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J Bacteriol. Jan 2013; 195(2): 173–179.
PMCID: PMC3553842

Are There Acyl-Homoserine Lactones within Mammalian Intestines?

Abstract

Many Proteobacteria are capable of quorum sensing using N-acyl-homoserine lactone (acyl-HSL) signaling molecules that are synthesized by LuxI or LuxM homologs and detected by transcription factors of the LuxR family. Most quorum-sensing species have at least one LuxR and one LuxI homolog. However, members of the Escherichia, Salmonella, Klebsiella, and Enterobacter genera possess only a single LuxR homolog, SdiA, and no acyl-HSL synthase. The most obvious hypothesis is that these organisms are eavesdropping on acyl-HSL production within the complex microbial communities of the mammalian intestinal tract. However, there is currently no evidence of acyl-HSLs being produced within normal intestinal communities. A few intestinal pathogens, including Yersinia enterocolitica, do produce acyl-HSLs, and Salmonella can detect them during infection. Therefore, a more refined hypothesis is that SdiA orthologs are used for eavesdropping on other quorum-sensing pathogens in the host. However, the lack of acyl-HSL signaling among the normal intestinal residents is a surprising finding given the complexity of intestinal communities. In this review, we examine the evidence for and against the possibility of acyl-HSL signaling molecules in the mammalian intestine and discuss the possibility that related signaling molecules might be present and awaiting discovery.

INTRODUCTION

One type of quorum sensing (QS) in Gram-negative bacteria is performed by LuxI/LuxR homologs. The LuxI homolog synthesizes a QS signal molecule, and the LuxR homolog binds the signal and responds by regulating gene transcription (1, 2, 3). LuxI homologs produce a spectrum of related N-acyl-homoserine lactone (acyl-HSL) signal molecules. The acyl-HSLs have a conserved homoserine lactone ring connected by an amide linkage to a variably structured acyl side chain. The acyl side chain can vary in length, ranging from 4 to 18 carbons, can be substituted with a carbonyl or hydroxyl group on the third carbon, and may or may not be saturated (the AinS/LuxM family of enzymes can also synthesize acyl-HSLs) (4, 5, 6). Each individual LuxI produces a type of acyl-HSL specific for detection by its cognate LuxR. The predominant signal produced by Vibrio fischeri LuxI is N-(3-oxo-hexanoyl)-l-homoserine lactone (abbreviated oxoC6), which has a six-carbon tail modified at the third position with a carbonyl group (7). Unusual variations, including aromatic side chains, branched-chain acyl tails, or carboxylated acyl tails, have also been reported (8, 9, 10, 11).

Among the bacterial species in which the LuxI/LuxR pairs are well characterized, the functions are often associated with host interactions, either with plant or animal, as a commensal or a pathogen. The paradigm is the LuxI/LuxR system of V. fischeri that regulates a commensal interaction between the bacterium and its host, Euprymna scolopes, the bobtail squid (1, 12). Numerous LuxI/LuxR systems are found in plant pathogens, including TraI/TraR of Agrobacterium tumefaciens (Alphaproteobacteria), the causative agent of crown gall tumor formation (13, 14, 15), ExpI/ExpR of Pectobacterium carotovorum (Gammaproteobacteria), which produces enzymes involved in plant soft rot (16, 17), and the more-recently described PssI/PssR of Pseudomonas savastanoi (Gammaproteobacteria), responsible for knot formation in olive trees (18). Mammalian pathogens, including Yersinia enterocolitica and Pseudomonas aeruginosa, also encode LuxI and LuxR homologs (19, 20, 21, 22, 23).

One branch of the Gammaproteobacteria that includes Escherichia, Salmonella, Klebsiella, and Enterobacter encodes a LuxR homolog named SdiA, but there are no acyl-HSL synthase genes in their genomes and it has been experimentally verified that Escherichia coli and Salmonella do not synthesize acyl-HSLs (24, 25). While E. coli and Salmonella do not produce acyl-HSLs, they can sense and respond to a variety of acyl-HSLs produced by other QS bacterial species, a phenomenon described as eavesdropping (26, 27, 28, 29, 30, 31). Because E. coli and Salmonella inhabit the intestinal environment of humans and many other animals (32), the simplest hypothesis is that E. coli and Salmonella use SdiA to detect the acyl-HSL production of the normal intestinal microbiota. However, this hypothesis currently appears to be incorrect. There is no evidence for acyl-HSLs in the mammalian intestinal tract except during infection with the acyl-HSL-producing pathogen Y. enterocolitica (33). Below, we outline the evidence for and against the possibility of acyl-HSLs in the mammalian intestinal tract.

