Quorum sensing-related activities of beneficial and pathogenic bacteria have important implications for plant and human health

Abstract Eukaryotic organisms coevolved with microbes from the environment forming holobiotic meta-genomic units. Members of host-associated microbiomes have commensalic, beneficial/symbiotic, or pathogenic phenotypes. More than 100 years ago, Lorenz Hiltner, pioneer of soil microbiology, introduced the term ‘Rhizosphere’ to characterize the observation that a high density of saprophytic, beneficial, and pathogenic microbes are attracted by root exudates. The balance between these types of microbes decide about the health of the host. Nowadays we know, that for the interaction of microbes with all eukaryotic hosts similar principles and processes of cooperative and competitive functions are in action. Small diffusible molecules like (phyto)hormones, volatiles and quorum sensing signals are examples for mediators of interspecies and cross-kingdom interactions. Quorum sensing of bacteria is mediated by different autoinducible metabolites in a density-dependent manner. In this perspective publication, the role of QS-related activities for the health of hosts will be discussed focussing mostly on N-acyl-homoserine lactones (AHL). It is also considered that in some cases very close phylogenetic relations exist between plant beneficial and opportunistic human pathogenic bacteria. Based on a genome and system-targeted new understanding, sociomicrobiological solutions are possible for the biocontrol of diseases and the health improvement of eukaryotic hosts.


Introduction
As result of the evolution of life on Earth, all higher organisms are living as holobiots characterized by tight interaction with a div ersity of micr obes .T he hologenome concept considers holobionts as units of coevolution and selection of well-adapted proand eukaryotic organisms leading to constructive co-operations (Stencel et al. 2018 ).In the evolution of land plants, soil microbes found roots as most attractive interaction area.More than 100 years ago, the term 'Rhizosphere' was defined by Professor Lorenz Hiltner as the plant root-dominated habitat where soil microbes live on the expense of low and high molecular weight root exudates (Hiltner 1904, Hartmann et al. 2008 ).Symbiotic and plantbeneficial inter actions e volv ed in specific bacteria and fungi contributing to major needs of the plant, such as the supply with essential nutrients like nitrogen from the air and macro-and micr onutrients fr om the soil.Nitr ogen-fixing bacteria or mycorrhizal fungi ar e pr ominent examples for plant-symbiotic micr obes.As alr eady Lor enz Hiltner r ecognized, not onl y sa pr ophytic and beneficial but also pathogenic microbes are attracted by root exudates, causing chances and challenges for plant health (Mendes et al. 2013, Abedini et al. 2021 ).Most r ecentl y, rhizospher e pha ge comm unities wer e identified to suppr ess bacterial plant disease (Yang et al. 2023 ).Mec hanisms hav e been identified by which plants can form the rhizosphere microbiome in a kind of 'rhizosphere school' to support healthy plant development (Berendsen et al. 2012 ).Biofilms are the natural habitats for microbes, and therefor e cooper ativ e and competitiv e inter actions within complex surface microbial biofilms are of k e y importance during root colonization (Nadell et al. 2016 ).These interactions decide about success or failure of beneficial microbes to support plant health or of pathogens to de v elop diseases.In the densely populated biofilms of the rhizosphere, bacteria optimize the expression of their genetic potential using diffusible signal molecules to sense the density of their own and neighbouring population (Fuqua et al. 1994 ).
Quorum sensing (QS) is of central importance for successful adaptation to changing environmental conditions and colonization of and e v entual establishment within an eucaryotic host (Mukherjee and Bassler 2019 ).The rhizosphere also provides a stage for multiple avenues of natural genetic engineering, involving horizontal gene transfer (Van Elsas et al. 2003 ), transduction of genetic elements with plasmids (Shintani et al. 2020 ), enhanced mutation rates, and phenotypic variations (Achouak et al. 2004, van de Broek et al. 2005, Li et al. 2012, Lalaouna et al 2011 ).For example, man y bacteria acquir ed m ultiple luxI-and/or luxR-QS gene homologues from independent sources via horizontal gene transfer (Ler at and Mor an 2004 ).QS activities ar e pr e v alent in commensalic , beneficial/symbiotic , and pathogenic plant-associated bacteria (von Bodman et al. 2003 ).
The first evidence for the involvement of QS-signals and their per ceptions b y plant hosts w er e r e v ealed by Mathesius et al. ( 2003 ) anal ysing the r esponse to AHL-QS-signals by Medicago truncatula and by Schuhegger et al. ( 2006 ) studying induction of pathogen r esistance after AHL-a pplication to r oots of tomato plants.Furthermor e, QS-r elated genes were identified in the endosphere bacterial metagenome of rice by Sessitsch et al. ( 2012 ) and in the bacterial microbiome of Populus deltoides (Schaefer et al. 2013 ).In addition, bacteria harbouring QS-genes wer e fr equentl y isolated fr om the rhizospher e and endospher e of plants .T he ability to communicate with each other and to trigger essential functions in a timely and optimized manner is an important feature for single cell organisms to efficiently use their genetic potential as an or ganized comm unity (Hense et al. 2007 ).Among the QS systems, N-acyl-homoserine lactone (AHL, AI-1) circuits are present in man y Gr am-negativ e bacteria (Fuqua et al. 1994 ).AHLs are small diffusable molecules having differ ent structur es consisting of a fatty acid moiety with differ ent c hain length (4-20), and lhomoserine lactone (Fig. 1 ).The fatty acid chain can be modified at the C3-position with a hydroxy-or oxogroup or replaced by a p -coumar oyl-or cinnamon-r esidue (Sc haefer et al. 2008, Ahlgr ee et al. 2011 ).AHL-biosynthesis and perception occurs through a two-component LuxI/LuxR system.The LuxI-enzyme catalyses the binding of acylcarrier protein-bound S -adenosylmethionine to the acyl chains resulting in AHLs .T he LuxR-receptor binds AHLs and the LuxR-AHL-complex finally activates diverse promotors, including the LuxI-promotor.The special feature of QSsignalling is that small and diffusible molecules are constitutively pr oduced in v ery low amounts.When AHL-concentr ations rise in more dense populations above a critical concentration, called quorum, its biosynthesis is autoinduced.At high signal concentrations, a set of genes (the QS-activated transcriptomes) is induced by the LuxR-AHL complex.This opens up new areas of functions essential, e.g. for efficient colonization of a new host.QS-controlled genes often code for the construction of biofilms, hydr ol ysis and degr adation of nutritional carbon pol ymers and substances, the induction of virulence, and the synthesis of div erse sider ophor es and antibiotics (Hense and Schuster 2015 ).The so-called autoinducer-2 (AI-2), furanosyl borate diester, are produced by some Gr am-negativ e and Gr am-positiv e bacteria (P apenfort and Bassler 2016 ) (Fig. 1 ).AI-2 is synthesized by the LuxSprotein, and specific AI-2 receptors (e.g.LuxPQ-receptor protein of Vibrio harveyi ).The lack of genomic evidence of AI-2 receptors in some bacteria may suggest a non-QS role for LuxS in these bacteria (Rezzonico and Duffy 2008 ).In Gr am-positiv e bacteria, like Streptococcus pneumoniae or Staphylococcus aureus , different autoinducing peptides (AI-P) are produced (Fig. 1 ), which activate e.g.virulence and toxin production during growth in biofilms in a density-dependent manner (Parsek and Gr eenber g 2005 ).Further QS-signal molecules are mentioned by Hartmann et al. ( 2021 ).Besides QS-signals, root-associated microbes produce a high diversity of signalling compounds, like volatiles (Schultz-Bohm et al. 2017, de Boer et al. 2019 ), and diverse plant hormones, which influence plant hosts in multiple ways (Gamalero et al. 2023 ).
Since microbes interact with all eukaryotes in holobiotic-type life forms, comparable signalling mechanisms and principles of cooperation and/or competition are present in all holobionts, which will be discussed in this perspective publication.Likewise, differ ent or gans of mammalian hosts, including human, like skin, oral cavity, lung, or gut ar e colonized with QS-activ e bacteria of various types, which have beneficial or pathogenic features (Whiteley et al. 2017 ).It also needs to be considered that in some cases very close phylogenetic relationships exist between plant beneficial and opportunistic human pathogenic bacteria (Berg et al. 2005, 2014, Abreo and Altier 2019, Faoro et al. 2019 ).In the tr anslation of potentiall y ther a peutic or supportiv e a ppr oac hes for sustainable a gricultur e or human health, the application of metabolites or pr obiotic micr obes with health-supporting signalling capabilities could be of central importance to better control pathogens and support health and well-being of eukaryotic hosts based on natural socio-microbiological mechanisms.

