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Gastroenterology & Hepatology
An imbalance in gut microbiota, termed dysbiosis, has been shown to affect host health. Several factors, including dietary changes, have been reported to cause dysbiosis with its associated pathologies that include inflammatory bowel disease, cancer, obesity, depression, and autism. QS is a complex network of cell–cell communication that is mediated by small diffusible molecules known as autoinducers (AIs). Using AIs, bacteria interact with one another and coordinate their gene expression based on their population density for the benefit of the whole community or one group over another. Bacteria that cannot synthesize their own AIs secretly “listen” to the signals produced by other bacteria, a phenomenon known as “eavesdropping”. AIs impact gut microbiota equilibrium by mediating intra- and interspecies interactions as well as interkingdom communication.
- gut
- bacteria
- quorum sensing
- autoinducers
- normobiosis
- dysbiosis
1. Introduction
The gut ecosystem has the greatest concentration and variety of microbial species of any natural environment. An estimated 1014 bacteria and other microbial species including viruses, archaea, and fungi have been reported to inhabit the human gut [1]. This collection of microbial species coevolved with the host over time to create a delicate and beneficial association that essentially promotes health and well-being. It has been shown that the “gut microbiota “contains more bacterial cells—about 10 times as many as there are in other human organs—and its genomic content is more than 100 times as abundant as the human genome [2]. The major phyla of gut microbiota include Bacteroidetes, Firmicutes, Proteobacteria, Actinobacteria, Verrucomicrobia, and Fusobacteria, with Firmicutes and Bacteroidetes accounting for over 90% of the entire gut microbiota [3]. Evaluation of the makeup of microbial species found in the human gut reveals distinct inter-individual variances [4], with the average total number of diverse commensal bacterial strains approximated at over 500 per individual [5]. While the diversity of dominating species appears to be constant throughout time and between individuals, that of subdominant taxa is far less stable, largely as a result of genomic plasticity [4].
2. Normobiosis
The term “normobiosis” is used to describe the normal balance of the different types of microbial species in the gut. In a symbiotic association, the gut microbiota performs vital functions while the host offers a nutrient-rich environment [5]. The gut microbiota serves the host in a variety of physiological ways, including maintaining gut epithelium integrity, facilitating digestion, producing vital metabolites and vitamins, suppressing pathogen expansion, and regulating host immunity [1,3,6].
Despite the enormous variety of microorganisms and complexity observed in the adult intestine, the microbiota is initially an uncomplicated ecosystem that gradually goes through successional modifications until it reaches great diversity [7,8]. For many years, it was thought that the infant’s gut was sterile and that colonization after delivery came solely from the mother, nutrition, and the environment [9,10,11,12]. The discovery of bacterial DNA from placenta samples [13] and meconium [8] gave an indication initially that the placenta may be a possible pathway through which horizontal bacterial DNA transfer occurs from mother to fetus [13]. However, other investigations show bacteria in the umbilical cord blood [14] and meconium of healthy newborns including from murine amniotic fluid taken during a cesarean operation [15], thus indicating that bacterial exposure may begin in utero. Infants with a balanced gut microbiota have healthier growth and development, a stronger immune system, and a lower chance of developing chronic diseases [16].
2.1. Mode of Delivery
Mode of delivery has a significant impact on bacterial species that first colonize the infants’ gut [8]. Through vaginal deliveries, bacteria such as Bifidobacterial strains from the mother’s gut and vagina are passed to the infant’s gut [22,23,24], whereas cesarean deliveries introduce colonizing bacteria from the environment, such as from the hospital environment [25]. Examples of hospital bacteria include opportunistic pathogens like Klebsiella and Enterococcus [26].
2.2. Diet
The gut microbiota is highly dynamic during the first few weeks of life, with nutrients controlling the changing ecosystem [27]. Infants who are fed formula often have a microbiota that is more diverse than the microbiota of those who are breastfed, typically dominated by Bifidobacteria [8,28]. Following the introduction of solid foods, the bacterial succession continues to slowly diversify and includes adult-type species such as Bacteroides spp. and Clostridium clusters IV and XIV [8,17]. Although the precise age for the attainment of a permanent adult-type composition is still unknown, it is generally accepted that this age is in the range of 3 years [29,30,31].