CHEMICAL EVIDENCE SUGGESTING A LACK OF ACYL-HSLs IN THE MAMMALIAN INTESTINE

Attempts to chemically extract acyl-HSLs from the mammalian intestine have failed. An A. tumefaciens biosensor strain was used to screen extracts from bovine rumen, small intestine, and cecum for acyl-HSLs (34, 35, 36). While the majority of rumen samples had activity consistent with the presence of acyl-HSLs, the intestinal samples did not (34, 35, 36, 37). Chemical extracts of mouse intestines were tested for acyl-HSLs using a LuxR-based biosensor (38). Although acyl-HSLs were found in systemic organs infected with Y. enterocolitica, no acyl-HSLs were observed in the intestine (38). Both studies suggest that acyl-HSLs are not present in the bovine or murine intestine. The caveat to these results is the use of biosensors for detection. These have a detection limit in the nanomolar to micromolar range, depending on the acyl-HSL, and may not detect some acyl-HSLs at all. As described below, many new types of HSL signaling molecules that may have been missed by these particular biosensors have been discovered. New biosensors and mass spectrometry approaches should be applied to assay for the presence/absence of acyl-HSLs in the mammalian intestine.

BIOLOGICAL EVIDENCE SUGGESTING A LACK OF ACYL-HSLs IN THE MAMMALIAN INTESTINE

An in vivo Salmonella reporter system failed to detect acyl-HSLs in mammalian gastrointestinal (GI) tracts. The Salmonella LuxR homolog SdiA can detect acyl-HSL variants at concentrations ranging from 1 nM to 1 μM depending on the variant (24, 39). This is similar to the sensitivities of other LuxR homologs, although SdiA seems to detect a broader range of variants than other LuxR family members. Salmonella enterica serovar Typhimurium is a broad-host-range enteric pathogen capable of colonizing over 40 different animal species (32), making the Salmonella SdiA system a versatile reporter for determining whether or not acyl-HSLs exist within host animals. However, it was recently determined that indole at concentrations of 1 mM can inhibit the ability of SdiA to respond to acyl-HSLs (40). Indole concentrations in the mouse and human intestine range from 100 μM to 1 mM (41, 42, 43), so it is possible that indole might reduce the sensitivity of an SdiA reporter in vivo. A Salmonella recombination-based in vivo expression technology (RIVET) reporter system in which sdiA-dependent detection of acyl-HSLs results in a permanent deletion of a tetracycline resistance gene in the Salmonella Typhimurium chromosome was constructed (33, 44, 45). With this system, if SdiA becomes active at any point during the transit of Salmonella Typhimurium through an animal, the Salmonella reporter permanently changes to tetracycline susceptible. Surprisingly, the RIVET reporter system failed to detect acyl-HSLs during transit through the GI tract of a variety of animals, including a guinea pig, a rabbit, a cow, mice, pigs, and chickens (45). However, it did become active in turtles, which correlated with the presence of Aeromonas hydrophila, an important aquaculture pathogen (45, 46, 47). It also became active in mice that had been previously infected with the mammalian intestinal pathogen Y. enterocolitica (33). While A. hydrophila produces acyl-HSLs and seems to be a normal member of the turtle GI microbiota, Y. enterocolitica is considered to be a pathogen rather than a normal member of the mammalian intestinal microbiota. Therefore, the normal mammalian microbiota does not appear to include species that can activate the Salmonella SdiA reporter (33, 45).