QS-AHL signalling: different AHL functions in plants, LuxR solo receptors, QQ activities, AHL uptake, and signal perception
Man y Gr am-negativ e pathogenic bacteria or ganize their virulence using the AHL-circuit to attack plants (Pollumaa et al. 2012 ), while symbiotic nitrogen-fixing rhizobia initiate and coordinate root colonization and nodule formation with a diversity of AHLautoinducers (González and Marketon 2003 ).The importance and wide distribution of QS-signals in bacteria-plant interaction provide the coevolutionary rational for the sensitive recognition and perception of AHLs by plants leading to an effective stimulation of the innate immune defence system also by beneficial rhizosphere bacteria initiating specific pathogen defence measures or impr oving abiotic str ess toler ance (Sc hik or a et al. 2016 ).The AHLbased priming of defence is an cost-efficient strategy to fight back pathogens (Shrestha et al. 2020 ).

LuxR-solo receptors
In addition to the cognate LuxI/LuxR-signal circuit, many Gramnegative bacteria harbour one or several so-called LuxR solos, whic h ar e not pair ed with a classical LuxI-type synthetase, and are thus unable to produce AHLs themselves (González and Venturi 2013 ).These luxR-solos play a pivotal role in intra-and interspecies, as well as interkingdom, comm unication.Differ ent classes of LuxR-solo systems can be distinguished, which perceive endogenous and exogenuos AHLs as well as non-AHLs signals (Bez et al. 2023 ).LuxR regulators are widely distributed bacterial helix-turn-helix transcription factors involved in QS-type mechanisms .T hey are also found in 50% of the genomes of Grampositive Actinobacteria for traits at environmental and medical le v els in connection with QS and virulence strategies (Santos et al. 2012 , Sarveswari andSolomon 2019 ).As example for non-AHL exogenous signals, host-specific signals of kiwifruit are per ceived b y PsaR2 LuxR solo in Pseudomonas syringae pv.actini-diae , aimed to induce virulence factors like biofilm formation, motility and endophytic colonization (Cellini et al. 2022 ).This subclass of LuxR solos is fr equentl y found in plant-associated bacteria, both beneficial/symbiotic or pathogenic bacteria responding to different plant signals (Patel et al. 2013 ).In some cases the signals are similar to AHLs; e.g.Br aR fr om the stemnodulating legume symbiont Bradyrhizobium japonicum responds to cinnamoyl-homoserine-HSL, derived from the plant metabolite cinnamon (Ahlgreen et al. 2011 ).RpaR from Rhodopseudomonas palustris binds to p -coumar oyl-HSL deriv ed fr om the exogenous pcoumar ate (Sc haefer et al. 2008 ).The LuxR-solo QscB receptor and the QscR regulon in the pathogen P. aeruginosa is different from the also present canonical LuxI/LuxR tandem and stimulates virulence activities through increased biosynthesis of the antibiotic phenazine (Fuqua et al. 1994 ).

QQ activities by AHL hydr olysis, o xidoreductase, and other quenching mechanisms
In the light of the centr al r ole of QS for virulence acquisition, the inhibition of QS, including quorum quenching (QQ) by cleaving and inactivating the QS-moieties or by inhibiting the QSautoinducer action is attracting high attention.Inhibitory mechanisms include blocking the QS-signal synthesis, inhibition of the autoinducer reception, and signal transport (summarized by Hartmann et al. 2021 ).A large number of especiall y Gr am-positiv e bacteria and e v en fungi, but also plant and mammalian hosts, harbour different types of AHL-quenching activities (Grandclément et al. 2016 ).AHL-signals can undergo different modes of degradation and inactivation in the rhizosphere.Chemical hydrolysis of AHLs occurs at neutral and alkalic pH-values but AHLs are stable at acid pH-values.Efficient enzymatic degradation occurs through AHL-lactonases and AHL-acylases/amidases.In addition, AHLoxido-r eductases wer e described (Chowdhary et al. 2007 ).Growth and QQ-activity of Rhodococcus erythropolis R138 was efficiently stimulated by the organic amendment of gammaheptalactone leading to efficient biocontrol of potato (Cirou et al. 2012 ).Also, a strong inhibition of the QS-regulated pathogen Pectobacterium atrosepticum w as sho wn b y gamma-lactone stimulated R. erythropolis resulting in efficient in planta biocontrol (Barbey et al. 2013 ).Furthermore , a no vel type of AHL-acylase of Ochrobactrum sp.A44 was demonstrated to quench the AHL-dependent virulence of P. carotovorum in planta (Czajkowski et al. 2011 ).In the context of cor al r eef disease-a case of high global importance-the a pplication of QS-antagonists to white band disease-infected Acropora cervicornis inhibited disease-causing bacteria and stopped coral reef disease de v elopment (Certner and Vollmer 2018 ).Most r ecentl y, a novel type IVA secretion system (T4ASS) effector was discovered in Lysobacter enzymogenes OH11 (Liao et al. 2023 ).This T4ASS is able to deliver a protein (Le1288) into P. fluorescens SPL4, which acts there as a AHL-synthase inhibitor.It was shown that this T4ASS-mechanism is working also to inhibit the human pathogen P. aeruginosa and the plant pathogen Ralstonia solanacearum (Liao et al. 2023 ).QS-r elated interv entiv e actions within host-associated micr obiomes ar e of high gener al r ele v ance also for the balance of beneficial and pathogenic bacteria in mammalian and human health (see below).In Arabidopsis thaliana and some other dicotyledonous plants, especially legumes, fatty acid amid hydrolases cleave AHLs by liberating the fatty acid tail and l -homoserine (HS;Palmer et al. 2014 ).Interestingly, l -HS is not only able to stim ulate r oot gr owth but also impr ov e water and nutrient uptake into the plant (Palmer et al. 2014 ).It was e v en found that AHL-producing rhizobacteria, like Pseudomonas putida IsoF, itself  (Sieper et al. 2014 ) to the shoot, if AHLs are not degraded by plant lactonases.In the roots, hyperpolarization and K + -uptake occurs and growth and later al r oot formation is incr eased (von Rad et al. 2008, Liu et al. 2012, Rankl et al. 2016 ).In addition, abiotic and defence gene ar e activ ated in the shoots (Götz-Rösch et al. 2015 ).Lipophilic AHLs like C12-and C14-HSLs are perceived by a membrane protein (ALI1) (Shrestha et al. 2022 ).In the roots, NO is produced and a systemic signalling cascade to the shoots is activated including salicylic acid and oxylipin (cis-OPA/12-oxo-phytodienolic acid) leading to increased expression of MAP-kinases (MAKs) and defence-related transcription factors WRKY22 and 29 (Shrestha et al. 2019(Shrestha et al. , 2020 ) ).
harbour AHL-degrading activities, leading to reduced intra-and extr acellular AHL-concentr ations (F ekete et al. 2010 ).T he biosynthesis of C10-HSL in batch as well as contiuous cultures of P. putida IsoF and the simultaneous appearance of the cleavage product l -HS were quantified using high resolving UPLC-measurements and ELISA-technique (Chen et al. 2010, Buddrus-Schiemann et al. 2014 ).The ecological meaning of this activity could be to limit the AHL-production to a specific culture phase.Alternatively, it could provide plants in another growth phase with the stimulatory l -HS (Palmer et al. 2014 ).

