Thus, D -amino acids produced by nasal microbiota can inhibit innate immune response through sweet taste receptors and may shape the microbial community of the upper airways. Kepert et al.
Oral supplementation of D -tryptophan in mice alters diversity of gut microbiota, increases numbers of regulatory T cells in the lung and colon, decreases lung Th2 responses, and ameliorates allergic airway inflammation and hyperresponsiveness Kepert et al. Although further mechanisms underlying connection between innate and acquired immunity modified by bacterial D -amino acids remain largely unknown, recognition of bacterial D -amino acids by the mammalian enzyme or receptors may play a significant role in the mucosal immunity and homeostasis.
In mammals, intrinsic D -serine and D -aspartate have received great attention for their neuromodulatory roles in the central nervous system. In this mini-review, we have shed light on previously less-focused D -amino acids originated from commensal or pathogenic bacteria.
As bacteria produce and release a largely distinct set of D -amino acids from mammals, accumulating evidence show that bacterial D -amino acids serve as inter-kingdom signals linked to innate defense in mammals. At the host—microbe interfaces, host reacts to bacteria through enantioselective recognition of D -amino acids by DAO or sweet taste receptors, and provides direct toxic response or indirect actions through modulating antimicrobial peptides.
Furthermore, such recognition of bacterial D -amino acids by host may further mediate signals to modulate adaptive immunity. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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Lam, H. D-amino acids govern stationary phase cell wall remodeling in bacteria. Science , — Lee, R. Bacterial d-amino acids suppress sinonasal innate immunity through sweet taste receptors in solitary chemosensory cells.
Bitter and sweet taste receptors regulate human upper respiratory innate immunity. Loetscher, Y. Salmonella transiently reside in luminal neutrophils in the inflamed gut. PLoS One 7:e Margolskee, R. Three amino acids can be deaminated directly: glutamate catalysed by glutamate dehydrogenase , glycine catalysed by glycine oxidase and serine catalysed by serine dehydrogenase. Two of these enzymes, glutamate dehydrogenase and glycine oxidase, are especially important, since the keto-acid products ketoglutarate and glyoxylate respectively can readily be reaminated to the parent amino acid by transfer of the amino acid from a donor amino acid - the process of transamination.
All of the amino acids apart from lysine undergo transamination; some transaminases use ketoglutarate as the acceptor keto-acid, forming glutamate which is then a substrate for glutamate dehydrogenase.
Many others use oxaloacetate as the acceptor keto-acid, forming aspartate, which then transfers its amino group to ketoglutarate. For example, Kao et al. A similar situation was observed for Staphylococcus aureus. Hochbaum and colleagues found that S. D -Amino acids did not prevent the initial attachment of the bacterial cells to the surface, but inhibited subsequent growth of the initial microcolonies into larger assemblies by affecting the protein component of the EPS.
Production and localization of exopolysaccharide was not significantly affected. The D -amino acid mixture was also able to disassemble already existing S.
On the contrary, Sarkar and Pires reported that S. A similar mechanism of biofilm disassembly as in B. The biofilm of S. The authors hypothesize that the polymerization ability of Aap is affected by D -amino acids, which ultimately leads to biofilm disassembly. Different sensitivity to D -amino acids during biofilm formation has been demonstrated for a wide set of pathogenic and non-pathogenic S.
D -Met was the most efficient to inhibit biofilm formation, followed by D -Phe. Inconsistencies in the activity of D -amino acids as biofilm disassembly agents and variations in the active concentrations were addressed in a methodological paper of Kolodkin-Gal group Bucher et al. In an attempt to categorize the effect of D -amino acids on bacteria, Yu et al.
D -Tyr had opposite impact on the EPS production in the two studied bacteria. Exopolysaccharide production in P. These results suggest that distinct mechanisms might be involved at different D -Tyr concentrations and they might be species specific. A systematic approach to test the differential activity of D -amino acids was taken by Rumbo et al.
Some D -amino acids inhibited bacterial growth, biofilm formation and adherence to eukaryotic cells, as well as protected alveolar cells from P. However, even though some protective effect was observed in mice, the difference in survival of treated and non-treated groups was not statistically significant. In addition, some of the D -amino acids tested affected bacterial growth suggesting an indirect effect in biofilm formation.
Recently, Alvarez et al. Previous screenings failed to identify D -Arg in the stationary phase supernatant, since they relied on the rod-to-sphere morphological transition induced by the supernatant active fractions in a cell wall sensitive mutant mrcA Lam et al. In sensitive organisms, like Caulobacter crescentus and Agrobacterium tumefaciens , D -Arg toxicity was suppressed by mutations in the DnaJ chaperone system and in the phosphate uptake machinery, confirming the different roles that D -amino acids play in bacterial physiology.
