (FMO1 and FMO3). In the past few decades, gut-microbial-host cometabolites have been identified via metabolomics analysis in serum to predict the risk of cardiovascular diseases (99–101). TMAO enhances atherosclerosis by inducing multiple macrophage receptors, acting as a hallmark of thrombosis, and enhancing platelet reactivity (99, 100). Here, the gut microbiota facilitates the regulation of hepatic inflammation by the TMA, TMAO and FMO pathways.

Isotopic labeling studies have revealed that alterations of nutritional L-carnitine, a rich amino acid derived from red meat, increases TMA through microbiota-dependent conversion and leads to > 20-fold growth in atherogenic TMAO in omnivores vs. vegans and lactovegetarians (102). Recently, trimethyllysine (TML) was identified as a precursor to TMAO and could be used as a predictor of major adverse cardiac events. TML has improved risk stratification in acute coronary syndrome. TML is used to predict the risk of major adverse cardiac incidents and acts as a clinical biomarker for myocardial infarction (103, 104).

The B vitamins pyridoxine (vitamin B6), folic acid (vitamin B9) and cobalamin (vitamin B12) play essential roles in one-carbon metabolism. These vitamins act as cofactors in folate metabolism and one-carbon metabolic pathways. Moreover, B vitamins are not adequate in host synthesis to optimize metabolic conditions. B vitamins are also obtained from nutritional sources and de nova produced via the gut microbiota (105, 106). With the help of folate metabolism, the production of B vitamins by the colonic microbiota actually exceeds the dietary intake (107). Eight B vitamins (B1, B2, B3, B5, B6, B7, B9, and B12) have been discovered, and 40–65% of human gut bacteria have the genomic possibility to produce these vitamins. As per a prior database, 88% of vitamins in the gut microbiome were validated (106).

Folate metabolism (methotrexate and sulfasalazine) and genetic disorders very commonly occur due to B vitamin shortages and poor nutritional consumption. Pellagra (vitamin B3), anemias (vitamins B9 and B12), cerebellar ataxia (vitamin B12), and cognitive impairment (vitamins B9 and B12) have been linked with dietary deficiency that can be treated with vitamin supplementation. Here, there are age-dependent alterations in gut microbial metabolism of B vitamins (79, 108). An infant gut microbiome revealed that enriched genes could confuse the de novo biosynthesis of folate. The adult microbiome is enriched for those involved in the metabolism of folate and it is condensed from tetrahydrofolate (109, 110). Therefore, the gut microbiota is a fundamentally significant source for vitamin manufacture, which may be important for vitamin deficiencies. Finally, as shown in Table 4, metabolites and pathways associated with the gut microbiome in various liver diseases are summarized.

Gut Microbiome and Liver Ammonia Metabolism

Human liver is continually involved in ammonia detoxification. Ammonia fixation in the liver by glutamine and urea synthesis play main role in hepatic ammonia detoxification, and pH regulation under pathogenic condition. The liver and gut microbiota play a central role in nitrogen metabolism (127). Bacteria have involved in protein utilization and amino acid degradation. The understanding of bacteria process that carry out proteolysis and their following metabolic reactions is extremely relevant to human gut health. In large intestine, due to the protein catabolism, the toxic products of ammonia, indoles, and phenols were produced (128, 129). Amino acid fermentation has been primarily produced that the acetic, propionic, butyric, isobutyric, and isovaleric acid. From amino acid catabolism, the ammonia is constantly produced as a metabolic waste. The free ammonia is very toxic which rapidly converted to non-toxic urea via urea cycle in the liver and frequently excluded in urine (130). The liver can generate many enzymes which could change ammonia into urea (128). While ammonia level in blood becomes high, it may convert to toxic to brain. This condition is called as hyperammonemia (131). Hyper-ammonia producing ruminal bacteria (HAB) such as Peptostreptococcus anaerobius, Clostridium sticklandii, and Clostridium aminophilum has been involved to generate ammonia at high level (132). In this condition, the oxidation of ammonium to nitrite () with help of Betaproteobacteria and Gammaproetobacteria can happen by ammonia oxidizing bacteria (AOB). Liver failure and hepatocellular metabolic dysfunction can happen due to disturbed body nitrogen homeostasis. Due to the ammonia imbalance, hepatic encephalopathy is formed, which occurs when liver is high risk condition (133). Finally, chronic liver insufficiency is frequently associated with metabolic acidosis.

Intestinal Microbiota and Bile Acid Metabolism

Bile acids (BAs) are important for cholesterol synthesis metabolism and fat breakdown and are synthesized from the liver and deposited in the gallbladder (134). In the small intestine, these BAs are secreted during digestion. BAs are reabsorbed in the terminal ileum by over 95% and returned to the liver by the portal vein. The absorption of directory fats, fat-soluble vitamins, and cholesterol is promoted by BAs (135). In addition, BAs act as signaling molecules that regulate glucose and lipid metabolism via farnesoid X receptor (FXR) activation and binding of G-protein coupled BA receptor 1 (136–138).

BAs are amphipathic molecules that influence intestinal mucosal integrity. The liver synthesizes BAs that are then involved in synthesizing antibacterial peptides, cholic acid, and chenodeoxycholic acid (139). Antimicrobial peptides (angiogenin 1) are formed when BAs bind to FXR. Activated FXR is involved in reducing the activity of the CYP7A1 gene through the nuclear receptor FXR. These peptides may inhibit intestinal mucosa overgrowth via the intestinal epithelial cell potential to block bacterial uptake, improving the gut barrier role (139). Most intestinal BAs are reabsorbed by the intestine, with 90–95% of BAs involved in enterohepatic circulation. The remaining BAs enter the colon, where the gut microbiome converts them into secondary and tertiary BAs (140, 141). Alterations in circulating BAs act as signaling molecules that disturb glucose and lipid metabolism and predispose individuals to NAFLD. The dysbiosis and disparity of BAs has been shown to play a significant role in liver disease control (141).

BAs are key signaling microbial metabolites involved in lesser-known axes. BAs are steroid acids, the conclusive end products of the liver cholesterol digestion system. There are four types of BAs: essential BAs, bile salts (or conjugated BAs), auxiliary BAs, and tertiary BAs. Essential BAs are liver-derived compounds and comprise a hydroxylated steroid center (142, 143). Cholic scarring and chenodeoxycholic corrosion could be caused by dysfunction of BAs. Bile salts are essential BAs that are conjugated with glycine or taurine (in people, higher primates, and rats) or taurine (in most other warm-blooded creatures) within liver metabolism (144).

