The AHL-dependent QS systems allow gut microbes to interact with one another. AHL QS regulates bacterial phenotypic traits, which directly impact the host cell metabolism [144]. Lactobacillus and other proteobacteria are found in abundance in the human small intestine. These microorganisms employ AHL, AI-2, and other QS signals to control population density and prevent the development of gut infections. P. aeruginosa is a notorious bacterium responsible for a wide variety of illnesses [145]. P. aeruginosa regulates the expression of virulence factor synthesis and biofilm formation through AHL-dependent QS [146]. Novel techniques targeting P. aeruginosa QS may aid in developing novel anti-infective medicines against MDR P. aeruginosa infections. In addition, QS signal molecules have shown their potential role in cancer therapy. The P. aeruginosa QS signal (3-OC12HSL) has been shown to suppress the growth of human breast cell lines by causing apoptosis in cancer cells [147]. AHL homologs of natural and synthetic QS molecules may protect against infection and cancer. AHL molecules have shown potent immunomodulatory activity against immune cells [148], and the conjugation of AHLs with carrier proteins has been explored as a novel conjugate vaccine development strategy against P. aeruginosa infection [149]. AHL molecule detection in urine samples has been used as a diagnostic strategy against P. aeruginosa-dependent urinary tract infection [150]. Beneficial microorganisms or genetically modified microbes with AHL QS may be shown to have clinically significant effects on disease and cancer therapy. Plant extracts (garlic [151], ginger [152], and cranberry [153]) have shown QS inhibitory potential. Phytochemical-based QS inhibition has shown promising results as novel anti-QS and anti-biofilm agents. Zingerone [146], the villain [154], and curcumin [155] have shown anti-virulence effects against P. aeruginosa via targeting AHL QS pathways.

The overproduction of QS signals by epiphytic bacteria may result in QS suppression in P. syringae [156]. This might potentially inhibit swarming motility and infection prevention in tobacco plants [157]. Therefore, genetically engineered epiphytic bacteria may be employed as plant disease protective agents [158]. AHL-degrading microorganisms have a crucial function in combating plant diseases. The application of M. testaceum (AHL-degrading bacterium) protects against the plant pathogen P. carotovorum [159]. Quorum-quenching enzymes, such as acylases [160] and lactonases [161], have shown protective efficacy as anti-QS agents. A significant limitation of using these enzymes in animals is the allergic reactions and immune response against the proteins; however, in plants, these can provide high efficacy and applicability. The genetic engineering of plant or microbe genomes with QQ enzymes can be applied to control the concentration of AHL molecules and the pathogenic bacteria’s virulence. Lactonase (Aiia enzyme)-producing transgenic plants may resist E. carotovora infection in tobacco, potato, and cauliflower plants [162]. M. tranculata and P. sativum can produce structurally similar AHL compounds that mimic the AHL signal and interfere with their QS signaling pathway [163].

Rhizobacteria employ AHL signals to regulate their growth and virulence. Plants can recognize AHLs at early stages of their expression [164]. Leguminous plant Medicago truncatula has been found to identify bacterial signal molecules. M. truncatula responded to 3-oxo-C14-HSL (Ensifer meliloti) and 3-oxo-C16-HSL (P. aeruginosa) [165]. The plant responded by inducing the genes associated with auxin-responsive and flavonoid biosynthesis pathways. Plants also expressed small signal molecules such as AHLs in response to bacterial AHLs disrupting the bacterial signaling system. The tomato plant, in response to C6- and C8-HSL-producing Serratia liquefaciens MG1 and P. putida, showed increased resistance against the fungal pathogen Alternaria alternata [166]. Bacteria induced the production of salicylic acid and ethylene-dependent defense genes (PR1a and chitinase). The protective effect was not detected with bacteria lacking the AHL signaling system. Verticillium dahlia-mediated wilt in Brassica napus was suppressed by rhizosphere bacterium S. plymuthica [167]. The effect was attributed to extracellular chitinase production mediated by AHL (C4-, C6-, and 3-oxo-C6-HSLs) and fungal inhibitory volatiles. Short-chain HSL molecules showed increased root length with variable phytohormones expressions in A. thaliana roots. Furthermore, the impact of long-chain AHLs (C14- and C12-HSL) significantly affects the biological control of the plant pathogen P. syringe in A. thaliana [168].