AHL-uptake
Some plants, like wheat and barley, a ppar entl y lac k AHLdegrading enzymes and take up unhydrolyzed AHLs.Water soluble C6-C10 AHLs w ere sho wn to be taken up into the shoot via activ e tr ansport (Götz et al. 2007, Sieper et al. 2014 ).The transport inside the roots occurs in the central cylinder as w as sho wn b y autor adiogr a phy using 3 H-labelled C8-and C10-HSL; the transport was inhibited by ortho vanadate , demonstrating that ABCtr ansporters ar e involv ed.The identity of the transported AHLs in the shoots was pr ov en and quantified by AHL-specific monoclonal antibodies, de v eloped by Chen et al. ( 2010 ), and AHLsensor strains (Sieper et al. 2014 ).In contrast to Hordeum vulgare (cv Barke), the legume Pachyrhizum erosus (L.) did not take up AHL efficiently, as was shown by ultra-performance liquid c hr omatogr a phy (UPLC) and Fourier transform ion cyclotron resonance (FTICR)-mass spectrometry (Götz et al. 2007 ), due to AHLdegradation in the roots.Further detailed analysis via FTICR-MS and UPLC r e v ealed a metabolism to w ar ds C3-hydroxy-and C3-oxo-HSLs in the root compartment especially for C8-and C10-HSL, which may contribute to reduce the transport into the shoot (Götz-Rösch et al. 2015 ).In addition, a c hir al separation of d / l -forms by GC-MS demonstrated that barley selects the l -forms during activ e tr ansport (Götz et al. 2007, Sieper et al. 2014 ).

AHL perception as plant growth stimulans and priming agent for pathogen and abiotic stress tolerance
In barley, initial reactions occurs in root cells after treatment with 10 μM C6-, C8-, and C12-HSL (Rankl et al. 2016 ).Nitric oxide (NO) accumulates in the calyptra and root elongation zone and also the later al r oot formation is c hanged.In addition, incr eased K +uptake occurs in root cells, and membrane hyperpolarization is promoted in epidermal root cells especially by C8-HSL (Rankl et al. 2016 ).Upon application of C6-, C8-, and C10-HSL to the roots, the antio xidati ve and deto xifying ca pacities ar e incr eased in the shoots of barley (Fig. 2 ).As compared to control plants, the activity of dehydroascorbate reductase in barley shoots after C10-HSL treatment is greatly increased, whereas superoxide dismutase activity is slightly decreased after application of C6-HSL to the root system (Götz-Rösch et al. 2015 ).In contrast, the response of antio xidati v e enzymes in leav es of y am beans w as lo w probably due to reduced uptake of AHLs.In addition, the response of cytosolic glutathion-S-tr ansfer ase (GST) isoforms in r oots and leaves to AHLs were increased or decreased dependent on the isoform tested in root or shoot compartments in comparison with yam bean (Götz-Rösch et al. 2015 ).In the light of the observed responses of antioxidant and detoxifying plant activities to w ar ds AHLs , these QS-signals ma y be r egarded as str engthening a gents or plant antistress boosters.
The molecular structure of AHL-autoinducers determines the mode of action to w ar ds plant gro wth stimulation or priming of pathogen resistance (Fig. 2 ).For example in barley and wheat, whic h ar e de void of AHL-lactonases and -hydr olases, watersoluble AHLs are taken up into the shoots by an energy-dependent transport leading to enzymatic changes in leaves (Sieper et al. 2014, Götz-Rösch et al. 2015 ).Water-soluble C4-, C6-, and C8 HSLs were also shown to change the phytohormone balance of A. thaliana seedlings, modifying root/shoot growth and metabolism (von Rad et al. 2008 ).When these AHLs were added to roots (at 10 μM concentration) a multitude of genes, mostly connected with phytohormone r egulation, wer e ne wl y induced in r oots and shoots, while others were repressed (von Rad et al. 2008 ).A special role in this stimulation with C6-and C8-AHLs was identified for the GCR1/GPA1 genes in A. thaliana (Liu et al. 2012 ).While r oot gr owth of GCR1-m utants failed to be stim ulated by C6-and C8-HSL, ov er expr essing m utants sho w ed incr eased gr owth r esponses.In ad dition, calmodulin rece ptors w ere inv olved in primary root elongation, caused by 3-oxo-C6 HSL (Zhao et al. 2015 ).Furthermore , AtMYB44 was in volved in enhanced elongation of the primary root by increasing cell divisions in the root meristem and enhanced cell elongation in the elongation zone (Zhao et al. 2016 ); this was accompanied by altering the cytokinin and auxin metabolism in roots.In Arabidopsis and wheat, 3-oxo-C6 HSL was able to enhance salt tolerant growth (Zhao et al. 2020 ).In 3-oxo-C6-tr eated salt-str essed plants, the content of c hlor ophyll as well as the osmolyte proline was increased and the content of malonedialdehyde and the Na + /K + -r atio wer e decr eased (Zhao et al. 2020 ).
AHLs with long aliphatic chains (C12-and C14-HSL), which cannot be transported into the shoot, are also able to modify plants by conferring systemic resistance towards biotrophic and hemibiotrophic pathogens via altered activation of AtMPK6 (Sc hik or a et al. 2011a ).In barley, this response was only present in certain cultivars and therefore has to be regarded as a genetically determined pr operty (Shesthr a et al. 2019 ).In Arabidopsis , as early response specific receptors could be involved to perceive the AHLsignal and to activate a signalling cascade including salicylic acid (SA) and oxylipin 12-oxo-phytodienolic acid (cis-OPDA) (Schenk and Sc hik or a 2015 ; Shr estha et al. 2020 ) (Fig. 2 ).In the presence of fla gellin-deriv ed peptide flg22 and C12-HSL, MAP-kinases MPK3, and MPK6 are increasingly stimulated and expressed for a prolonged time along with the upregulation of defence-related transcription factors WRKY22 and WRKY29 (Shrestha et al. 2019 ) (Fig. 2 ).Also, glutathione-S-tr ansfer ase GST6 -gene and the heat shoc k pr otein Hsp60 ar e induced.In Arabidosis exposed to mixtures of 3-o xo-C6-, 3-o xo-C8-, 3-o xo-C12-, and 3-o xo-C14-HSLs the response differ as compared to plants treated with single AHLs and jasmonates play an important role (Duan et al. 2023 ).The fast and stable decreased concentration of COOH-JA-Ile after challenge with flg22 as well as the JA-and SA-affected Arabidopsis m utants str engthened the conclusion that JA-homoeostasis is involved in AHL-priming (Duan et al. 2023 ).Ho w e v er, a deeper understanding of specific plant factors mediating the response to water-insoluble AHLs, like 3-oxo-C14-HSL, was missing.Most r ecentl y, the comparison of wild-type A. thaliana Col-0 and the o xo-C14-HSL insensiti v e m utant ali1 allo w ed deeper insights.In Arabidopsis , the gene AtGlcAk2 for glucuronokinase 2 is identical with ali1 (Shrestha et al. 2022 ) (Fig. 2 ).Zhao et al. ( 2013 ) had described this gene already as a putative kinase from the GHMP kinase family being involved in root and flo w er development, abscisic acid signalling, and str ess r esponse influencing the expression of various ABA-related genes as well as salt stress.MAPkinase activity measurements, gene expression, and transcriptome analyses as well as pathogenicity assays confirmed a loss of AHL-priming in AtGlcAK2/Ali1 mutants (Shrestha et al. 2022 ).Furthermor e, when fluor escentl y ta gged ALI1-pr otein was expr essed in tobacco lea ves , ALI1 colocalized with the plasma membrane, tonoplast, and endoplasmic reticulum in the cell periphery.T hus , the ALI1-protein may be regarded as surface receptor for 3-oxo-C14-HSL and other water-insoluble AHLs .T his no vel insights ma y further impr ov e the de v elopment of str ess r esistance of plants, useful for sustainable crop management (Shrestha et al. 2022 ).
Tr ansgenicall y modified plants with introduced QSautoinducer synthesis genes are able to communicate with bacteria in the rhizosphere by altering their QS-controlled activities (Fray et al. 1999 ).For example, tomato plants harbouring the AHL-biosynthesis genes yenI and lasI from Burkholderia graminis str ains alter ed the activity of these str ains in the rhizospher e, leading either to increased or decreased plant growth stimulation or resistance to w ar ds salt stress (Barriuso et al. 2008 ).