These amino acid adjustments permit the bile salts to remain within the gently acidic pH of the upper portion of the little digestive tract. Auxiliary BAs are shaped by means of the activity of colonic microbes on bile salts, which remove the amino conjugates and assist in dihydroxylation of the parent compounds. This leads to the generation of compounds such as deoxycholic corrosive and lithocholic corrosive compounds (145–147). The more hydrophobic and hepatotoxic auxiliary BAs (such as lithocholate) may be altered by glucuronidation, hydroxylation, or sulfation to assist in their production. Tertiary BAs are shaped by the liver when bacterially created auxiliary keto-bile acids return to the liver and are degraded. For example, chenodeoxycholic corrosive (an essential bile salt) is converted to 7-ketolithocholic corrosive (an auxiliary bile corrosive) and then back to ursodeoxycholic corrosive (a tertiary bile corrosive) (148–150). Figure 3 summarizes the basic function of the liver and gut microbiome.

Figure 3

For metabolomic analysis, BA examination is a perfect reference metabolite (151). Naturally, there are more than 100 known BAs (i.e., essential BAs, auxiliary BAs, and tertiary BAs). Sensitive and multifold BA examinations imply quickly surveying a large number of BAs. This often results in a distinctly better understanding of the BA connections to one another and their individual physiological parts (152, 153). Whereas, metabolomic research on bile acids is providing new knowledge about human physiology and human pathologies, a few cautionary considerations must be kept in mind when studying BAs in non-human models. For example, rodents can hydroxylate bile acids at the 6-beta position (muricholates), whereas pigs can hydroxylate BAs at the 6-alpha position. As a result, discoveries with respect to the BA digestion system in animal models may not match those in people. The biological signaling of metabolites in the liver cellular microenvironment has a pleiotropic effect. These metabolites and the small-molecule metabolome are widely synthesized by the gut microbiota, as described in Tables 1–4.

In this review, we provided a fundamental overview of the gut microbiota and clinical metabolomics, including their history and recent developments, and future biomarker candidate metabolites. Currently, gut microbiota-associated metabolomics is in an early phase and needs to be more extensively researched. Identifying therapeutic biomarkers for various gut microbiome- and metabolome-based liver diseases are mandatory.

Conclusions and Future Perspectives

In this review, we highlighted the SCFA, tryptophan, one-carbon metabolism, and bile acid metabolism in the gut microbiome from recent developments with the most promising microbial metabolites. The metabolites in the liver disease microenvironment provide deep knowledge of the metabolic pathways and microphysiological metabolism. The innovative approach of untargeted metabolomics is a quantitative method that is a unique, powerful new technology that can be combined with computational technologies. Improvements in the gut-liver metabolomics community, along with the continued effects of rapidly growing liver biology, have proven reasonably effective in understanding the gut-liver metabolic pathways and chemical reactions. Based on recent publications, the microbial metabolites of TMA, TMAO, tryptophan, SCFAs, vitamins, and the indole family have been found to come from the gut microbiota.

On the technology innovation front, we surveyed how gut microbiota and microbial metabolomics affect liver function and how to design and develop a clinical biomarker metabolite to protect the liver at the cellular microenvironmental level. The liver mechanisms and metabolic degradation analysis of the potential gut microbiome-associated liver metabolism are discussed. The key pitfall is still perhaps in the identification of microbial structural explanations of gut-liver metabolomics due to the lack of universal metabolite-specific libraries.

For the future perspective of gut-liver metabolomics in clinical biomarker development, we have realized a few thoughts:

• The thickness and weight of liver tissue biopsy should be considered in the experimental design. To achieve a highly effective microbial metabolite, low-cost and facile modification methods should be used as much as possible. It is necessary to apply gut-liver metabolomics chemistry to expand their biological properties.

• The solid liver tissue metabolome has a rich phenotypic response. This kind of metabolite production should be investigated further, including its processing and interfaces within the gut microbial environments.

• Gut microbial metabolomics and metabolite chemical reactions at the microlevel need more attention in all gut-liver diseases. Defining how to address biochemical boundary communication in the liver tissue metabolome will help to better understand and optimize metabolomics functions at the gut-liver microcellular level.

• The changes in molecular numbers should not be selectively mistreated for organic/inorganic metabolites in the gut microenvironment. High levels of change are a challenge when carrying out gut microbial metabolite-metabolite chemical reactions. Biological chemists are anticipated to develop novel microbial biomarkers/metabolites, tools, and materials for liver diseases with effective clinical applications.

• Metagenomics, metabolomics, microbial metabolite profiling, and microbial small molecule screening are urgently needed to evaluate gut-liver disease properties. Moreover, more standard molecular, clinical and analytical measurement methods for gut-liver diseases are needed, which should be benchmarked.

Funding

This research was supported by the Hallym University Research Fund and the Basic Science Research Program through the National Research Foundation (NRF) of Korea funded by the Ministry of Education, Science and Technology (NRF-2018M3A9F3020956, NRF-2019R1I1A3A01060447, NRF-2020R1I1A3073530, and NRF-2020R1A6A1A03043026).

Publisher's Note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

References

• 1.

  Bino RJ Hall RD Fiehn O Kopka J Saito K Draper J et al . Potential of metabolomics as a functional genomics tool. Trends Plant Sci. (2004) 9:418–25. 10.1016/j.tplants.2004.07.004

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 2.

  Caporaso JG Kuczynski J Stombaugh J Bittinger K Bushman FD Costello EK et al . QIIME allows analysis of high-throughput community sequencing data. Nat Methods. (2010) 7:335–6. 10.1038/nmeth.f.303

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 3.

  Nemet I Saha PP Gupta N Zhu W Romano KA Skye SM et al . A cardiovascular disease-linked gut microbial metabolite acts via adrenergic receptors. Cell. (2020) 180:862–77. 10.1016/j.cell.2020.02.016

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 4.

  Dodd D Spitzer MH Van Treuren W Merrill BD Hryckowian AJ Higginbottom SK et al . A gut bacterial pathway metabolizes aromatic amino acids into nine circulating metabolites. Nature. (2017) 551:648–52. 10.1038/nature24661

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 5.

  Blow N . Metabolomics: Biochemistry's new look. Nature. (2008) 455:697–700. 10.1038/455697a

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 6.

  Fessenden M . Metabolomics: small molecules, single cells. Nature. (2016) 540:153–5. 10.1038/540153a

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 7.

  Holmes E Wilson ID Nicholson JK . metabolic phenotyping in health and disease. Cell. (2008) 134:714–7. 10.1016/j.cell.2008.08.026

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 8.