The reason why D -Arg sensitivity is suppressed by mutations in these pathways remains still unknown, but provides new and interesting research possibilities. It is tempting to speculate about the induction and cross-complementation of different chaperone systems exerted by the anomalous incorporation of D -amino acids into proteins and concomitant alteration of the protein patterns.
Chaperone systems might help refold or degrade toxic misfolded proteins. The fact that one type of D -amino acids e. The role of inorganic phosphate Pi in resistance to D -Arg is even more elusive, being Pi a central element of numerous metabolic and regulatory networks. In addition, the study has shown that the ability to produce D -amino acids is not universally widespread Alvarez et al. BsrV orthologs are missing in some Vibrionaceae species, although all tested members of the family 41 species can grow at high mM concentrations of diverse D -amino acids.
Since Vibrio species normally coexist in diverse marine, fresh water and host ecosystems, it is highly possible that cooperative strategies have been established between them to benefit of the secreted D -amino acids as a community. The authors propose that D -Arg production could be a public good shared in Vibrio communities, i.
Given the relatively easy occurrence of suppressor mutations conferring resistance to certain D -amino acids, it seems reasonable that bacteria produce more than one type of amino acid, as these imply i divergent mechanisms to attack different targets at the same time, and ii the capacity to produce D -amino acids under varying L -amino acids availability.
Due to their antibiofilm and bactericidal effect, application of D -amino acids is an attractive antimicrobial strategy both alone or in synergy with existing antibiotics. Moreover, combinatory treatments with several D -amino acids can be more effective and prevent the emergence of suppressor mutants, since different D -amino acids target distinct pathways. A cocktail of D -amino acids efficiently enhanced sublethal concentration of THPS tetrakis hydroxymethyl phosphonium sulfate , a commonly used antimicrobial reagent used in water treatment processes, in two types of biofilm consortia Li Y.
However, the D -amino acid mix required for biofilm dispersal might vary depending on the species combinations. In addition, D -amino acids also enhanced the activity of the biocide NALCO active components: 5-chloromethylisothiazolinone and 2-methylisothiazolinone against biofilm on the steel coupons retrieved from a water cooling tower Jia et al.
D -Leu applied to citrus tree leaves alone, or in combination with copper, reduced the number of canker lesions and populations of Xanthomonas citri subsp. Interestingly, D -Leu inhibited biofilm formation in this bacterium, however, genes important for biofilm, chemotaxis and motility were not differentially expressed thereby suggesting a post-transcriptional mechanism of biofilm dissociation. D -Leu foliar application might be a promising strategy to reduce the usage of copper bactericides and avoid copper resistance in xanthomonad populations.
However, D -amino acids have been also found in different environments such as in the soil, lakes, rivers, and oceans Pollock et al. While both enantiomeric forms of Met and Leu supported growth, only the D -form of His and Val was accepted Pikuta et al. The draft genome sequence of LZ T revealed that bacterium has more than 30 potentially catabolic dehydrogenases, and a variety of genes associated with racemase and isomerase activities. Presence of dehydrogenases and other enzymes and metabolic pathways for D -amino acid utilization were reported in various bacteria, such as P.
In yeasts, oxidative deamination of amino acids is performed by D -amino acid oxidases, which also allows them to use D -amino acids for growth Simonetta et al. D -Amino acids have been also demonstrated to influence important physiological aspects of eukaryotic organisms. D -Ser is a neurotransmitter that regulates signaling in the cerebral cortex and is involved in memorization and learning Hashimoto et al.
The physiological function of other D -amino acids has posed a great interest and is currently being studied by many researchers. D -Amino acids not only exhibit a differential role in complex bacterial communities by directly interfering with the different bacteria populations, but hosts and microbes have evolved to interact, and several examples illustrate the great potential of D -amino acids as interkingdom signaling mechanisms Figure 2.
Effect of D -amino acids on human host. Bacteria are involved in various physiological processes in the human body by regulating L - and D -amino acid availability. Such modulation affects neural communication Kawase et al. Bacteria secrete D -amino acids to inhibit growth and biofilm of competitors Rasmussen et al. Gut microbiota is composed by a great diversity of bacterial species, some of which, release abundant and diverse D -amino acids in the host Sasabe et al.