QS-/AHL-systems in plant growth promoting and pathogenic bacteria
It has become a ppar ent that within bacterial gener a, whic h ar e known for efficient rhizosphere and endophytic root colonization, plant beneficial, symbiotic, and e v en opportunistic human pathogenic bacteria are closely related.Several examples are presented below, which demonstrate that plant beneficial bacteria with probiotic potential exist in the same species with opportunistic pathogens .T her efor e, the need for car eful e v aluation of possible health risks for applications of these bacteria in agricultural or for biotechnological purposes is necessary, if the separation from pathogens are not approved by clear phylogenetic criteria.
A high diversity of AHL-producing, plant beneficial Gramnegativ e bacteria ar e no w kno wn since se v er al decades to support growth of many crop plants under challenging abiotic and biotic conditions.Gluconacetobacter diazotrophicus PAL5 is an endophytic diazotrophic Gram-negative bacterium, first isolated in 1988 from inside sugar cane stems (Cavalcante and Döbereiner 1988 ).It can colonize numerous other plant species and confers se v er al beneficial effects including abiotic and biotic stress tolerance and improved plant growth.In addition to the biological nitrogen-fixation activity and the production of se v er al plant hormones, it was shown to harbour an active AHL-QS regulatory system (Bertini et al. 2014 ) producing eight different QS-signals based on C6-, C8-, C10-, C12-, and C14-HSL (Nieto-Penalver et al. 2012 ).When G. diazotrophicus PAL5 was inoculated to red rice plants growing under water stress conditions, the expression of the LuxI -gene was str ongl y stim ulated at incr easing water deficit conditions .T he transcription of the PR1-and PR10-genes along with se v er al antistr ess defence genes incr eased, like catalase and super oxide dism utase as well as ascorbate per oxidase (Filgueir as et al. 2020 ).The induced systemic tolerance to water deficit was accompanied by the accumulation of osmoprotectant solutes and the expression of defence genes against water deficit in plant shoots .Furthermore , mutations in the LuxI/R system of PAL5 resulted in strong reduction in endophytic root colonization of sugar cane seedlings (Hartmann et al. 2019 ).
Almost 50 years a go, diazotr ophic bacteria species of the genus Azospirillum ( A. lipoferum and A. brasilense ) were isolated and characterized by the group of Johanna Döbereiner in Brazil (Döbereiner and Day 1976 ).No w adays, at least 15 different species, mostly of root-associated plant growth-promoting bacteria are officially described within this genus, demonstrating the ric h div ersity of this efficient rhizosphere bacterium.Phytohormone interactions, based on indole acetic acid (IAA) production and other phytohormones by these bacteria, are prevalent for successful interaction with di verse plants, lik e wheat, maize, sorghum, causing multiple plant growth-stimulating effects.Although, LuxI -genes and the productions of AHLs were only found in some strains of A. lipoferum (Vial et al. 2006 ), the addition of C6-and C8-AHLs could stimulate biofilm formation, EPS-production and mobility in strain A. brasilense Ab-V5, a successfully applied A. brasilense inoculant strain (Fukami et al. 2018 ).It turned out that many Azospirillum spp.strains harbour multiple copies of luxR , so-called LuxR-solo or orphans (Gualpa et al. 2019 ).This had been documented for other rhizosphere bacteria too (Patel et al. 2013 ).The most r ecentl y c har acterized diazotr ophic plant gr owth pr omoting Azospirillum bacterium, A. argentinense type strain Az39 (formerly A. brasilense ), was isolated from roots of wheat plants in Argentina (Dos Santos Ferreira et al. 2022 ).It is a plant growthpr omoting rhizobacterium, pr oducing IAA besides other phytohormones and harbours se v er al other plant growth-supporting pr operties including nitr ogen fixation (Cassán and Diaz-Zorita 2016 ).Sur prisingl y it hydr ol yses AHLs, liber ating l -HS (Gualpa et al. 2019 ).Together with the phytohormone-based interaction, the AHL-degradation activity of Az39 may contribute to its strong plant gr owth-pr omotion activity, since l -HS has a plant stim ulating ability itslef (Palmer et al. 2014 ).Interestingly, A. argentinense Az39 like other strains from the A. brasilense cluster (including A. baldaniorum Sp245) harbours up to 25 LuxR-proteins (harbouring LuxR -solo-sequences) providing receptors for AHLs or related QS-signals from other bacteria or even possibly AHLunr elated signals fr om the plant for y et unkno wn interactions.It is a very efficient bioinoculant for gramineae crops in Argentina (Cassán and Diaz-Zorita 2016 ).The former species Azospirillum amazonense Y1, renamed to Nitrospirillum amazonense , carries a canonical LuxI/R -QS system and has ther efor e m ultiple ways of beneficial interactions with plant hosts based on AHL-signalling.Nitrospirillum amazonense strain Y1 is currently used as successful commercial inoculant in sugar cane plantations.Pr esumabl y opportunistic human pathogenic bacterial isolates, Roseomonas fauriae and Roseomonas genomospecies 6, were reported (Cohen et al. 2004 ), whic h ar e phylogeneticall y v ery closel y r elated to A. brasilense Sp7 T .Ho w e v er, DN A-DN A hybridization values of 61.2% and 54.2% place these Roseomonas isolates into a possibly new species within Azospirillum (Hartmann et al. 2019 ).
The genus Pseudomonas harbours a high number of species many of which are associated with diverse plants , ha ving different plant growth-promoting and protecting properties.For example, P. segetis P6 isolated from Salicornia europaea rhizosphere was c har acterized to harbour plant gr owth-pr omoting activity and QQ-mediated biocontrol (Rodriguez et al. 2020 ).Seed biopriming of tomato plants with strain P6 resulted in an increase in plant height and weight.Its QQ activity was c har acterized as an acylase .T hus , str ain P6 r educed soft r ot symptoms caused by the QS-bacteria Dickeya solani , Pectobacterium atropsepticum , and P. carotovorum on potato and carrot.The QQ-activities of P6 also protected tomato plants against P. syringae pv.tomato, which organizes its virulence through AHL-sensing.T hus , P. segetis P6 ma y ha v e biotec hnological a pplications.Pseudomonas putida IsoF, isolated from the rhizosphere of tomato, produces two AHLs, 3-o xo-C10, and 3-o xo-C12 fr om ppuI/ppuR circuit.Inter estingl y, the Ppu-system controls the expression of a large nonribosomal peptide synthetase, whic h dir ects the biosynthesis of tw o c yclic lipopeptide biosurfactants, putisolvin I and II.Putisolvins inhibit the biofilm formation and also break down existing P. aeruginosa biofilms (Cár camo-Oy ar ce et al. 2015 ).A br oad r ange of AHLs and other QS-active compounds are produced by Pseudomonas str ains , whic h ma y ha v e plant gr owth-pr omoting but also opportunistic human pathogenic potentials (Venturi 2006 ).For example, a dominant diazotrophic endophytic P. aerugionasa strain PM389 fr om P ennisetum glaucum (L.) was c har acterized by Gupta et al. ( 2013 ).This diazotrophic bacterium even moves upw ar ds to shoots, and r e v ealed v arious plant gr owth-pr omoting pr operties including mineral phosphate solubilization, siderophore production, and antagonistic biocontrol properties.Pseudomonas aerugi-nosa harbours two complete QS-circuits involving AHL signals and a third system using quinolones, which coordinate virulence acquisition and other behaviours (Miranda et al. 2022 ).The major AHL 3-oxo-C12-HSL regulates virulence gene expression and also induces mammalian cell responses, including apoptosis and immune modulation (see also below).
Rhizobium radiobacter F4 (syn.Agrobacterium tumefaciens ) was c har acterized as an endofungal bacterium of Piriformospora indica (no w kno wn as Serendipita indica ).Piriformospora indica is known as a plant gr owth-pr omoting, m ycorrhiza-lik e fungus, able to stimulate growth and performance of many plants especially under biotic and abiotic stress conditions (Varma et al. 2012 ).Like P. indica , the free-living bacterium increases plant biomass and enhances r esistance a gainst bacterial leaf pathogens and salt stress (Glaeser et al. 2016 ).Most inter estingl y, R. radiobacter F4 (RrF4) shows a high degree of similarity to the plant pathogenic R. radiobacter C58, formerl y named A. tumef aciens C58.Ho w e v er, it has important differences in the tumour-inducing plasmid (pTi) lacking the T-region (including the ipt -gene) and in the accessory plasmid, because the virH1 -gene is truncated (Glaeser et al. 2016 ).This documents, how a plant beneficial bacterium may hav e de v eloped fr om a plant pathogenic one.It could be shown that RrF4 produces a spectrum of QS-mediating AHLs with acyl-chains of C8, C10, and C12 as well as hydroxyl-or oxo-sustitutients at the C3-atom (Alabid et al. 2020 ), which is quite typical for Rhizobia.In R. radiobacter F4NM13, a lactonase-ov er expr essing tr ansconjugant of RfF4, the AHLs were missing and also the plant biomass stimulation as well as the systemic resistance was partially compromised in Arabidopsis and wheat.Furthermor e, the AHL-deficient tr ansconjugant was lac king cellulose-like fibre scaffolds for efficient root surface attachment.It could not penetrate into the intercellular spaces of the cortex, which is in contrast to the strongly root colonizing endofungal wildtype RrF4 (Alabid et al. 2020 ).T hus , AHLs contribute to the plant growth stimulation of Rrf4, which may play an important role in the P. indica symbiosis with a high diversity of crop and medicinal plants (Varma et al. 2012 ).
Acidovor ax r adicis N35 is an endoph ytic bacterium with plant gr owth-pr omoting activity in barley and wheat (Li et al. 2011 ); it was c har acterized to pr oduce onl y the QS-autoinducer C10-HSL.An araI mutant devoid of C10-HSL production lost the property to efficiently colonize roots of barley.Comparable transcriptome analysis of axenic uninoculated barley seedlings with N35 wild type strain or araI -mutant inoculated plants revealed that the mutant-inoculated barley plants accumulated several flavonoids (Han et al. 2016 ), which can efficiently inhibit root colonization.It may be concluded from this observation that AHL production of the A. radicis N35 wild type protect it from plant defence responses of fla vonoids .

