- Recent advances in microbial production of aromatic natural products and their derivatives.
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Citations Publications citing this paper. Tat translocase composition in Corynebacterium glutamicum and the effect of TorD coexpression Dan Oertel. Constructing the wonders of the bacterial world: biosynthesis of complex enzymes. Frank Sargent. Role of the twin-arginine translocase tat system in iron uptake in Listeria monocytogenes. Wilkinson , Radheshyam K. Plastid Biology John J. Harada , Steven M Theg , F. Remnant signal peptides on non-exported enzymes: implications for the evolution of prokaryotic respiratory chains.
References Publications referenced by this paper. Compensating reductions must thus be carried out. As recently reviewed for food fermentation involving lactic acid bacteria 34 , microbes apply a multitude of different reactions in order to find ultimate electron acceptors allowing them to balance their fermentative metabolism in the absence of oxygen. Similarly in the gut, indole pyruvate generated by transamination of tryptophan may thus be applied as electron acceptor and reduced to ILA by action of the ILA dehydrogenase Fig.
Such fine-tuning reactions might thus equilibrate the redox potential and give microbes a competitive advantage in the gut. Additionally, bacterial cross-feeding on degradation products of aromatic amino acids is likely to occur in the human colon 35 , and may provide specific bacteria with a growth advantage in the highly competitive gut ecosystem. Indole is well-described as an intercellular signal molecule that appears to be important in microbial communities by affecting spore formation, plasmid stability, drug resistance, biofilm formation, and virulence Similarly, indoleethanol IE, tryptophol has been identified as a quorum sensing molecule in fungi This metabolite also exerts antimicrobial activity towards Staphylococcus aureus , Salmonella enterica and Lactobacillus plantarum 37 , Moreover, IE inhibits bacteriophage replication in a thermophilic bacterium, Geobacillus sp.
E 39 , virus replication in shrimps 40 , and proliferation of parasitic protozoa Also ILA is reported to have antifungal activity against Penicillium strains 42 and anti-bacterial activity against E. Furthermore, there is evidence suggesting that indoles affect the survival of the nematode Caenorhabditis elegans 44 , Collectively, these diverse examples suggest that indoles play a role as modulators of microbial gut communities across kingdoms including bacteria, fungi and viruses.
Yet, whether the tryptophan catabolites modulate also the microbial community of the mammalian gut remains unexplored.ipdwew0030atl2.public.registeredsite.com/211200-how-to.php
Recent advances in microbial production of aromatic natural products and their derivatives.
AHR is a transcription factor widely expressed by cells in the immune system 48 and a number of studies have demonstrated that AHR activation alters innate and adaptive immune responses in a ligand-specific fashion 49 , 50 , Importantly, the affinities of tryptophan catabolites for the AHR differ between mice and humans 47 and even within laboratory mouse strains, where four alleles encoding different forms of the AHR are known to exist Whereas the rodent AHR has been found to bind the exogenous ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin TCDD or dioxin with approximately fold higher affinity than the human AHR 53 , recent studies suggest that the human AHR has higher affinity than the mouse AHR for a number of tryptophan-derived ligands Together, these studies reveal that rodent AHR and human AHR exhibit different ligand selectivity, which is very important to consider given that predictions about AHR ligand-receptor interactions in humans are often based on rodent studies.
Furthermore, in intestinal cell line models, the tryptophan catabolites have been found to be either agonists or antagonists depending on their molecular structure 46 , Recent studies have underlined that indole-induced AHR activation may be one way that bacteria contribute to mucosal homeostasis. In addition, treatment of mice with three Lactobacillus strains capable of metabolizing tryptophan attenuated intestinal inflammation via AHR activation, as the effects were abrogated in the presence of an AHR antagonist Thus, the discovery of tryptophan catabolites as AHR ligands may provide new insight about how microbial metabolites affect the immune system in the gut, as well as in systemic circulation.
In addition, indoles provided by commensal bacteria have been found to improve the health of a range of different organisms including Caenorhabditis elegans, Drosophila melanogaster and mice in an AHR-dependent way This raises the intriguing possibility that tryptophan catabolites via AHR may reduce frailty and improve health also in humans.
Both in vitro and in vivo studies have indicated that indole enhances intestinal epithelial barrier functions by increasing expression of genes involved in maintenance of epithelial cell structure and function 58 , Moreover, also IPA was found to regulate intestinal barrier function in vivo in mice by acting as a ligand for the xenobiotic sensor, pregnane X receptor PXR , particularly in the presence of indole Activation of PXR has been shown to protect the barrier function in a mouse model of colitis In addition, IPA was found to reduce intestinal permeability in mice fed a high fat diet Further emphasizing the link between IPA and intestinal barrier function, a recent study colonized germ-free mice with either a wild-type or fldC mutant C.