POTENTIALLY POSITIVE RESULTS FROM GENOMICS AND METAGENOMICS

The Human Microbiome Project (HMP; http://www.hmpdacc.org) includes an online database that can be used to scan deep-sequencing reads of various human samples, including the GI tract. Also included in the project is a catalog of reference genomes that were collected from the same body sites as the metagenomic samples (48). We searched for SdiA homologs among these genome sequences using the Basic Local Alignment Search Tool (BLAST), and as expected, numerous E. coli, Citrobacter, Enterobacter, and Klebsiella isolates carried sdiA (Table 1). Searching the metagenomic data gave a similar list of homologs (not shown). We then searched for LuxI and LuxR homologs in the draft and completed reference genomes using BLAST with LuxI/LuxR protein sequences from V. fischeri, P. aeruginosa, and A. tumefaciens. The search results indicated the presence of three organisms carrying LuxI/LuxR pairs in the GI tract: Hafnia alvei, Edwardsiella tarda, and Ralstonia sp. strain 5_7_47FAA (Table 2). Salmonella is known to detect the acyl-HSLs produced by H. alvei in vitro (24). Serratia odorifera DSM 4582 also encodes a LuxI/LuxR pair but was detected only in the airways (Table 2). However, previous reports have isolated S. odorifera from wild boar gut and horse manure (49, 50). Other organisms, such as Citrobacter rodentium and P. aeruginosa, may also produce acyl-HSLs in the gut based on the presence of LuxI homologs in their genomes, although these organisms do not appear in the HMP metagenomic data. A mutant of C. rodentium lacking its luxI homolog, croI, is hypervirulent in mice during oral infection, suggesting that acyl-HSLs play a role in infection, although the site in which they are produced is not yet clear (51). It will be interesting to determine how frequently all six of these organisms are found within the mammalian GI tract and if they synthesize acyl-HSLs in that particular environment. We also searched for AinS and LuxM homologs, but none were found. It should be noted that homology searches will miss acyl-HSL synthase genes of previously undiscovered families. For instance, some marine bacteria produce acyl-HSLs but do not encode LuxI or LuxM homologs (52).

Table 1
Organisms encoding SdiA in the Human Microbiome Projecta
Table 2
Organisms encoding LuxI/LuxR pairs in the Human Microbiome Projecta

The HMP does not report the presence of Acinetobacter baumannii in stool samples, but A. baumannii was recently found within mouse intestinal crypts (53). A. baumannii uses a LuxI homolog, AbaI, to produce 3-hydroxy-C12 (and other related molecules in lesser amounts) (54, 55). It is not known if the specific strains of A. baumannii found in mouse intestinal crypts have the ability to produce acyl-HSLs or if they actually produce acyl-HSLs in vivo. However, if this organism is producing acyl-HSLs in the crypts, further research is needed to determine why the Salmonella SdiA reporter system was not activated during the transit of Salmonella Typhimurium through mice. We recently used a cross-streak assay on Luria-Bertani agar at 37°C using a Salmonella biosensor (pJNS25 [25]) to test for an sdiA-dependent response to A. baumannii strain M2. The Salmonella SdiA reporter system did not respond to this strain of A. baumannii (M. C. Swearingen and B. M. M. Ahmer, unpublished data). It is somewhat surprising that SdiA did not respond to the A. baumannii acyl-HSL 3-OH-C12 because it does respond to 3-oxo-C12 at a concentration of 60 nM (39). SdiA responds to hydroxy variants with roughly 10-fold-less sensitivity than oxo variants, so while 3-OH-C12 has not yet been tested, one can surmise that it may be detected at a concentration of roughly 600 nM (39). More work is needed to determine the detection limit of Salmonella SdiA with regard to synthetic 3-OH-C12 and the concentrations of acyl-HSLs produced by A. baumannii in the gut and in culture.

Screening metagenomic libraries for their ability to activate a biosensor strain has been used successfully to identify three luxI homologs from activated sludge and soil (56). This approach was also used to identify signal synthases in a metagenomic library of the gypsy moth gut, revealing a monooxygenase that produces an acyl-HSL mimic compound (57). Theoretically, this type of approach may be used to identify acyl-HSL synthases among the mammalian intestinal microbiota, but to the best of our knowledge, this type of study has not been published.