Rela tionship betw een plant beneficial and human pathogenic bacteria
In the genus Burkholderia , harbouring saprophytic, beneficial, symbiotic , human pathogenic , or opportunistic pathogenic species, the assessment of the pathogenic potential of each species was for a long time the reason that regulatory authorities banned all envir onmental r elease pr oposals for an y Bur kholderia str ain.The application of whole genome-based comparative software tools together with the assessment of the human pathogenic potential made a clarification possible (Angus et al. 2014 ).Based on the complete genome sequence data, conserved sequence indels (CSI) wer e successfull y used as molecular marker for the precise identification of thr ee differ ent gener a within the Bur kholderia clus-ter: Burkholderia (sensu strictu) , with pathogenic and opportunistic pathogenic species, Paraburkholderia , comprising the plantassociated and -beneficial species (Sawana et al. 2014 ), and Caballeronia , with a group of 12 environmental species (Dobritsa and Samadpour 2016 ).Se v er al canonical QS-sensing systems mostly based on AHLs and/or also LuxR-solo genes are prevalent in almost all species in the Burkholderia cluster, which are the backbone to efficientl y or ganize either virulence or plant health supporting functions.
It is a matter of fact, that plant pathogens can cross the kingdom border and cause human diseases (as r e vie w ed b y Kim et al. 2020 ).In the other direction, some human pathogens, like Salmonella enterica typhim urium, ar e known to hav e affinity to colonize roots of diverse plants like barley, tomato, or Arabidopsis , being e v en able to colonize the plant hosts endophytically (Kutter et al. 2006, Sc hik or a et al. 2011b, Zarkani et al. 2019 ).T hus , ther e ar e common principles shared by a diversity of bacteria to colonize and enter plant roots as well as mammalian tissues.For example the genus Herbaspirillum harbours w ell-kno wn efficient plant gr owth-pr omoting nitr ogen-fixing rhizobacteria, but also clinical isolates in Herbaspirillum species 3 (Baldani et al. 1996 ).Strains belonging to H. seropedicae and H. frisingense (Kirchhof et al. 2001, Straub et al. 2013 ) were characterized as plant growth-promoting rhizobacteria, but they are also isolated from human skin wounds, sputum samples of cystis fibrosis patients, or other diseased human or gans (Faor o et al. 2019, Oliv eir a et al. 2021 ).Herbaspirillum frisingense Mb11, isolated from roots of the energy plant Pennisetum purpureum in Brasil produced AHLs, while the GSF30 T , deriv ed fr om Miscanthus spp. in Fr eising, German y, did not synthesize AHLs; both groups of strains efficiently colonized seedlings of Miscanthus and barley endophytically (Rothballer et al. 2008 ).Within H. hiltneri , isolated from surface disinfected wheat roots, which is phylogenetically apart from the H . seropedica / H . frisingense cluster (Rothballer et al. 2006 ), nosocomial strains were not yet found.A detailed genomic and proteomic study of clinical and environmental isolates of H. seropedicae revealed that clinical strains have lost the gene sets for biological nitrogen fixation ( nif ) and the type 3 secretion system (T3SS), which has been described to be essential for the interaction with plants.A different set of accessory genes and genomic islands could be found in the clinical strains, like genes related to lipopolysaccharide (LPS) biosynthesis and neuABC genes, responsible for the biosynthesis of sialic acid.The neuABC-linked LPS was able to increase the bacterial resilience in the mammalian host aiding in the esca pe fr om the imm une system (Faor a et al. 2019 ).In clinical and envir onmental isolates of H. frisingense , the genes in the core and accessory genomes wer e compar ed and numer ous unique clusters could be identified in clinical and rhizosphere strains.Some genomic islands wer e onl y found in clinical str ains, while others in all str ains.T hus , a pr eada ptation to differ ent hosts was concluded (Oliv eir a et al. 2021 ).
In the case of Serratia marcescens , harbouring a wide range of str ains fr om soil, water, and plant surfaces, also opportunistic human pathogens in hospitals and plant gr owth-pr omoting bacteria in crops are known.In a pangenome approach, based on available genomic data, whole genome multilocus sequence type sc hemes (MLSTs) wer e a pplied (Abr eo and Altier 2019 ).In most cases, genomes of nosocomial and environmental isolates could be assigned to proposed nosocomial or en vironmental MLSTs .A minority of nosocomial strains harboured environmental MLSTs, which suggest that these have been recently derived from the envir onment.One envir onmental clase had only low numbers of virulence and antibiotic resistance determinants and may r epr esent a group of prospective PGPR strains (Abreo and Altier 2019 ).In general, it is not entirely clear, whether so-called clinical or nosocomial strains are opportunistic pathogenic bacteria, which cause secondary infections only in imm uno-compr omised patients and thus worsen conditions in patients.It is a matter of fact that based on general phylogenetic terms, opportunistic pathogenic bacteria can be separated from commensalic and beneficial bacteria only with difficulty.Extensive experimental and genomic assessments of the pathogenic potential of each strain have to be conducted, to allow a case to case decision (Angus et al. 2014 ;Lee et al. 2014 ), if the strain should be used as inoculum for plants.A temperature optimum below 37 • C is another important criterium for an application in the field.An r eaddr essing of the biosafety le v el of some already used plant growth promoting rhizobacteria to biosafety le v el 2 pr ohibited the continuation of the application in agricultur e (K eswani et al. 2019 ).