Recently, a study from Waldor lab explored the role of D -amino acids in the gut homeostasis. The release of H 2 O 2 to the gut lumen has a toxic effect on sensitive bacterial populations and thus is an important host defense factor Nathan and Cunningham-Bussel, This effect was totally dependent on the production of D -amino acids D -Ala, D -Asp, D -Glu, and D -Pro by the commensal microbiota, since no D -amino acids were detected in germ-free mice, while abundant amounts of L -amino acids were detected even greater levels in germ-free mice, likely due to their consumption by the gut microbiota.
In vitro studies with DAO and D -amino acids resulted in reduced viability of diverse enteric pathogens tested, including V. Furthermore, this DAO-induced toxicity was attenuated by the catalase activity.
Strains deficient in D -amino acids production proved to be better intestinal colonizers than wild-type V. The work raised the possibility that DAO could play a role in the protection of the mucosal surface and concluded that the gut microbiota composition can be modulated by released microbial D -amino acids and their interplay with the intestinal DAO. The authors also suggested that additional mechanisms might contribute to the altered microbiota in DAO null mutants, which is consistent with the direct effect of some D -amino acids on the viability of other bacteria.
Another study revealed that the gut microbiota can be an important regulator of amino acid metabolism Kawase et al. The microbiome can modulate the amount of amino acids found in the blood and brain of the host, since gut microbiota secretes and metabolizes D -amino acids, influencing their absorption and thus, stimulating the immunological system. In a comparative experiment, the production of D -Ser by the host was inhibited by the gut microbiota: D -Ser concentration in the plasma was higher in germ free than in control mice, although the concentration of L -Ser remained fairly constant.
By altering the D -Ser metabolism, the gut microbiota can regulate neurological diseases in the host brain. Not only the nervous system is influenced by the gut microbiota. Kepert et al. A thorough screening for bioactive probiotic metabolites revealed the immunomodulatory role of D -Trp. Only D -Trp produced by different Lactobacillus species showed bioactivity and decreased the production of TH2 cytokines and chemokines, preventing the development of allergic airway inflammation and hyper-responsiveness.
An altered gut microbiota can hence impact the gut immunity directly or indirectly through the release of D -Trp. Bacterial diversity analysis revealed a reduced community richness on mice with allergic airway disease. Interestingly, supplementation with D -Trp led to an increased bacterial diversity, similar to that of healthy mice.
A last example illustrating the interkingdom signaling in the airway mediated by bacterial D -amino acids and the mammalian sweet taste receptor is presented in the study by Lee et al.
These specific D -amino acids activated the sweet taste receptors in the digestive and the upper respiratory tract, both inhibiting the bitter taste receptors-signaling mechanism and defensin secretion in sinonasal cells. It remains to be explored whether this mechanism provides a host benefit in vivo , like the attenuation of the immune responses against commensal bacteria, or whether this is an evasion mechanism by pathogenic bacteria.
Additionally, released D -amino acids secreted by non-pathogenic components of the normal respiratory flora Rasmussen et al. The researchers confirmed that opportunistic bacteria such as S. D -Amino acids are also building blocks of certain compounds used by both bacteria and host cells to combat each other or survive under stressful conditions. The presence of D -amino acids as building blocks of peptides and proteins dates back to the late 20s Morizawa, , when octopine, a derivative of L -arginine and D -alanine produced by octopuses was first described.
At first it was believed that only the L-configuration was allowed in the structure of peptides and proteins, however, numerous D -amino acid containing peptides have been described since the 80s numerous examples of eukaryotic and bacterial peptides are summarized in Cava et al. Soon it was demonstrated that most organisms are capable of producing diastereomeric peptides and proteins Ollivaux et al.
The presence of D -amino acids in the peptide structure generally enhances its activity and stability, and it can play a key role for receptor recognition Li H. This is one of the main reasons why D -amino acids in host defense peptides HDP improve the efficacy of the next generation of broad spectrum therapeutic agents. Antimicrobial peptides AMPs or HDP are efficient and versatile immune molecules bioactive against all types of pathogens, including bacteria, viruses, fungi, parasites even cancerous cells Wang et al.
AMPs are short peptides, between 12 and 50 residues, produced by all living organisms and they present not only antimicrobial activity but also immunomodulatory functions. Their mechanism of action can be diverse: i AMPs can bind and disrupt the membrane structural integrity, through pore formation or detergent like mechanisms Bahar and Ren, ; Wang, ; ii AMPs disperse biofilms by reducing the adhesion to surfaces, killing of embedded bacteria or interfering with the metabolic pathways involved in biofilm formation de la Fuente-Nunez et al.