THE POSSIBILITY OF DEGRADATION

Several factors, including pH and the presence of degradative enzymes, may affect the concentration of acyl-HSL in the intestine (58, 59). Acyl-HSLs are readily inactivated at alkaline pH, which may be relevant in the intestine (6062). The pH of most of the intestinal tract ranges from pH 5.7 to 6.7, but there is a mildly basic region of pH 7.4 in the terminal ileum (63). With regard to enzymatic degradation, numerous enzymatic activities that act on acyl-HSLs have been discovered. These include acylases, oxidoreductases, and lactonases (52, 6471). BLAST analysis of the gastrointestinal HMP reference genomes with the lactonase AhlK reveals one homolog in a Klebsiella species (Table 3). The same search with the acylase PvdQ reveals homologs in a Ralstonia species and in Bacteroides dorei (Table 3). A search with the short-chain hydrogenase/reductase BpiB09 reveals over 200 homologs (not shown). However, the primary function of this enzyme appears to be fatty acid metabolism, and homology does not guarantee acyl-HSL-modifying activity.

Table 3
Organisms encoding quorum-quenching enzymes in the Human Microbiome Projecta

The human genome also encodes acyl-HSL-degrading enzymes. The paraoxonases are a family of aryl-esterases that can cleave lactone rings, although it is probably not their primary function. Human paraoxonase 1 (PON1) and PON3 are derived from the liver and kidneys and circulate in the blood. PON2 has been reported to have the strongest acyl-HSL-inactivating effect and is widely distributed throughout many tissue types, including the colon and small intestine (7275). An acylase that can degrade acyl-HSL has been isolated from porcine kidney, so this type of activity may be present in humans as well (76). Thus, if acyl-HSLs are produced by the normal microbiota, it is possible that the host or other microbes degrade them. The kinetics of acyl-HSL degradation in various tissues needs further investigation.

NEW HSL VARIANTS

To date, there has been no direct detection of acyl-HSLs within the normal mammalian intestinal tract, yet there are caveats to all of the negative results. It is possible that the LuxR-type biosensors used were not compatible with or sensitive to the concentration of acyl-HSLs found in the intestine. The chemical extraction reports used LuxR and TraR reporters, and the Salmonella in vivo reporter system used SdiA (33, 34, 38). While SdiA, LuxR, and TraR can detect acyl-HSLs at concentrations as low as 1 nM, Bradyrhizobium japonicum has a LuxR homolog, BjaR, that can detect a novel branched-chain isovaleryl-HSL at concentrations as low as 10 pM (9). If the concentrations of isovaleryl-HSL that are found in nature are lower than 1 nM, it is unlikely that any of the standard LuxR-type reporter systems could detect them. Even if the environmental concentrations are much higher, the standard LuxR-type reporter systems may not be able to detect the unique branched acyl chain.

Similarly, a family of aryl-HSLs that have aromatic side chains (rather than acyl chain tails) was reported in the alphaproteobacteria, specifically in Rhodopseudomonas and Bradyrhizobium (10, 77). Related members of the Rhizobiales have been identified within the human intestine (78), but it has not been determined if these organisms produce aryl-HSLs in the intestinal environment. It is not known if the SdiA, LuxR, or TraR biosensor system can detect aryl-HSLs. Thus, it is possible that aryl-HSLs are present in the intestine but were not detected in previous experiments (33, 45). It is even possible that the aryl-HSLs quenched the reporter systems since synthetic aryl-HSLs have been found to act as antagonists for Pseudomonas and Aeromonas quorum sensing (79).

Finally, it was recently discovered that a member of the Archaea, Methanosaeta harundinacea, produces a novel type of acyl-HSL (11). The filI gene product produced a carboxylated 10- to 14-carbon acyl-HSL that was detectable by an Agrobacterium TraR biosensor. This particular methanogen was not isolated from the mammalian GI tract, but other archaea are abundant in the intestinal community. Further work is required to determine if the intestinal archaea also synthesize acyl-HSL signaling molecules.