Control of the ecological balance of health supporting and threatening bacteria in mammalian habitats
In comparison to the health situation in the rhizospher e, whic h is str ongl y influenced by the plant and the soil micr obiome (Hartmann et al. 2009, Sc hr eiter et al. 2014 ), the microbiological and metabolic quality of food has an important role for the establishment of a balanced structure and function as well as a healthy status of human microbiomes in habitats, such as the oral cavity and the gut.From the early life times as baby and infant, edible plant and other food microbiomes together with a nutritionally balanced food with low fat content and a healthy life style are a good basis for a sustainable health state (Berg et al. 2015, Wassermann et al. 2019, Soto-Giron et al. 2021 ).It was r ecentl y shown that a high diversity of potentially health supporting bacteria are associated with fresh fruits and vegetables harbouring functions for an ov er all healthy and balanced gut microbiome (Wicaksono et al. 2023 ).In general, a high diversity of human microbiomes is crucial for persistent health.High fat diet causes a clear shift in the gut micr obiome, r esulting in a decreased ratio of Bacillota/Actinomycetota (formerl y named: Firmicutes/Bacter oidetes) (Daniel et al. 2013, Walker et al. 2014 ) favouring a disbalanced gut microbiome.Specific sulfonolipids as metabolite markers and related bacterial Alistipes and Odoribacter species were found specific for this unhealthy situation in the gut of mice (Walker et al. 2017 ).

QS-signal production and degr ada tion in the oral cavity
The equilibrium of microbes is maintained through competitive and cooper ativ e inter actions.An imbalance of the r esident microbiota could be caused by changes in host-dependent habitat conditions or external factors like the quality of food.The development of major oral diseases is usually not dependent on a single oral pathogen, but on the entire microbial community and its activity in the oral cavity (Muras et al. 2020 ).For example, a reduction of bacterial coaggregation and biofilm formation during dental plaque formation is beneficial for oral and teeth health (Simón-Sor o and Mir a 2015 ).Ther efor e, QS activities, which positiv el y influence biofilm structur es, certainl y play a major role in caries and peridontal diseases.AI-Ps fr om Gr am-positiv e bacteria have been identified in different oral streptococci, and AI-2 were frequently found in different Gram-positive and Gramnegativ e or al pathogens like Streptococcus mutants or P orph yromonas gingivalis (Frias et al. 2001 ).Furthermore, different isolates of Enterobacter sp ., Pseudomonas sp ., and Burkholderia sp .from human tongue surface and dental plaque samples wer e c har acterized as AHL-producers (Goh et al. 2014 ).AHLs could also be detected in saliva and sputum samples indicating a possible role in the dental plaque formation (Goh et al 2014 ).In ad dition, QQ-acti vities were detected in many bacterial isolates from healthy and peridontal patients (Muras et al. 2020 ).These findings were corroborated by the demonstration that the addition of AHL-lactonase Aii20J had an inhibitory effect on the de v elopment of or al biofilms.Using confocal laser scanning microscopy, Aii20J inhibited in vitro mixed-species and also saliva biofilms (Muras et al. 2020 ).Apparentl y, not onl y AI-2 inhibitors but also AHL-lactonases or AHLquenching bacteria are QQ-strategies for the control of oral diseases.

QQ of bacterial virulence by food substances
Many dietary metabolites were demonstrated to interfere with bacterial virulence and inhibition of QS (Dingeo et al. 2020, Fala et al. 2022 ).For example, pyrogallol competes with bacterial QS signals for receptor binding, polyphenols and lignans sequester bacterial QS molecules, and the flavanon naringenin reduces the production of QS-controlled virulence in P. aeruginosa PAO1.Capsicum frutescens is a spicy chilli pepper, which is rich in bioactive compounds such as capsaicin and luteolin.Capsicum frutescens extract and pure luteolin-inhibited QS in the model bacterium Chromobacterium violaceum and biofilm formation in P. aeruginosa PAO1 (Riv er a et al. 2019 ).Apigenein and luteolin are compounds of Gnapalium h ypoleucum DC extracts sho wing also strong QS-inhibitory activity (Li et al. 2022 ).In the model bacterium C. violaceum ATCC 12472 vioB , vioC , and vioD genes were strongly downregulated by apigenin and luteolin.The effective treatment of bacterial infections b y G. h ypoleucum extracts could thus originate from QS inhibition by these natural compounds and provides a potential mechanism for alternative applications of medicinal plants (Li et al. 2022 ).It was demonstrated that secondary metabolites of medicinal plants, such as terpenoids , fla vonoids , and phenolic acids are antibacterial agents.In ad dition, the y exhibit n umerous anti-QS mechanisms via the inhibition of autoinducer releases, sequestration of QS-mediated molecules, and deregulation of QS gene expression (Bouy ahy a et al. 2022 ).
Microbes in fresh products such as salate or fruits can have a considerable health impact on the gut.Indeed, reconstructed metagenome-assembled genomes from 156 fruits and vegetables r e v ealed that the microbiomes of fresh fruit and vegetables ar e r epr esented by members of Enter obacteriales, Burkholderiales, and Lactobacillales in the gut microbiome.In these bacterial families diverse QS-signalling activities, but also QQ and quoruminhibiting microbes and metabolites are represented (Wicaksono et al. 2023 ).