  Miele L Marrone G Lauritano C Cefalo C Gasbarrini A Day C et al . Gut-liver axis and microbiota in NAFLD: insight pathophysiology for novel therapeutic target. Curr Pharm Des. (2013) 19:5314–24. 10.2174/1381612811319290011

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 9.

  Raja G Jang Y-K Suh J-S Prabhakaran V-S Kim T-J . Advanced understanding of genetic risk and metabolite signatures in construction workers via cytogenetics and metabolomics analysis. Process Biochemistry. (2019) 86:117–26. 10.1016/j.procbio.2019.07.016

  • CrossRef
  • Google Scholar

• 10.

  Raja G Kim S Yoon D Yoon C Kim S . 1H NMR based metabolomics studies of the toxicity of titanium dioxide nanoparticles in zebrafish (Danio rerio). Bull Korean Chem Soc. (2018) 39:33–9. 10.1002/bkcs.11336

  • CrossRef
  • Google Scholar

• 11.

  Raja G Kim S Yoon D Yoon C Kim S . 1H-NMR-based metabolomics studies of the toxicity of mesoporous carbon nanoparticles in zebrafish (danio rerio). Bull Korean Chem Soc. (2017) 38:271–7. 10.1002/bkcs.11080

  • CrossRef
  • Google Scholar

• 12.

  Sumner LW Amberg A Barrett D Beale MH Beger R Daykin CA et al . Proposed minimum reporting standards for chemical analysis. Metabolomics. (2007) 3:211–21. 10.1007/s11306-007-0082-2

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 13.

  Srivastava A Kowalski GM Callahan DL Meikle PJ Creek DJ . Strategies for extending metabolomics studies with stable isotope labelling and fluxomics. Metabolites. (2016) 6:32. 10.3390/metabo6040032

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 14.

  Zamboni N Saghatelian A Patti GJ . Defining the metabolome: size, flux, and regulation. Mol Cell. (2015) 58:699–706. 10.1016/j.molcel.2015.04.021

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 15.

  Melnik AV da Silva RR Hyde ER Aksenov AA Vargas F Bouslimani A et al . Coupling targeted and untargeted mass spectrometry for metabolome-microbiome-wide association studies of human fecal samples. Anal Chem. (2017) 89:7549–59. 10.1021/acs.analchem.7b01381

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 16.

  Caporaso JG Lauber CL Walters WA Berg-Lyons D Huntley J Fierer N et al . Ultra-high-throughput microbial community analysis on the Illumina HiSeq and MiSeq platforms. ISME J. (2012) 6:1621–4. 10.1038/ismej.2012.8

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 17.

  Bultman SJ Jobin C . Microbial-derived butyrate: an oncometabolite or tumor-suppressive metabolite?Cell Host Microbe. (2014) 16:143–5. 10.1016/j.chom.2014.07.011

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 18.

  Turnbaugh PJ Hamady M Yatsunenko T Cantarel BL Duncan A Ley RE et al . A core gut microbiome in obese and lean twins. Nature. (2009) 457:480–4. 10.1038/nature07540

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 19.

  Ramirez-Gaona M Marcu A Pon A Guo AC Sajed T Wishart NA et al . YMDB 2. 0: a significantly expanded version of the yeast metabolome database. Nucleic Acids Res. (2017) 45:D440–5. 10.1093/nar/gkw1058

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 20.

  Sajed T Marcu A Ramirez M Pon A Guo AC Knox C et al . ECMDB 2. 0: A richer resource for understanding the biochemistry of E coli. Nucleic acids research. (2016) 44:D495–501. 10.1093/nar/gkv1060

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 21.

  Xia J Sinelnikov IV Han B Wishart DS . MetaboAnalyst 3. 0—making metabolomics more meaningful. Nucleic Acids Research. (2015) 43:W251–7. 10.1093/nar/gkv380

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 22.

  Wishart DS Sykes BD Richards FM . The chemical shift index: a fast and simple method for the assignment of protein secondary structure through NMR spectroscopy. Biochemistry. (1992) 31:1647–51. 10.1021/bi00121a010

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 23.

  Hu J Lin S Zheng B Cheung PCK . Short-chain fatty acids in control of energy metabolism. Crit Rev Food Sci Nutr. (2018) 58:1243–9. 10.1080/10408398.2016.1245650

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 24.

  Hoyles L Fernández-Real JM Federici M Serino M Abbott J Charpentier J et al . Molecular phenomics and metagenomics of hepatic steatosis in non-diabetic obese women. Nat Med. (2018) 24:1070–80. 10.1038/s41591-018-0061-3

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 25.

  Nicholson JK Holmes E Kinross J Burcelin R Gibson G Jia W et al . Host-gut microbiota metabolic interactions. Science. (2012) 336:1262–7. 10.1126/science.1223813

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 26.

  Fukuda S Toh H Hase K Oshima K Nakanishi Y Yoshimura K et al . Bifidobacteria can protect from enteropathogenic infection through production of acetate. Nature. (2011) 469:543–7. 10.1038/nature09646

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 27.

  Fukuda S Toh H Taylor TD Ohno H Hattori M . Acetate-producing bifidobacteria protect the host from enteropathogenic infection via carbohydrate transporters. Gut Microbes. (2012) 3:449–54. 10.4161/gmic.21214

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 28.

  Van Deun K Pasmans F Van Immerseel F Ducatelle R Haesebrouck F . Butyrate protects Caco-2 cells from Campylobacter jejuni invasion and translocation. Br J Nutr. (2008) 100:480–4. 10.1017/S0007114508921693

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 29.

  Ochoa-Zarzosa A Villarreal-Fernández E Cano-Camacho H López-Meza JE . Sodium butyrate inhibits Staphylococcus aureus internalization in bovine mammary epithelial cells and induces the expression of antimicrobial peptide genes. Microb Pathog. (2009) 47:1–7. 10.1016/j.micpath.2009.04.006

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 30.

  Zhang S-L Wang S-N Miao C-Y . Influence of microbiota on intestinal immune system in ulcerative colitis and its intervention. Front Immunol. (2017) 8:1674. 10.3389/fimmu.2017.01674

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 31.

  Louis P Flint HJ . Diversity, metabolism and microbial ecology of butyrate-producing bacteria from the human large intestine. FEMS Microbiol Lett. (2009) 294:1–8. 10.1111/j.1574-6968.2009.01514.x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 32.

  Duncan SH Louis P Flint HJ . Lactate-utilizing bacteria, isolated from human feces, that produce butyrate as a major fermentation product. Appl Environ Microbiol. (2004) 70:5810–7. 10.1128/AEM.70.10.5810-5817.2004

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 33.