So far, no natural AMPs composed only of D -amino acids have been described. Some antibiotics like penicillins and cephalosporins, contain a D -Val moiety and a cycloserine derived from D -Ser Baldwin and Schofield, ; Schofield et al. Other more complex peptide antibiotics gramicidin, actinomycin, bacitracin, or polymyxin are assembled in a stepwise fashion by the action of specific peptide synthetases that catalyze individual reactions Ollivaux et al.
Gramicidin was the first antibiotic peptide to be used clinically Gall and Konashev, ; Kelkar and Chattopadhyay, These molecules produced by Bacillus brevis alternate L - and D -amino acids in their sequence and act through the formation of ion channels that disrupt cell membranes Hladky and Haydon, ; Kelkar and Chattopadhyay, This is the case of the lantibiotics, bacteriocins produced by Gram-positive bacteria Skaugen et al. It is tempting to speculate about the effect on antimicrobial production of bacteria harboring broad spectrum racemases that can modulate the availability of D -amino acids in the media.
It is plausible that such racemases could be produced as defensive mechanisms by reducing the substrate availability and hence the biosynthesis flow of antimicrobial compounds. Recently, a novel metal scavenging molecule named staphylopine has been discovered to be produced by S. Since metals are essential elements for all organisms, the phenomenon known as nutritional immunity Corbin et al. However, different metal uptake mechanisms have also been devised by the invading bacteria. Staphylopine is synthetized by combination of D -His, amino butyrate and pyruvate, it is then released to the extracellular media where it traps the target metals, including nickel, zinc, cobalt, copper and iron, and finally an import system recovers the complex, abolishing the metal starvation state imposed by the host.
As expected, S. Other bacteria and plants also use His or other amino acids such as nicotianamine in plants for the synthesis of metal chelators Schauer et al. The fact that different bacteria produce and release a wide set of D -amino acids to the extracellular media raises the question whether these molecules could also be playing a key role in the synthesis of other metallophores with different metals affinities.
Therefore, production of such molecules might provide a competitive advantage against other bacteria within the same niche. It would be interesting to investigate whether metal homeostasis, bacterial fitness and population dynamics in the host is influenced by microbial D -amino acid production.
It was documented that plants are readily able to uptake D -amino acids from the soil Aldag and Young, ; Svennerstam et al.
For a long time, plant growth inhibition by certain D -amino acids, and slow degradation of D -amino acids by plants neglected the possibility that D -amino acids could be serving as nitrogen source or play a role as important regulatory molecules Figure 3 Erikson et al.
D-Ser 0. However, not all the D -amino acids have detrimental effect on plants, and some D -amino acids can even promote plant growth, such as 5 mM D-Ile and 1 mM D-Val enhanced Arabidopsis growth Erikson et al. In addition, plants respond differently to the presence of D -amino acid in growth medium and foliar application, and submillimolar less toxic concentrations might be a more realistic representation of physiological concentration found in the soil in nature Erikson et al.
D -amino acids modulate plant development and health. However, different D -amino acids not only inhibit plant growth Erikson et al. Certain D -amino acids have a potential to be used for disease prevention in plants Li and Wang, Broad spectrum racemase bacteria are likely to be an important modulator of D -amino acids availability in the soil, thus affecting various processes in plants and selecting plant associated bacterial populations.
There is also growing evidence that D -amino acids can be both produced and metabolized by plants, since D -amino acid synthesizing and degrading enzymes, such as racemases, D -amino acid aminotransferases or D -amino acid oxidases, have been described in different plants Fujitani et al. Moreover, Hill et al. This finding opposes the idea that D -amino acids are irrelevant for plants and serve only as phytotoxic molecules. Michard et al. Their study has shown that D -Ser influences pollen tube development in Arabidopsis and tobacco, and D -serine racemase is important for D -Ser mediated signal transduction Michard et al.
Given the great importance of D -amino acids, the bacteria that produce them play a key role in the regulation of L - and D -amino acids availability in various environments. Summarizing information about the activity of bacterial secreted D -amino acids, their autocrine effect on producer organisms as well as their impact on other microbes or hosts suggests that we cannot think of D -amino acids as just one single type of molecule, but rather as specific effector with unique biological activities.
Therefore, coming research efforts will be heading to figure out the mechanism of each D -amino acid in a specific organism and their ecological significance. All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Aldag, R. D-amino acids in soils. Uptake and metabolism by seedling maize and ryegrass. Alvarez, L. Bacterial secretion of D-arginine controls environmental microbial biodiversity.
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