Also IA has recently been shown to promote intestinal epithelial barrier function and mitigate inflammatory responses in mice by promoting goblet cell differentiation and mucus production, possibly mediated by AHR activation Collectively, these studies suggest that tryptophan catabolites signal through PXR and AHR to fortify the intestinal epithelial barrier function. Indole has been seen to function as a signaling molecule, which is able to modulate the secretion of glucagon-like peptide-1 GLP-1 from immortalized and primary mouse colonic enteroendocrine L cells GLP-1 plays a critical role in stimulating insulin secretion from pancreatic beta cells, suppressing appetite and slowing gastric emptying Thus, intestinal levels of indole may this way affect appetite.
Higher serum concentrations of IPA have recently been associated with reduced prevalence of type 2 diabetes and better insulin secretion and sensitivity 65 , which adds to the evidence pointing towards a putative role of indoles in modulating glucose metabolism, possibly via L cell-induced secretion of GLP In line with this, a recent study found that rats fed a diet containing IPA had significantly lower fasting blood glucose level compared to rats fed a control diet Although the sensing of indole derivatives by L-cells remains elusive, it seems plausible that G protein-coupled receptors GPCRs , which are responsive to a range of nutrients and other food components 67 , may also be responsive to microbial metabolites including tryptophan catabolites as reviewed elsewhere Nonetheless, these studies call for more research to be done to elucidate how tryptophan catabolites may modulate the enteroendocrine system and metabolic homeostasis including glucose metabolism.
Tryptamine, a tryptophan catabolite produced by C. In the gut, tryptamine is known to induce the release of the neurotransmitter 5-hydroxytryptamine 5-HT, serotonin by enterochromaffin cells 69 , which are located at the mucosal surfaces In addition, using an Ussing chamber with a segment of proximal-mid murine colon mucosa, it was found that tryptamine itself induced a significant change in short circuit current, confirming that it can affect ion secretion in intestinal epithelial cells 20 , which plays an important role in gastrointestinal motility.
Thus, tryptamine may act as a signaling molecule that affects intestinal transit time, which is strongly associated with the gut microbial composition, diversity and metabolism in humans 10 , Whether bacterial production of tryptamine plays a role in the pathogenesis of irritable bowel syndrome, which often manifests as either chronic diarrhea or chronic constipation 72 , currently remains unanswered. One species of particular interest could be R. Indeed, R. Tryptophan catabolites may also systemically affect host physiology as they are absorbed through the intestinal epithelium and enter the bloodstream 19 before they are excreted in the urine 10 , Previous studies have suggested IPA as a scavenger of hydroxyl radicals 80 , and a protector against oxidative damage in different tissues 81 , 82 , Similarly, IAA and tryptamine attenuated pro-inflammatory cytokine responses in murine macrophage cultures and hepatocyte cultures in an AHR-dependent way 86 , suggesting that microbial tryptophan catabolites could influence inflammatory responses in the liver as well.
The effects of tryptophan catabolites on production of cytokines may depend on AHR activation, since it has been shown that AHR signaling modifies Toll-like receptor TLR -regulated responses in human dendritic cells Although indoles in general appear to be beneficial, an exception to this is indoxyl sulfate IS , which is a host-microbial co-metabolite generated from indole in the liver by the actions of cytochrome P enzymes, including CYP2E1, and sulfotransferase SULT IS is a potent agonist for AHR 92 , which induces tubulointerstitial fibrosis 93 , glomerular sclerosis 94 , vascular endothelial cell dysfunction 95 and oxidative stress in endothelial cells IS is undetectable in germ-free mice, as the production of IS depends on commensal bacteria Thus, manipulation of the gut microbial tryptophan catabolism may be one strategy to lower circulating levels of IS, as recently demonstrated in gnotobiotic and conventional mice Whether diversion of intestinal tryptophan catabolism away from IS will be beneficial in renal diseases needs to be determined in future studies.
In light of the effects of tryptophan catabolites on various physiological processes, we discuss three areas in which tryptophan catabolites may play a vital role. In light of the great changes of the composition of the gut microbiota occurring during the first years of life 97 , 98 , which to a large extent is driven by changes in diet 99 , , it is highly likely that the gut microbial tryptophan metabolism also changes in this period.
Indeed, indole-producing E. Later, as complementary diet is introduced, bacterial genera including tryptophan catabolizing species such as Lactobacillus , Ruminococcus, Bacteroides, Peptostreptococcus and Clostridium become abundant in the gut of infants Combined with the fact that tryptophan catabolites via AHR activation modulate and educate the immune system as reviewed above, this makes microbial tryptophan catabolites in early life a very relevant area of research, which has not received much attention. Moreover, delivery mode and gestational age of infants are reported to affect urinary levels of metabolites belonging to the tryptophan pathway A recent study revealed that dietary protein depletion compromised adaptive immune responses and altered tryptophan amino acid homeostasis in human infant microbiota-transplanted pigs infected with human rotavirus , and another study in neonatal pigs showed that formula feeding compared to sow feeding reduced enterochomaffin cell number and shifted tryptophan metabolism from serotonin to tryptamine Collectively, these studies suggest that factors such as maternal microbiota and diet, delivery mode, gestational age, infant microbiota and diet influence tryptophan metabolism in early life, which may be essential for the development of intestinal barrier functions and immune system.