  Allen-Vercoe E Daigneault M White A Panaccione R Duncan SH Flint HJ et al . Anaerostipes hadrus comb. nov., a dominant species within the human colonic microbiota; reclassification of Eubacterium hadrum Moore et al. 1976. Anaerobe. (2012) 18:523–9. 10.1016/j.anaerobe.2012.09.002

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 34.

  Alva-Murillo N Ochoa-Zarzosa A López-Meza JE . Short chain fatty acids (propionic and hexanoic) decrease Staphylococcus aureus internalization into bovine mammary epithelial cells and modulate antimicrobial peptide expression. Vet Microbiol. (2012) 155:324–31. 10.1016/j.vetmic.2011.08.025

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 35.

  Connolly JPR Slater SL O'Boyle N Goldstone RJ Crepin VF Ruano-Gallego D et al . Host-associated niche metabolism controls enteric infection through fine-tuning the regulation of type 3 secretion. Nat Commun. (2018) 9:4187. 10.1038/s41467-018-06701-4

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 36.

  Jacobson A Lam L Rajendram M Tamburini F Honeycutt J Pham T et al . A gut commensal-produced metabolite mediates colonization resistance to salmonella infection. Cell Host Microbe. (2018) 24:296–307. 10.1016/j.chom.2018.07.002

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 37.

  Hung CC Garner CD Slauch JM Dwyer ZW Lawhon SD Frye JG et al . The intestinal fatty acid propionate inhibits Salmonella invasion through the post-translational control of HilD. Mol Microbiol. (2013) 87:1045–60. 10.1111/mmi.12149

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 38.

  Lawhon SD Maurer R Suyemoto M Altier C . Intestinal short-chain fatty acids alter Salmonella typhimurium invasion gene expression and virulence through BarA/SirA. Mol Microbiol. (2002) 46:1451–64. 10.1046/j.1365-2958.2002.03268.x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 39.

  Zhang ZJ Pedicord VA Peng T Hang HC . Site-specific acylation of a bacterial virulence regulator attenuates infection. Nat Chem Biol. (2020) 16:95–103. 10.1038/s41589-019-0392-5

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 40.

  Rivera-Chávez F Zhang LF Faber F Lopez CA Byndloss MX Olsan EE et al . Depletion of butyrate-producing clostridia from the gut microbiota drives an aerobic luminal expansion of salmonella. Cell Host Microbe. (2016) 19:443–54. 10.1016/j.chom.2016.03.004

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 41.

  Byndloss MX Olsan EE Rivera-Chávez F Tiffany CR Cevallos SA Lokken KL et al . Microbiota-activated PPAR-γ signaling inhibits dysbiotic Enterobacteriaceae expansion. Science. (2017) 357:570–5. 10.1126/science.aam9949

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 42.

  Schulthess J Pandey S Capitani M Rue-Albrecht KC Arnold I Franchini F et al . The Short chain fatty acid butyrate imprints an antimicrobial program in macrophages. Immunity. (2019) 50:432–45. 10.1016/j.immuni.2018.12.018

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 43.

  Morita N Umemoto E Fujita S Hayashi A Kikuta J Kimura I et al . GPR31-dependent dendrite protrusion of intestinal CX3CR1(+) cells by bacterial metabolites. Nature. (2019) 566:110–4. 10.1038/s41586-019-0884-1

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 44.

  Luethy PM Huynh S Ribardo DA Winter SE Parker CT Hendrixson DR . Microbiota-derived short-chain fatty acids modulate expression of campylobacter jejuni determinants required for commensalism and virulence. mBio. (2017) 8:e00407-17. 10.1128/mBio.00407-17

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 45.

  Ferreyra JA Wu KJ Hryckowian AJ Bouley DM Weimer BC Sonnenburg JL . Gut microbiota-produced succinate promotes C. difficile infection after antibiotic treatment or motility disturbance. Cell Host Microbe. (2014) 16:770–7. 10.1016/j.chom.2014.11.003

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 46.

  Curtis MM Hu Z Klimko C Narayanan S Deberardinis R Sperandio V . The gut commensal Bacteroides thetaiotaomicron exacerbates enteric infection through modification of the metabolic landscape. Cell Host Microbe. (2014) 16:759–69. 10.1016/j.chom.2014.11.005

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 47.

  Kimura I Inoue D Hirano K Tsujimoto G . The SCFA receptor GPR43 and energy metabolism. Front Endocrinol. (2014) 5:85. 10.3389/fendo.2014.00085

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 48.

  Inoue D Tsujimoto G Kimura I . Regulation of energy homeostasis by GPR41. Front Endocrinol. (2014) 5:81. 10.3389/fendo.2014.00081

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 49.

  Fujii H Kawada N . NAFLD JSGo. The role of insulin resistance and diabetes in nonalcoholic fatty liver disease. Int J Mol Sci. (2020) 21:3863. 10.3390/ijms21113863

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 50.

  Barataud A Vily-Petit J Goncalves D Zitoun C Duchampt A Philippe E et al . Metabolic benefits of gastric bypass surgery in the mouse: the role of fecal losses. Mol Metab. (2020) 31:14–23. 10.1016/j.molmet.2019.11.006

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 51.

  de Vadder F Mithieux G . Gut-brain signaling in energy homeostasis: the unexpected role of microbiota-derived succinate. J Endocrinol. (2018) 236:R105–r8. 10.1530/JOE-17-0542

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 52.

  Koh A De Vadder F Kovatcheva-Datchary P Bäckhed F . From dietary fiber to host physiology: short-chain fatty acids as key bacterial metabolites. Cell. (2016) 165:1332–45. 10.1016/j.cell.2016.05.041

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 53.

  Blacher E Levy M Tatirovsky E Elinav E . Microbiome-modulated metabolites at the interface of host immunity. J Immunol. (2017) 198:572–80. 10.4049/jimmunol.1601247

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 54.

  den Besten G Bleeker A Gerding A van Eunen K Havinga R van Dijk TH et al . Short-chain fatty acids protect against high-fat diet-induced obesity via a PPARγ-dependent switch from lipogenesis to fat oxidation. Diabetes. (2015) 64:2398–408. 10.2337/db14-1213

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 55.

  Mitchell RW On On NH Del Bigio MR Miller DW Hatch GM . Fatty acid transport protein expression in human brain and potential role in fatty acid transport across human brain microvessel endothelial cells. J Neurochem. (2011) 117:735–46. 10.1111/j.1471-4159.2011.07245.x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 56.