QS-related microbe-host interactions in the gut
Functional QS-systems are found not only in pathogenic but also in commensalic gut residents or probiotic bacteria (Fujii et al. 2008 ).In a healthy situation, gut microbiota mutually interacts with coe volv ed gut epithelial and immune cells in a beneficial r ecipr ocal way (Coquant et al. 2020 ).QS-signalling of bacteria was shown to have important roles in beneficial bacteria intestinal cross-talk and contribute substantially to establish cross-kingdom symbiotic interactions (Wu and Luo 2021 ).In the d ysbiosis state, lik e inflammatory bo w el disease (IBD), microbeintestine interactions drive inflammatory responses .T he distribution of AHL-compounds detected in the feces of healthy and IBD-subjects correlated with the disease state (Landman et al. 2018 ).One of the AHL-compounds, 3-oxo-C12:2-HSL, was highly decreased in fecal samples of IBD patients as compared to remission and healthy persons .T hus , the absence of this particular AHL corr elated with dysbiosis.Concomitantl y, a decr eased le v el of Firmicutes whic h ar e indicativ e for normobiosis indicated dysbiosis.Furthermore, Landman et al. ( 2018 ) sho w ed that 3-oxo-C12:2-HSL exerts anti-inflammatory properties on intestinal model cell lines Caco-2/T17.Ther efor e, AHL-pr ofiles may be considered as noninv asiv e biomarkers for gut normobiosis.AI-2, whic h ar e pr oduced by opportunistic pathogenic bacteria, wer e successfull y demonstrated in vivo to modulate the gut microbiome and cause inflammation (Thompson et al. 2015 ).ON the other hand, it was demonstrated that mammalian epithelial cells in the gut produce an AI-2 mimicking molecule in response to secreted bacterial factors and tight-junction disruption, whic h activ ate QS in bacteria.This was detected by bacterial AI-2 receptors LuxP/LsrB, and by the activation of QS-controlled gene expression of S. typhimurium (Ismail et al. 2016 ).T hus , members of the gut microbiome could be activated to colonize damaged sites and to repair epithelial tight junctions.In mammalian systems the QS-autoinducer 3-oxo-C12-HSL and similar long acylcarbon-chain AHLs produced by Pseudomonas and Bur kholderia spp.ar e important signalling compounds involved in serious diseases, like COPD.QS-autoinducers are of central importance to coordinate , e .g. biofilm formation and virulence development (Whiteley et al. 2017 ).While Gram-negative bacteria are known for diverse AHL-production, Gram-positive bacteria, mainly Bacillota and Antinomycetota, are strong players in anti-AHL-QS-quenc hing systems, possibl y acquir ed by horizontal gene transfer (Rajput and Kumar 2017 ).QQ-activities of probiotic bacteria w ere sho wn to influence the micr obial comm unity in the gut as well as immune functions in pigs (Kim et al. 2018 ).Antagonists of QS-systems of se v er e pathogens ar e of gr eat importance, because mec hanisms tar geting QS hav e onl y minor c hallenge on bacterial cell viability and thus the selection for antibiotic resistant pathogens should be pr e v ented (Zhong and He 2021 ).In addition, nov el scr eening str ategies wer e de v eloped for QS-inhibitors to combat bacterial infections (Lu et al. 2022 ).
QS-signalling can organize competing strategies to neighbouring microbes.For example Gram-positive Propionibacteria, like Propionibacterium freudenreic hii , hav e pr omising pr obiotic pr operties (Rabah et al. 2017, Savijoki et al. 2023 ).Pr ogr ess in defining such metabolic interactions by in situ screening test was made possible by using biofilm-forming C. violaceum as a QS-reporter and a microscale screening platform.In this way, anti-QS effects of Lactobacillus acidophilus , Lacticaseinbacíllus rhamnosus , P. freudenreichii , and other cheese-associated strains could be identified as potent competitors for virulent pathogens (Savijoki et al. 2023 ).

Mechanisms of signal perception
Similar to the plant innate immune system, pathogen-associated molecular patterns are recognized by highly sensitive and specific r ecognition r eceptors suc h as the toll-lik e rece ptors in mammals.In addition, the ada ptiv e imm une system with differ entiating dendritic cells (DC) and a guild of T-cells and macr opha ges ar e activ e in a coor dinated w ay building up the most efficient ada ptiv e imm une r esponse of mammals.Furthermor e, specific r eceptors ar e involv ed for bacterial sensing and perception by the mammalian/human system, including QS-associated molecules and activities (Holm and Vikstrom 2014 ).In this context, numerous LuxR-solo type orphan genes in the human genome may code for receptors responding to bacterial products, including QScompounds, but also for unrelated metabolites of the host or other members of complex holobiont in a still unkno wn w ay (Yong andZhong 2013 , Uhlig andHyland 2022 ).The production of short chain fatty acids (SCFA) produced by commensal bacteria and probiotics in the gastrointestinal tract (GT) contribute to a balanced situation by stimulating e.g. the bacteriocin production of pr obiotic Lactobacillus str ains, whic h contr ol the virulence status of pathogens (Meng et al. 2021 ).
G pr otein-coupled r eceptors (GPCRs) ar e potential tar gets facilitating bacteria-host interactions by microbial-derived molecules including QS-signals .T his w as sho wn for the stim ulation of r oot gro wth b y AHLs with C6-and C8-fatty acid chain lengths in A. thaliana (von Rad et al. 2008, Liu et al. 2012 ) (see above) In gener al, GPCRs ar e members of a fr equentl y found gene famil y in the plant and human genomes, some of whic h ar e involv ed in bacterial sensing (Kr asulov a and Illes 2021 ).Other non-GPCR tar gets were also described in sensing bacterial QS signals.
In mammalian systems, an uptake of 3-oxo-C12-HSL was shown in experimental human lung epithelial cells (Bryan et al. 2010 ).An micr oarr ay of tr anscriptional r esponses of lung epithelial cells after exposure to 3-oxo-C12-HSL revealed the expression of se v er al xenobiotic-sensing and drug tr ansport genes.Using r adiolabelled autoinducer uptake assa ys , incr eased intr acellular 3oxo-C12-HSL le v els wer e found after exposur e, whic h decr eased afterw ar ds to bac kgr ound le v els.Since this pr ocess was inhibited by the ABC transporter ABCA1, it was concluded that mammalian cells detect and take up 3-oxo-C12-HSL, but expel it later after activation of protective transport systems (Bryan et al. 2010 ).
AHLs wer e r ecognized as activ ators of the cytosolic arylhydr ocarbon r eceptors (AhRs), whic h r espond to plant pr oducts, xenobiotics , indole molecules , and SCFAs .AhR-activity is differ entl y r egulated by distinct QS molecules (Sun et al. 2020 ), which could constitute a crucial role of AhR in the regulation of host metabolism by pathogenic, commensal, and probiotic bacteria (Karlsson et al. 2012, Natividad et al. 2018 ).Inter estingl y, dtryptophan ( d -Trp) was identified as excreted metabolite of sever al pr obiotic bacteria, including L. rhamnosus GG, whic h may interact with the AhR-receptor (Kepert et al. 2017 ).d -Trp was shown to have stimulatory functions on developing DC-cells, to exert antialler gic r esponses, and to modify the gut micr obiome of mice (Kepert et al. 2017 ).In addition to known receptor-type sensors, the lipid composition of the cell membrane, and the expression of gl ycolipids and tr ansmembr ane pr oteins wer e r ecentl y suggested to modulate the perception of QS and other signals and their perception (Uhlig and Hyland 2022 ).
Bacteria defective in QS signalling are less efficient in colonizing the GT, which was found in commensal, probiotic, and pathogenic strains (Whiteley et al. 2017 ).For example, Streptococcus gallolyticus subsp.gallolyticus can only colonize the murine intestine when the QS-regulated bacteriocine-like peptides blpA and blpB are produced, since Blp-deficient mutants could not sustain in the intestine.LuxS-signalling of L. rhamnosus GG and Bifidobacterium breve UCC2003 is r equir ed for the adhesion to intestinal cells (Jiang et al. 2021 ) and persistence in the gastro-intestinal (GI) tract (Christiaen et al. 2014 ).