During the last decade, IBD has been one of the most studied human conditions linked to the gut microbiota. In addition, plasma tryptophan levels are reported to be reduced in CD , , whereas fecal tryptophan levels are elevated compared to healthy individuals These observations suggest that changes in tryptophan metabolism are involved in the etiology of IBD. In line with this, a tryptophan free diet increased susceptibility to DSS-induced inflammation in mice Importantly, not only tryptophan appears to play a role in the etiology of IBD.
Consistent with this, AHR is downregulated in the intestinal tissue of patients with IBD and AHR activation protects humanized mice against colitis by induction of regulatory T cells Furthermore, IPA is selectively diminished in circulating serum from human subjects with active colitis compared to healthy individuals 31 , and oral administration of indole, as well as IPA is found to ameliorate colonic inflammation in mice 31 , Gut microbial tryptophan metabolism thus holds promise as a therapeutic target in patients with IBD, provided that future research will untangle the relations between the individual tryptophan catabolites and the propensity of inflammation.
Multiple sclerosis MS is a neurodegenerative autoimmune disorder. Astrocytes, a population of cells in the central nervous system CNS , are thought to play an important role in the pathogenesis of MS. A recent study revealed that microbial catabolites of dietary tryptophan combined with type I interferon signaling activates AHR signaling in astrocytes and suppress CNS inflammation in an experimental autoimmune encephalomyelitis EAE animal model of MS In addition, they found decreased circulating levels of AHR agonists in individuals with MS, suggesting that imbalances in the uptake, production, or degradation of AHR agonists may contribute to the pathogenesis of MS and other autoimmune disorders Interestingly, plasma levels of IPA were significantly lower in subjects with HD compared to healthy controls Thus, targeting the gut microbial tryptophan metabolism by modulating the endogenous gut microbiota or changing the diet may represent alternative strategies to prevent and treat MS and other neurological diseases.
As we forge ahead to determine the contributors, we propose to combine profiling of microbes metagenomics with quantification of tryptophan catabolites metabolomics in stool samples from human cohorts. This will allow us to identify important associations between tryptophan catabolites and microbial species, which can be verified using classic in vitro cultivation and metabolic phenotyping. Since tryptophan catabolites are also produced by other microorganisms than bacteria, it is imperative that we move away from profiling only the bacterial community and start exploring the human gut microbiota across kingdoms.
Once we identify the relevant microorganisms and tryptophan catabolites in the gut of infants, adults and elderly, we must identify the exact role of each tryptophan catabolite in host patho physiology and unravel their precise mechanisms in the different segments and cells of the intestine, as well as in the different tissues by use of animal models and by conducting human interventions Fig.
In addition, there is a need to identify the receptors recognizing the metabolites. Furthermore, the AHR species-dependent ligand preferences for tryptophan catabolites seen when comparing different mammals 22 , 47 underline the importance of studying tryptophan catabolite interactions in human cells and not solely in murine models. Currently, the connections between tryptophan catabolites and human health remain rather tentative, with most data being associative or originating from mouse models. Therefore, a more comprehensive understanding of the dynamics of tryptophan catabolites and their functional implications in the different stages of life from birth to old age, from health to disease is needed.
This may crucially extend our understanding of intestinal host-microbial cross-talk in health and disease. Proposed strategy to identify tryptophan-catabolite-producing microbes and to investigate their role in human health and disease. Therefore, we suggest to start from human studies and combine metagenomics and metabolomics data in order to pinpoint the most relevant and potential tryptophan-catabolite producing microbes. Based on these associations, selected target species should be cultured in the laboratory and their in vitro production of tryptophan catabolites should be assessed by growth experiments and metabolic profiling.
Combined with knowledge about their genomes, this will allow the identification of genes responsible for generation of tryptophan catabolites. Knocking out identified genes of interest will subsequently allow for confirmation of the function of the gene and for testing the importance of the particular gene in relevant animal models as recently exemplified Colonizing mice with a given mutant strain and the wild-type counterpart will furthermore allow the investigation of modes of action of the tryptophan catabolites on e.
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This study demonstrates how a long colonic transit time in humans cause a shift in bacterial catabolism from saccharolytic to proteolytic fermentation. Geypens, B.
Physiology, phylogeny, and LUCA
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- Recent advances in microbial production of aromatic natural products and their derivatives..
- Microbial tryptophan catabolites in health and disease.
- ADVANCES IN MICROBIAL PHYSIOLOGY, VOLUME 48: COMMULATIVE INDEX VOLUMES 26-47.
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