Biofouling the membrane filters by microbes limits the durability of the filtration system. This influences the membrane filtration performance and the destruction of the filters leading to the decreased performance and quality. Most biofilms are formed by P. putida and Aeromonas hydrophila [169]. Using QS inhibitors as membrane coating or using QQ enzymes expressing genetically engineered microbes may reduce the formation of biofilms on the membrane filters [170]. Yeon et al. (2010) showed that using an acylase-based membrane may minimize biofilm formation up to 24% [171]. Rhodococcus and the recombinant E. coli strain, capable of degrading AHL molecules, showed antibiofilm activity in wastewater treatment protocols [172]. Vanillin as an AHL signal activity modulator prevented biofilm in reverse osmosis (RO) apparatus on a cellulose acetate membrane filter [170]. Membrane biofouling prevention is an emerging field with promising applications in water purification and wastewater treatment strategies.

Microbes play a central role in bioremediation by degrading toxic and harmful chemical compounds. QS has been shown to play an essential role in the degradation of many poisonous compounds, such as phenols [173], phenanthrene [174], hexadecane [175], and total organic carbon. Phenol is used in bulk quantities by industries (such as petroleum, tanneries, textile, dye, plastic, and agriculture) and hospitals (such as a disinfectant) [176]. Environmental phenol buildup harms human and animal health. Phenol may induce nervous system damage, renal dysfunction, corneal whitening, skin rash, dysphasia, gastric compilations, and cancer [177]. Pseudomonas (P. putida, P. aeruginosa, and P. pictorum), Bacillus (Bacillus brevis), Arthrobacter (A. citreus and A. chlorophenolicus), and Cyanobacterium synechococcus are known phenol-degrading microbes [178]. Phenol stress upregulates genes involved in cofactor biosynthesis, cell division, DNA repair and replication, heat shock proteins, fatty acid, and energy metabolism. P. putida phenol stressed fatty acid biosynthesis genes (FabB and FabH2) [179]. P. putida LPS biosynthesis genes (LpxC, MurA, and VacJ) and heat shock proteins (HtpG and GrpE) are also upregulated under phenol stress [180]. The AHL supplementation during wastewater treatment has enhanced phenol’s biodegradation for longer time intervals [181]. ΔrhlI and ΔrhlR mutant strains of P. aeruginosa have shown reduced phenol degradation capabilities compared to the wild-type strains [182]. Acinetobacter sp. showed increased hexadecane degradation by 3-OH-C12-HSL supplementation [183]. QS pathways also regulate the expression of the enzymes involved in bioremediation or biotransformation. The expression of catechol-1,2-dioxygenase, which is responsible for the biodegradation of anthranilate and phenol by P. aeruginosa, is enhanced by the exogenous supplementation of C4-HSL, C8-HSL, and C10-HSL [184]. The PQS-based QS system in P. aeruginosa regulates NO reductase, NO₃⁻ reductase, and NO₂⁻ reductase [185].

AHL-based biosensor development has been used for Gram-negative pathogen detection. AHL biosensors consist of AHL-responsive promoters, AHL receptors, and a reporter gene. The bio-detection of AHL has been linked to the indirect detection of pathogenic bacteria in clinical products, environmental samples, dairy products, meat products, and drinking water. AHL-based biosensors have been developed to detect E. coli O157:H7 [186]. AHL-based biosensors can be designed to detect Shiga toxin inputs from the bacteria. This input information can be processed via the AHL-based engineered QS circuit, and a reporter gene output can be produced. Lactic acid bacteria can be engineered to express reporter gene expression in the presence of gut microbes by utilizing the potential of QS circuits [187].