  Eom JA Kwon GH Kim NY Park EJ Won SM Jeong JJ et al . Diet-regulating microbiota and host immune system in liver disease. Int J Mol Sci. (2021) 22:6326. 10.3390/ijms22126326

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 57.

  Gebru YA Choi MR Raja G Gupta H Sharma SP Choi YR et al . Pathophysiological roles of mucosal-associated invariant T cells in the context of gut microbiota-liver axis. Microorganisms. (2021) 9:296. 10.3390/microorganisms9020296

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 58.

  Alkhalaf LM Ryan KS . Biosynthetic manipulation of tryptophan in bacteria: pathways and mechanisms. Chem Biol. (2015) 22:317–28. 10.1016/j.chembiol.2015.02.005

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 59.

  Roager HM Licht TR . Microbial tryptophan catabolites in health and disease. Nat Commun. (2018) 9:3294. 10.1038/s41467-018-05470-4

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 60.

  Raja G Gupta H Gebru YA Youn GS Choi YR Kim HS et al . Recent advances of microbiome-associated metabolomics profiling in liver disease: principles, mechanisms, and applications. Int J Mol Sci. (2021) 22:1160. 10.3390/ijms22031160

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 61.

  Cervenka I Agudelo LZ Ruas JL . Kynurenines: Tryptophan's metabolites in exercise, inflammation, and mental health. Science. (2017) 357:eaaf9794. 10.1126/science.aaf9794

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 62.

  Houtkooper RH Cantó C Wanders RJ Auwerx J . The secret life of NAD+: an old metabolite controlling new metabolic signaling pathways. Endocr Rev. (2010) 31:194–223. 10.1210/er.2009-0026

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 63.

  Atarashi K Tanoue T Shima T Imaoka A Kuwahara T Momose Y et al . Induction of colonic regulatory T cells by indigenous Clostridium species. Science. (2011) 331:337–41. 10.1126/science.1198469

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 64.

  Rhee SJ Walker WA Cherayil BJ . Developmentally regulated intestinal expression of IFN-gamma and its target genes and the age-specific response to enteric Salmonella infection. J Immunol. (2005) 175:1127–36. 10.4049/jimmunol.175.2.1127

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 65.

  Zelante T Iannitti RG Cunha C De Luca A Giovannini G Pieraccini G et al . Tryptophan catabolites from microbiota engage aryl hydrocarbon receptor and balance mucosal reactivity via interleukin-22. Immunity. (2013) 39:372–85. 10.1016/j.immuni.2013.08.003

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 66.

  Vujkovic-Cvijin I Dunham RM Iwai S Maher MC Albright RG Broadhurst MJ et al . Dysbiosis of the gut microbiota is associated with HIV disease progression and tryptophan catabolism. Sci Transl Med. (2013) 5:193ra91. 10.1126/scitranslmed.3006438

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 67.

  Lee J Attila C Cirillo SL Cirillo JD Wood TK . Indole and 7-hydroxyindole diminish Pseudomonas aeruginosa virulence. Microb Biotechnol. (2009) 2:75–90. 10.1111/j.1751-7915.2008.00061.x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 68.

  Nikaido E Giraud E Baucheron S Yamasaki S Wiedemann A Okamoto K et al . Effects of indole on drug resistance and virulence of Salmonella enterica serovar Typhimurium revealed by genome-wide analyses. Gut Pathog. (2012) 4:5. 10.1186/1757-4749-4-5

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 69.

  Kohli N Crisp Z Riordan R Li M Alaniz RC Jayaraman A . The microbiota metabolite indole inhibits Salmonella virulence: Involvement of the PhoPQ two-component system. PLoS ONE. (2018) 13:e0190613. 10.1371/journal.pone.0190613

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 70.

  Oh S Go GW Mylonakis E Kim Y . The bacterial signalling molecule indole attenuates the virulence of the fungal pathogen Candida albicans. J Appl Microbiol. (2012) 113:622–8. 10.1111/j.1365-2672.2012.05372.x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 71.

  Lee JH Cho HS Kim Y Kim JA Banskota S Cho MH et al . Indole and 7-benzyloxyindole attenuate the virulence of Staphylococcus aureus. Appl Microbiol Biotechnol. (2013) 97:4543–52. 10.1007/s00253-012-4674-z

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 72.

  Mueller RS Beyhan S Saini SG Yildiz FH Bartlett DH . Indole acts as an extracellular cue regulating gene expression in vibrio cholerae. J Bacteriol. (2009) 191:3504–16. 10.1128/JB.01240-08

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 73.

  Hirakawa H Kodama T Takumi-Kobayashi A Honda T Yamaguchi A . Secreted indole serves as a signal for expression of type III secretion system translocators in enterohaemorrhagic Escherichia coli O157:H7. Microbiology. (2009) 155:541–50. 10.1099/mic.0.020420-0

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 74.

  Lee JH Cho MH Lee J . 3-indolylacetonitrile decreases Escherichia coli O157:H7 biofilm formation and Pseudomonas aeruginosa virulence. Environ Microbiol. (2011) 13:62–73. 10.1111/j.1462-2920.2010.02308.x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 75.

  Bommarius B Anyanful A Izrayelit Y Bhatt S Cartwright E Wang W et al . A family of indoles regulate virulence and shiga toxin production in pathogenic E. coli. PLOS ONE. (2013) 8:e54456. 10.1371/journal.pone.0054456

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 76.

  Lee J Bansal T Jayaraman A Bentley WE Wood TK . Enterohemorrhagic Escherichia coli biofilms are inhibited by 7-hydroxyindole and stimulated by isatin. Appl Environ Microbiol. (2007) 73:4100–9. 10.1128/AEM.00360-07

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 77.

  Choi SH Kim Y Oh S Oh S Chun T Kim SH . Inhibitory effect of skatole (3-methylindole) on enterohemorrhagic Escherichia coli O157:H7 ATCC 43894 biofilm formation mediated by elevated endogenous oxidative stress. Lett Appl Microbiol. (2014) 58:454–61. 10.1111/lam.12212

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 78.

  Williams BB Van Benschoten AH Cimermancic P Donia MS Zimmermann M Taketani M et al . Discovery and characterization of gut microbiota decarboxylases that can produce the neurotransmitter tryptamine. Cell Host Microbe. (2014) 16:495–503. 10.1016/j.chom.2014.09.001

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 79.

  Jia W Li H Zhao L Nicholson JK . Gut microbiota: a potential new territory for drug targeting. Nat Rev Drug Disc. (2008) 7:123–9. 10.1038/nrd2505

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 80.