Interactions with the human immune system
Concerning responses of gut microbiota to host metabolites, Gr am-negativ e bacteria Esc heric hia coli , Shigella sp., and Salmonella sp.express QseC, a membrane-bound histidine sensor kinase that allows them to react to host-stress signals such as e pine phrine and nore pine phrine.Qsec inhibitors wer e de v eloped as antivirulence a ppr oac h a gainst Gr am-negativ e diseases (Rask o and Sperandio 2010 , Curtis and Russell 2014 ).This interkingdom activation is referred to the autoinducer-3 (AI-3) system leading to the activation of QS gene expression.QseC sensor kinase is involved in GI disease caused by E. coli pathogens in rabbits .T he habitat for direct interference of gut microbiota and human host are the inner mucus and the gut epithelial barrier.The structure of the intestinal mucus and epithelial barrier functions are greatly influenced by the host defence status and the QS-activity of the gut microbiome.While probiotics enhance barrier functions in vitro and in animal studies, QS-regulated virulence factors from pathogenic Citrobacterium difficile , E. coli , and S. typhimurium decr ease tr ansepithelial r esistance by modulation tight barrier junctions.In contrast, QS-associated acti vities, involving 3-o xo-C12 HSL, were found to negatively impact gut integrity through the activation of inflammatory pathways that impair intestinal barrier function (Adiliaghdam et al. 2019 ).AHLs, mostly 3-oxo-C12-HSL fr om P. aeruginosa , stim ulate inflammatory r esponses thr ough the inhibitory interaction with neutr ophils, macr opha ges, and DC, finall y causing a poptosis of those imm une cells .In this wa y, 3oxo-C12-HSL producing bacteria pathogens effectiv el y inhibits attempts oft he immune system to eliminate the a ggr essor (Coquant et al. 2020 ).When LPS-stim ulated human DC wer e exposed to 3oxo-C12-HSL, in vitro flow cell cytometric anal yses r e v ealed that important DC surface markers like CD80, CD40, CD184, and HLA-DR were diminished, while 3-oxo-C4-HSL had no effect (Binder T, PhD thesis LMU Munic h, 2010).Accordingl y, the inflammation inhibitory cytokine IL-10 was decreased and the inflammation stimulatory cytokine IL-8 was increased, leading to a severe damping effect on the immune response .Furthermore , the migration of DCcells after treatment with LPS and 3-oxo-C12-HSL was decreased as well as their phagocytotic activity.This causes se v er e health problems of cystic fibrosis patients infected with P. aeruginosa (Cohen et al. 2015 ). Figure 3 shows a schematic drawing of activities of the autoinducer 3-oxo-C12-HSL of P. aeruginosa to w ar ds the human innate and ada ptiv e imm une system.

Conclusions
Microbial health in the rhizosphere is interconnected with 'One Health', because the health of each of its components is determined by the omnipresence of microorganisms (Banerjee et al. 2023 ).Rhizospher e micr obiomes ar e tightl y linked to soil and plant microbiomes and their reservoirs for extr emel y div erse micr obioms also influence animal and human health (Hartmann et al. 2009, Sc hr eiter et al. 2014 ).In the rhizosphere, a ric h suppl y of substr ates leaking out of roots guarantees excellent conditions for microbial activities, which also provide the basis for efficient coevolution of environmental and plant microbes with each other in the context of the plant host as master.This includes natural genetic engineering using horizontal gene tr ansfer, plasmid tr ansduction, high m utation r ates, and phenotypic switching.In the efficient 'rhizosphere schools' of evolution the selection of adapted rhizosphere communities through changing the exudation pattern constantly occurs (Berendsen et al. 2012 ).Under these selective conditions QS-signalling-based micr obe-host inter actions to w ar ds beneficial/cooper ativ e as well as pathogenic/competitive relations have evolved.The knowledge about responses of plant and mammalian/human hosts to bacterial QS-signalling compounds and their pr oducers ar e consider able adv anced.A lar ge body of data about the interaction of pathogenic, symbiotic/beneficial, and commensalic bacteria accum ulated, whic h ar e involv ed in plant or human health (LaSarre and  this context, QS r esearc h pr ovides ne w perspectiv es to better understand the interaction between gut microbiota and the human host (Yang et al. 2022 ).This may provide an additional key to be able to a ppl y micr obiome science for plant and human health (Russ et al. 2023 ).No w ada ys , first experiences about the possibility of translation into practice with recognized specific 'thera peutic' micr obes and QS-r elated substances (Uhlig and Hyland 2022 ), QS-signals (Moshynets et al. 2019 ), and synthetic microbial communities (syn-coms) (Jiang et al. 2022, Schmitz et al. 2022 ) are a vailable .Apparently, an effective syn-com may harbour QS-activ e bacteria, whic h pr ovide the applied synthetic community a dynamic character to modulate the rhizosphere microbiome and stimulate the plant host to develop abiotic and biotic resistance properties (Andres- Barrao et al. 2017 ).Further pr ogr ess in r e v ealing the involv ement of QS-r egulation in plant as well as in human health is still dependent on further optimization of the sensitivity and specificity of QS-signal analytical a ppr oac hes (Mellini et al. 2024 ).Concerning the se v er e pr oblem of r a pid spr eading of c hr onic infections in humans because of the immense danger ous thr eat by m ultir esistant pathogens, the application of QS-affecting approaches, which target virulence acquisition processes of pathogens promised to avoid the selection of antibiotic resistances, because growth of pathogens is not dir ectl y tar geted.This could finall y lead to substantial human health impr ov ements in the contr ol of m ultir esistant pathogens when combined with other strategies (Zhong andHe 2021 , Naga et al. 2023 ).Ho w e v er, since QS-systems ar e important for bacterial fitness, QS-inhibition w ould unav oidingly affect the targeted pathogens and, may hence impose a selective pressure.Experimental evidences for this problem was published by Maeda et al. ( 2012 ) andImperi et al. ( 2019 ).T hus , strategies based on systemle v el ecologic principles of microbial social beha viour ma y contribute to successful personalized treatments of patients.Applications of QS-targeted treatments could allow important pr ogr ess to impr ov e sustainable a gricultur e and contribute to better contr ol de v astating diseases for plant and human health.

Figure 2 .
Figure2.AHL interactions with plants (example: Arabidopsis , barley): the perception of AHLs by plants can be divided into interactions with short-and long-carbonyl side chain AHLs.Water-soluble AHLs (like C6-to C10-HSLs) are transported in an active transport process through the central cylinder(Sieper et al. 2014 ) to the shoot, if AHLs are not degraded by plant lactonases.In the roots, hyperpolarization and K + -uptake occurs and growth and later al r oot formation is incr eased(von Rad et al. 2008, Liu et al. 2012, Rankl et al. 2016 ).In addition, abiotic and defence gene ar e activ ated in the shoots(Götz-Rösch et al. 2015 ).Lipophilic AHLs like C12-and C14-HSLs are perceived by a membrane protein (ALI1)(Shrestha et al. 2022 ).In the roots, NO is produced and a systemic signalling cascade to the shoots is activated including salicylic acid and oxylipin (cis-OPA/12-oxo-phytodienolic acid) leading to increased expression of MAP-kinases (MAKs) and defence-related transcription factors WRKY22 and 29(Shrestha et al. 2019(Shrestha et al. , 2020 ) ).

Figure 3 .
Figure 3. AHL-interactions with mammalian immune system (example: 3-oxo-C12-HSL of P. aeruginosa and lung) (Binder, PhD thesis, LMU Munich 2010 ): DC are influenced by 3-oxo-C12-HSL during their ripening process stimulated by lipopolysacharide (LPS), leading to diminished phagocytosis and reduced expression of surface mark ers, lik e CXCR4, MHC, CD83, and CD80.The CXCR4-marker is involved in the regulation of migration of DC to lymph nodes, while the reduction of other surface markers lead to the induction of cyclooxygenase (Cox-2) having a modulatory role in inflammation pr ocesses; pr osta glandines ar e incr eased supporting the Th2-r esponse in the l ymph node, whic h support a r educed ripening of DC-cells, meaning reduced inflammation response (Skindersoe et al. 2009 ).Downregulation of cytokines, like IL-12 and the anti-inflammatory cytokine IL-10, causes a T h1/T h2-imbalance in the infected host (Ritchie et al. 2005 ).