CONCLUSIONS

LuxI homologs are present in the insect gut (8082). Turtles are frequently colonized by Aeromonas hydrophila, which produces acyl-HSLs (45), and biosensors have detected acyl-HSLs in chemical extracts of goat and cow rumens (3437). However, chemical extractions and a Salmonella SdiA reporter both failed to detect acyl-HSLs (or other HSL variants) within mammalian intestines (33, 34, 38, 45). The Salmonella SdiA reporter was able to detect the acyl-HSL production of the pathogen Yersinia enterocolitica in mice (33). This leads to the hypothesis that the function of SdiA is to detect the acyl-HSL production of other pathogens rather than the normal microbiota. In addition to Y. enterocolitica, other microbes also have the potential to produce acyl-HSLs within the mammalian intestine (A. baumannii, C. rodentium, H. alvei, E. tarda, P. aeruginosa, S. odorifera, Ralstonia sp.), but this has not yet been confirmed. In response to acyl-HSL, Salmonella Typhimurium increases the expression of the invasin Rck and a putative type three secretion system (T3SS) effector of unknown function (29). The advantage that Salmonella would gain from detecting these other pathogens and activating these particular genes is not clear. Alternatively, it has been proposed that SdiA of enterohemorrhagic E. coli is used to detect the normal microbiota of the bovine rumen, where it increases the expression of acid resistance genes and represses the locus of enterocyte effacement (LEE) pathogenicity island (3436). SdiA then fails to detect acyl-HSLs in the bovine intestine, which allows derepression of the LEE pathogenicity island. The regulon of SdiA is very different in E. coli and Salmonella Typhimurium, suggesting different scenarios in which SdiA provides a benefit (29, 36). Interestingly, Klebsiella, Enterobacter, Citrobacter, and Cronobacter also encode SdiA orthologs (83). The SdiA regulon of Enterobacter cloacae is completely different from the regulons of E. coli and Salmonella Typhimurium, so it appears that the SdiA regulon has different functions in each genus (A. Sabag-Daigle and B. M. M. Ahmer, unpublished data).

Several new types of HSL signaling molecules have been discovered, and it is currently unknown which of the typical gammaproteobacterial LuxR-type biosensors can detect them or at what concentrations. Intestinal extracts need to be screened with reporter systems based on these new LuxR homologs. Additionally, mass spectrometry methods should be applied to these questions. Mass spectrometry might detect HSLs with higher sensitivity and without the detection biases inherent to biosensors (70, 84, 85). This would determine the concentration of each type of signaling molecule in different regions of mammalian intestines, which would allow predictions of which LuxR family members might be activated. Kinetic studies of signal molecule synthesis and decay in the intestine and other body sites can also be addressed with these methods.

ACKNOWLEDGMENTS

We thank Benjamin Daigle for critical review of the manuscript, Phil Rather for A. baumannii strains, and Young-Mo Kim, Thomas Metz, and Joshua Adkins for helpful discussions.

The project was supported by awards R01AI073971 and R01AI097116 from the National Institute of Allergy and Infectious Diseases.

Biographies

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Matt Swearingen obtained a B.S. in biology at Bethany College in Bethany, WV. At Bethany, he completed a research project investigating circadian rhythms in tooth pain sensitivity for which he received two consecutive scholarship awards from the West Virginia NASA Space Grant Consortium. Matt also received four years of academic scholarships and was a member of the Tri-Beta biological honor society. He graduated with honors in 2007. Matt is currently a doctoral candidate at The Ohio State University in the Department of Microbiology in the Ahmer laboratory and has spent four years investigating Salmonella quorum sensing in vivo. Matt is a member of the Center for Microbial Interface Biology and served as the student representative to the Microbiology Department admissions committee. Matt plans to graduate in the spring of 2013 and looks to continue research in bacterial quorum sensing.

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Anice Sabag-Daigle obtained a B.A. in microbiology from Ohio Wesleyan University, where she was involved in an independent research project sequencing the ancient DNA of an American mastodon. In 2009, Anice received her Ph.D. in microbiology at The Ohio State University under the guidance of Dr. Charles J. Daniels. Her doctoral research focused on the transcriptional response of a halophilic archaeon to nitrogen availability and the regulation of histidine catabolism. Anice is currently a postdoctoral researcher in the Ahmer group and is studying Salmonella quorum sensing and the regulation of virulence factors in vivo.

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Brian Ahmer obtained a B.S. in microbiology at Colorado State University in 1990. In 1994, he received his Ph.D. in genetics and cell biology from Washington State University, where he researched E. coli iron acquisition. His postdoctoral research focused on Salmonella pathogenesis in the lab of Dr. Fred Heffron at Oregon Health Sciences University. In 1999, he moved to The Ohio State University, where he is currently an Associate Professor in the Department of Microbiology and the Department of Microbial Infection and Immunity. His main research interests are the interactions of Salmonella with its hosts and other microbes, with the overarching goal being the reduction of infectious disease burden through the identification of effective therapeutic and preventative measures.

Footnotes

Published ahead of print 9 November 2012

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