  Mawe GM Hoffman JM . Serotonin signalling in the gut–functions, dysfunctions and therapeutic targets. Nat Rev Gastroenterol Hepatol. (2013) 10:473–86. 10.1038/nrgastro.2013.105

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 81.

  Takaki M Mawe GM Barasch JM Gershon MD Gershon MD . Physiological responses of guinea-pig myenteric neurons secondary to the release of endogenous serotonin by tryptamine. Neuroscience. (1985) 16:223–40. 10.1016/0306-4522(85)90059-4

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 82.

  Lukić I Getselter D Ziv O Oron O Reuveni E Koren O et al . Antidepressants affect gut microbiota and Ruminococcus flavefaciens is able to abolish their effects on depressive-like behavior. Transl Psychiatry. (2019) 9:133. 10.1038/s41398-019-0466-x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 83.

  Amala K Karthi S Ganesan R Radhakrishnan N Srinivasan K Mostafa AE-ZMA et al . Bioefficacy of Epaltes divaricata (L.) n-hexane extracts and their major metabolites against the lepidopteran pests spodoptera litura (fab) and dengue mosquito aedes aegypti (Linn). Molecules. (2021) 26:3695. 10.3390/molecules26123695

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 84.

  Zeisel SH da Costa K-A . Choline: an essential nutrient for public health. Nutr Rev. (2009) 67:615–23. 10.1111/j.1753-4887.2009.00246.x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 85.

  Craciun S Balskus EP . Microbial conversion of choline to trimethylamine requires a glycyl radical enzyme. Proc Natl Acad Sci U S A. (2012) 109:21307–12. 10.1073/pnas.1215689109

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 86.

  Choi YR Kim HS Yoon SJ Lee NY Gupta H Raja G et al . Nutritional status and diet style affect cognitive function in alcoholic liver disease. Nutrients. (2021) 13:185. 10.3390/nu13010185

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 87.

  Holmes E Kinross J Gibson GR Burcelin R Jia W Pettersson S et al . Therapeutic modulation of microbiota-host metabolic interactions. Sci Transl Med. (2012) 4:137rv6-rv6. 10.1126/scitranslmed.3004244

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 88.

  Weingarden AR Chen C Bobr A Yao D Lu Y Nelson VM et al . Microbiota transplantation restores normal fecal bile acid composition in recurrent Clostridium difficile infection. Am J Physiol Gastrointest Liver Physiol. (2014) 306:G310–9. 10.1152/ajpgi.00282.2013

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 89.

  Buffie CG Bucci V Stein RR McKenney PT Ling L Gobourne A et al . Precision microbiome reconstitution restores bile acid mediated resistance to Clostridium difficile. Nature. (2015) 517:205–8. 10.1038/nature13828

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 90.

  Kang JD Myers CJ Harris SC Kakiyama G Lee I-K Yun B-S et al . Bile acid 7α-dehydroxylating gut bacteria secrete antibiotics that inhibit clostridium difficile: role of secondary bile acids. Cell Chem Biol. (2019) 26:27–34. 10.1016/j.chembiol.2018.10.003

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 91.

  Steed AL Christophi GP Kaiko GE Sun L Goodwin VM Jain U et al . The microbial metabolite desaminotyrosine protects from influenza through type I interferon. Science. (2017) 357:498–502. 10.1126/science.aam5336

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 92.

  Miki T Goto R Fujimoto M Okada N Hardt WD . The bactericidal lectin RegIIIβ prolongs gut colonization and enteropathy in the streptomycin mouse model for salmonella diarrhea. Cell Host Microbe. (2017) 21:195–207. 10.1016/j.chom.2016.12.008

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 93.

  Toyosawa T Suzuki M Kodama K Araki S . Highly purified vitamin B2 presents a promising therapeutic strategy for sepsis and septic shock. Infect Immun. (2004) 72:1820–3. 10.1128/IAI.72.3.1820-1823.2004

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 94.

  Schramm M Wiegmann K Schramm S Gluschko A Herb M Utermöhlen O et al . Riboflavin (vitamin B2) deficiency impairs NADPH oxidase 2 (Nox2) priming and defense against Listeria monocytogenes. Eur J Immunol. (2014) 44:728–41. 10.1002/eji.201343940

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 95.

  Hochbaum AI Kolodkin-Gal I Foulston L Kolter R Aizenberg J Losick R . Inhibitory effects of D-amino acids on Staphylococcus aureus biofilm development. J Bacteriol. (2011) 193:5616–22. 10.1128/JB.05534-11

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 96.

  Connolly JPR Gabrielsen M Goldstone RJ Grinter R Wang D Cogdell RJ et al . A highly conserved bacterial D-Serine uptake system links host metabolism and virulence. PLoS Pathog. (2016) 12:e1005359-e. 10.1371/journal.ppat.1005359

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 97.

  You JS Yong JH Kim GH Moon S Nam KT Ryu JH et al . Commensal-derived metabolites govern Vibrio cholerae pathogenesis in host intestine. Microbiome. (2019) 7:132. 10.1186/s40168-019-0746-y

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 98.

  Sasabe J Miyoshi Y Rakoff-Nahoum S Zhang T Mita M Davis BM et al . Interplay between microbial d-amino acids and host d-amino acid oxidase modifies murine mucosal defence and gut microbiota. Nat Microbiol. (2016) 1:16125. 10.1038/nmicrobiol.2016.125

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 99.

  Wang Z Klipfell E Bennett BJ Koeth R Levison BS DuGar B et al . Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature. (2011) 472:57–63. 10.1038/nature09922

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 100.

  Zhu W Gregory JC Org E Buffa JA Gupta N Wang Z et al . Gut microbial metabolite TMAO enhances platelet hyperreactivity and thrombosis risk. Cell. (2016) 165:111–24. 10.1016/j.cell.2016.02.011

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 101.

  Tang WH Wang Z Levison BS Koeth RA Britt EB Fu X et al . Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk. N Engl J Med. (2013) 368:1575–84. 10.1056/NEJMoa1109400

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 102.

  Koeth RA Lam-Galvez BR Kirsop J Wang Z Levison BS Gu X et al . l-Carnitine in omnivorous diets induces an atherogenic gut microbial pathway in humans. J Clin Invest. (2019) 129:373–87. 10.1172/JCI94601

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 103.

  Li XS Obeid S Wang Z Hazen BJ Li L Wu Y et al . Trimethyllysine, a trimethylamine N-oxide precursor, provides near- and long-term prognostic value in patients presenting with acute coronary syndromes. Eur Heart J. (2019) 40:2700–9. 10.1093/eurheartj/ehz259

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 104.