3-oxo-C12-HSL, produced by P. aeruginosa, induces apoptosis in human breast cancer cells. However, its direct utilization is prohibited due to its immunomodulation, cell cytotoxicity, and hypervirulence activity in immunocompromised patients [188]. However, this may provide a chemical scaffold to develop novel anti-cancer drugs with targeted anti-cancer activities. Furthermore, tumors in vivo microbial communities may be exploited to design biosensors or therapeutics against cancer cells. The previous report has shown that the microbial population density can be used to invade cancer cells by engineered bacterial cells. This research uses the invasion gene (Yersinia pestis) by E. coli to invade cancer cells expressing the beta1-integrin receptor [189]. The threshold population density triggers the AHL production and causes an expression in the invasion and penetration of human cancer cells. Furthermore, Bacillus- and Enterococcus faecium-derived QS peptides invade and promote the angiogenesis of colon cancer cells, thereby promoting cancer cell metastasis [190,191]. At the molecular level, there is a need to explore the link between QS-derived bacterial phenotypes and colon cancer. In short, QS-based approaches can be used to develop biosensors and targeted drug delivery vehicles. The biggest challenge is controlling the immune response against such biosensors and the ability to distinguish between normal and cancer cells. Because of this, the primary exploratory site for developing such technologies is a colon, where microorganisms coexist closely with human cells. This allows bacteria adaption strategies to be developed for potential application, such as whole-cell biosensors, drug carriers, and treatment options for colon cancer and gut-associated diseases.

Overall, the QS regulatory systems details for the transcriptional regulators, associated virulence factors, and desirable functions is presented in Table 2.

QS Regulator	Phenotype/ Virulence Factor	Genetic Marker	Function	References
LasI/R	Protease	lasA	Epithelial barrier disruption, the adaptation and spread of infection, and immune evasion	[192]
	Elastase	lasB	The degradation of elastin, collagen, and related matrix proteins; the spread of infection; and extracellular iron acquisition	[193]
	Alkaline protease	aprA	The degradation of host proteins (complement, and cytokines), the establishment of infection, and immune evasion	[194]
	AHL synthase	lasI	Autoinducer expression	[195]
	Transcriptional activator protein	Anr and Mhr	Biofilm formation under low-oxygen conditions	[84]
RhlI/R	Rhamnolipids	rhlAB	The necrosis of host immune cells, biofilm formation, and immune evasion	[88,91]
	Pyocyanin	phzABCDEFG and phzM	Oxidative stress, inflammatory response, neutrophil toxicity, the establishment of infection, and damage to host cells	[196]
	Hcn hydrogen cyanide (RhlR)	hcnABC	Cell toxicity and infection establishment, lung cell damage, and poor lung function	[79]
	Autoinducer production	lasI and rhlI	The production of AHL molecules	[197]
QscR	Pyocyanin and hydrogen cyanide production	phz and hcn	Virulence factors, cell toxicity, and host cell damage	[95,96]
	Las/Rhl quorum-sensing-dependent genes	lasIR and rhlIR and associated genes	Quorum-sensing-dependent genes	[198]
TraI/R	Regulatory gene	mrtR and tmsP	Transcription regulation	[103]
	Conjugative transfer protein	TraA, TraC, and TraD	Conjugation	[110]
	Type IV secretion family	trb genes	The transfer of Ti plasmid	[111]
	Conjugative transfer protein	trbJ and trbK	Conjugation	[112]
CviI/R	Pigment production	vioA, vioB, vioC, vioD	Violacein pigment production, known for its antioxidant properties	[116,125]
	AHL synthesis and detection	cviI cviI and cviR	AHL synthase activity to enhance the production of AHL molecules via a positive feedback loop	[116,125]
	Chitinase production	Chitinase genes	Degrade chitin	[119]
SdiA	Cell division	ftsQ, ftsA and ftsZ	The positive regulation of the ftsQAZ gene cluster	[129]
	Acid tolerance	GadW, and GadY	Acid tolerance in E. coli	[137]
	Cell attachment and biofilm formation	rck and srgE locus	Enhanced cell adhesion, invasion, and biofilm formation by enteric pathogen Salmonella enterica	[133,199]
	Bacterial motility	fliC and csgA	The repression of flagella and curli fimbriae	[134]