  Yogarajalakshmi P Venugopal Poonguzhali T Ganesan R Karthi S Senthil-Nathan S Krutmuang P et al . Toxicological screening of marine red algae Champia parvula (C. Agardh) against the dengue mosquito vector Aedes aegypti (Linn) and its non-toxicity against three beneficial aquatic predators. Aquat Toxicol. (2020) 222:105474. 10.1016/j.aquatox.2020.105474

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 105.

  Hill MJ . Intestinal flora and endogenous vitamin synthesis. Eur J Cancer Prev. (1997) 6:S43–5. 10.1097/00008469-199703001-00009

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 106.

  Magnúsdóttir S Ravcheev D de Crécy-Lagard V Thiele I . Systematic genome assessment of B-vitamin biosynthesis suggests co-operation among gut microbes. Front Genet. (2015) 6:148. 10.3389/fgene.2015.00148

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 107.

  Aufreiter S Gregory JF Pfeiffer CM Fazili Z Kim YI Marcon N et al . Folate is absorbed across the colon of adults: evidence from cecal infusion of (13)C-labeled [6S]-5-formyltetrahydrofolic acid. Am J Clin Nutr. (2009) 90:116–23. 10.3945/ajcn.2008.27345

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 108.

  Dinan TG Cryan JF . Regulation of the stress response by the gut microbiota: implications for psychoneuroendocrinology. Psychoneuroendocrinology. (2012) 37:1369–78. 10.1016/j.psyneuen.2012.03.007

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 109.

  Yatsunenko T Rey FE Manary MJ Trehan I Dominguez-Bello MG Contreras M et al . Human gut microbiome viewed across age and geography. Nature. (2012) 486:222–7. 10.1038/nature11053

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 110.

  Karthi S Vasantha-Srinivasan P Ganesan R Ramasamy V Senthil-Nathan S Khater HF et al . Target activity of isaria tenuipes (hypocreales: clavicipitaceae) fungal strains against dengue vector aedes aegypti (Linn.) and its non-target activity against aquatic predators. J Fungi. (2020) 6:196. 10.3390/jof6040196

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 111.

  Macfarlane S Macfarlane GT . Regulation of short-chain fatty acid production. Proc Nutr Soc. (2003) 62:67–72. 10.1079/PNS2002207

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 112.

  Cummings JH Pomare EW Branch WJ Naylor CP Macfarlane GT . Short chain fatty acids in human large intestine, portal, hepatic and venous blood. Gut. (1987) 28:1221–7. 10.1136/gut.28.10.1221

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 113.

  den Besten G van Eunen K Groen AK Venema K Reijngoud DJ Bakker BM . The role of short-chain fatty acids in the interplay between diet, gut microbiota, and host energy metabolism. J Lipid Res. (2013) 54:2325–40. 10.1194/jlr.R036012

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 114.

  Smith EA Macfarlane GT . Dissimilatory amino acid metabolism in human colonic bacteria. Anaerobe. (1997) 3:327–37. 10.1006/anae.1997.0121

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 115.

  Deehan EC Yang C Perez-Muñoz ME Nguyen NK Cheng CC Triador L et al . Precision microbiome modulation with discrete dietary fiber structures directs short-chain fatty acid production. Cell Host Microbe. (2020) 27:389–404. 10.1016/j.chom.2020.01.006

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 116.

  Agus A Planchais J Sokol H . Gut microbiota regulation of tryptophan metabolism in health and disease. Cell Host Microbe. (2018) 23:716–24. 10.1016/j.chom.2018.05.003

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 117.

  Devlin AS Marcobal A Dodd D Nayfach S Plummer N Meyer T et al . Modulation of a circulating uremic solute via rational genetic manipulation of the gut microbiota. Cell Host Microbe. (2016) 20:709–15. 10.1016/j.chom.2016.10.021

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 118.

  Saito Y Sato T Nomoto K Tsuji H . Identification of phenol- and p-cresol-producing intestinal bacteria by using media supplemented with tyrosine and its metabolites. FEMS Microbiol Ecol. (2018) 94:fiy125. 10.1093/femsec/fiy125

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 119.

  Zhang LS Davies SS . Microbial metabolism of dietary components to bioactive metabolites: opportunities for new therapeutic interventions. Genome Med. (2016) 8:46. 10.1186/s13073-016-0296-x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 120.

  Yano JM Yu K Donaldson GP Shastri GG Ann P Ma L et al . Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis. Cell. (2015) 161:264–76. 10.1016/j.cell.2015.02.047

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 121.

  Fung TC Vuong HE Luna CDG Pronovost GN Aleksandrova AA Riley NG et al . Intestinal serotonin and fluoxetine exposure modulate bacterial colonization in the gut. Nat Microbiol. (2019) 4:2064–73. 10.1038/s41564-019-0540-4

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 122.

  Barcik W Wawrzyniak M Akdis CA O'Mahony L . Immune regulation by histamine and histamine-secreting bacteria. Curr Opin Immunol. (2017) 48:108–13. 10.1016/j.coi.2017.08.011

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 123.

  Valles-Colomer M Falony G Darzi Y Tigchelaar EF Wang J Tito RY et al . The neuroactive potential of the human gut microbiota in quality of life and depression. Nature Microbiology. (2019) 4:623–32. 10.1038/s41564-018-0337-x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 124.

  Koh A Molinaro A Ståhlman M Khan MT Schmidt C Mannerås-Holm L et al . Microbially produced imidazole propionate impairs insulin signaling through mTORC1. Cell. (2018) 175:947–61. 10.1016/j.cell.2018.09.055

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 125.

  Maini Rekdal V Bess EN Bisanz JE Turnbaugh PJ Balskus EP . Discovery and inhibition of an interspecies gut bacterial pathway for levodopa metabolism. Science. (2019) 364:eaau6323. 10.1126/science.aau6323

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 126.

  van Kessel SP Frye AK El-Gendy AO Castejon M Keshavarzian A van Dijk G et al . Gut bacterial tyrosine decarboxylases restrict levels of levodopa in the treatment of Parkinson's disease. Nat Commun. (2019) 10:310. 10.1038/s41467-019-08294-y

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 127.

  Niranjan-Azadi AM Araz F Patel YA Alachkar N Alqahtani S Cameron AM et al . Ammonia level and mortality in acute liver failure: a single-center experience. Ann Transplant. (2016) 21:479–83. 10.12659/AOT.898901

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 128.

  Vince AJ Burridge SM . Ammonia production by intestinal bacteria: the effects of lactose, lactulose and glucose. J Med Microbiol. (1980) 13:177–91. 10.1099/00222615-13-2-177

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 129.

  Nsenga Kumwimba M Meng F . Roles of ammonia-oxidizing bacteria in improving metabolism and cometabolism of trace organic chemicals in biological wastewater treatment processes: a review. Sci Total Environ. (2019) 659:419–41. 10.1016/j.scitotenv.2018.12.236

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 130.

  Olde Damink SWM Deutz NEP Dejong CHC Soeters PB Jalan R . Interorgan ammonia metabolism in liver failure. Neurochem Int. (2002) 41:177–88. 10.1016/S0197-0186(02)00040-2

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 131.

  Liu J Lkhagva E Chung H-J Kim H-J Hong S-T . The pharmabiotic approach to treat hyperammonemia. Nutrients. (2018) 10:140. 10.3390/nu10020140

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 132.

  Paster BJ Russell JB Yang CM Chow JM Woese CR Tanner R . Phylogeny of the ammonia-producing ruminal bacteria peptostreptococcus anaerobius, clostridium sticklandii, and Clostridium aminophilum sp. Nov. Int J Syst Bacteriol. (1993) 43:107–10. 10.1099/00207713-43-1-107

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 133.

  Richardson AJ McKain N Wallace RJ . Ammonia production by human faecal bacteria, and the enumeration, isolation and characterization of bacteria capable of growth on peptides and amino acids. BMC Microbiol. (2013) 13:6. 10.1186/1471-2180-13-6

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 134.

  Staley C Weingarden AR Khoruts A Sadowsky MJ . Interaction of gut microbiota with bile acid metabolism and its influence on disease states. Appl Microbiol Biotechnol. (2017) 101:47–64. 10.1007/s00253-016-8006-6

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 135.

  Long SL Gahan CGM Joyce SA . Interactions between gut bacteria and bile in health and disease. Mol Aspects Med. (2017) 56:54–65. 10.1016/j.mam.2017.06.002

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 136.

  Sinal CJ Tohkin M Miyata M Ward JM Lambert G Gonzalez FJ . Targeted disruption of the nuclear receptor FXR/BAR impairs bile acid and lipid homeostasis. Cell. (2000) 102:731–44. 10.1016/S0092-8674(00)00062-3

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 137.

  Hylemon PB Zhou H Pandak WM Ren S Gil G Dent P . Bile acids as regulatory molecules. J Lipid Res. (2009) 50:1509–20. 10.1194/jlr.R900007-JLR200

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 138.

  Copple BL Li T . Pharmacology of bile acid receptors: evolution of bile acids from simple detergents to complex signaling molecules. Pharmacol Res. (2016) 104:9–21. 10.1016/j.phrs.2015.12.007

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 139.

  Parséus A Sommer N Sommer F Caesar R Molinaro A Ståhlman M et al . Microbiota-induced obesity requires farnesoid X receptor. Gut. (2017) 66:429–37. 10.1136/gutjnl-2015-310283

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 140.

  Ridlon JM Kang DJ Hylemon PB Bajaj JS . Bile acids and the gut microbiome. Curr Opin Gastroenterol. (2014) 30:332–8. 10.1097/MOG.0000000000000057

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 141.

  Mouzaki M Wang AY Bandsma R Comelli EM Arendt BM Zhang L et al . Bile acids and dysbiosis in non-alcoholic fatty liver disease. PLoS ONE. (2016) 11:e0151829. 10.1371/journal.pone.0151829

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 142.

  Urdaneta V Casadesús J . Interactions between Bacteria and Bile Salts in the Gastrointestinal and Hepatobiliary Tracts. Front. Med. (2017) 4:163. 10.3389/fmed.2017.00163

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 143.

  Wahlström A Sayin Sama I Marschall H-U Bäckhed F . Intestinal crosstalk between bile acids and microbiota and its impact on host metabolism. Cell Metab. (2016) 24:41–50. 10.1016/j.cmet.2016.05.005

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 144.

  Ramírez-Pérez O Cruz-Ramón V Chinchilla-López P Méndez-Sánchez N . The role of the gut microbiota in bile acid metabolism. Ann Hepatol. (2017) 16:S21–S6. 10.5604/01.3001.0010.5672

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 145.

  Chávez-Talavera O Tailleux A Lefebvre P Staels B . Bile acid control of metabolism and inflammation in obesity, Type 2 diabetes, dyslipidemia, and nonalcoholic fatty liver disease. Gastroenterology. (2017) 152:1679–94.e3. 10.1053/j.gastro.2017.01.055

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 146.

  Wishart DS . Metabolomics for investigating physiological and pathophysiological processes. Physiol Rev. (2019) 99:1819–75. 10.1152/physrev.00035.2018

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 147.

  Antonarakis SEBALKKWSCRVDLVB . OMMBID: The Online Metabolic & Molecular Bases of Inherited Disease (2005).

  • Google Scholar

• 148.

  Kakiyama G Pandak WM Gillevet PM Hylemon PB Heuman DM Daita K et al . Modulation of the fecal bile acid profile by gut microbiota in cirrhosis. J Hepatol. (2013) 58:949–55. 10.1016/j.jhep.2013.01.003

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 149.

  Grüner N Mattner J . Bile Acids and microbiota: multifaceted and versatile regulators of the liver–gut axis. Int J Mol Sci. (2021) 22:1397. 10.3390/ijms22031397

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 150.

  Wishart DS Tzur D Knox C Eisner R Guo AC Young N et al . HMDB: the human metabolome database. Nucleic Acids Res. (2007) 35:D521–6. 10.1093/nar/gkl923

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 151.

  Han J Liu Y Wang R Yang J Ling V Borchers CH . Metabolic profiling of bile acids in human and mouse blood by LC-MS/MS in combination with phospholipid-depletion solid-phase extraction. Anal Chem. (2015) 87:1127–36. 10.1021/ac503816u

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 152.

  Jäntti SE Kivilompolo M Ohrnberg L Pietiläinen KH Nygren H Orešič M et al . Quantitative profiling of bile acids in blood, adipose tissue, intestine, and gall bladder samples using ultra high performance liquid chromatography-tandem mass spectrometry. Anal Bioanal Chem. (2014) 406:7799–815. 10.1007/s00216-014-8230-9

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 153.

  Liu Y Rong Z Xiang D Zhang C Liu D . Detection technologies and metabolic profiling of bile acids: a comprehensive review. Lipids Health Dis. (2018) 17:121. 10.1186/s12944-018-0774-9

  • Pubmed Abstract
  • CrossRef
  • Google Scholar