2.3. Genetics
Studies suggest that genetics can influence the composition of gut microbiota. One of the basic approaches to determining how host genotype influences gut microbiota is through twin studies [35]. Fraternal (dizygotic; DM) twins often share 50% of their genes compared to 100% shared by identical (monozygotic; MZ) twin pairs [36]. Twin heritability studies as well as the assumption that twins raised together experience similar environmental conditions [37].
2.4. Geographical Location
The environment in which a person resides can play a crucial role in determining the structure and composition of a person’s gut microbiota. To examine how gut microbiomes vary between human populations, Yatsunenko and colleagues characterized the bacterial species and their gene content found in fecal samples taken from 531 healthy individuals representing Amerindians from the Venezuelan Amazon, people living in rural Malawi, and people living in urban areas in the United States [29]. The findings reveal that people living in the USA have significantly different bacterial species compositions and functional gene repertoires than people living in the other two nations, thus indicating the possible impact of Westernization on gut microbiota. Due to their shared genes, similar bacterial richness and heritability for MZ twins compared to DZ twins have been observed [35,39]. However, twins’ microbial similarity decreased when they started to live apart, suggesting that the environment may have a greater influence on the gut microbiota than does genetics [43].
2.5. Other Factors
Throughout the world, antibiotics are a treatment of choice for bacterial infections. However, the downside is that they can disrupt the balance of the gut microbiome. Antibiotic use can cause the microbiota to become less diverse and rid the gut of beneficial bacteria which have an impact on people’s health and how resistant they are to illnesses [49]. A person’s gut microbiota can also be impacted by a lack of access to sanitary facilities. People who reside in unsanitary settings have been reported to be more susceptible to infections and disruption of the gut flora [50]. Moreover, stress has been implicated in gut microbiota imbalance. Host stress hormones are advantageous for enteric bacterial infections. Hormones secreted during host stress, such as catecholamines, can impact host–bacterial interactions, bacterial pathogenicity, and susceptibility to infection [51]. Enteric pathogens use stress hormones as signaling molecules to modify their virulence genes [52]. As an individual ages, changes in microbiota are introduced. Older adults show less diverse and imbalanced gut microbiota including immune system disruption and disease vulnerability [53].
3. Quorum Sensing
Our understanding of chemical communication among bacteria has undergone a significant shift since the discovery of QS. From being seen as distinct noncooperative species, bacteria are now understood as socially cooperative organisms with the ability to engage in multicellular behaviors [63]. Via QS, bacteria live a multicellular life, coordinating group behaviors that are often impossible for a single cell to carry out [64]. Hastings and colleagues [65] were the first to discover QS over 50 years ago. In their investigation, they found that Vibrio fischeri (known then as Photobacterium fisheri) a bioluminescent bacterium rapidly produced light, which was not a result of cell growth but rather the “conditioning” of media by the developing cells. In freshly inoculated cultures, the bacterial cells did not begin to produce light until the mid-logarithmic phase. The researchers later named this conditioning phenomenon “autoinduction”. To describe and make the phenomenon clearer, Greenberg and colleagues introduced the phrase “quorum sensing” in 1994 [66]. Later studies showed that QS exists across various bacterial species, including pathogens [67,68,69,70,71,72,73,74,75].
QS is driven by chemical messengers known as autoinducers (AI), by which bacteria communicate with one another and coordinate their gene expression in response to their population density [71,72,73]. In the gut though, not every species produces AIs. When bacteria cannot produce their own AIs, they secretly “listen” to the signals produced by other bacteria, a phenomenon known as “eavesdropping” [76]. Using QS, numerous group activities are performed. These activities include biofilm formation [77,78], virulence factor production [74,79,80], sporulation [81,82], bioluminescence [65,83], nucleotide biosynthesis [84], DNA horizontal transfer [81,85], antibiotic synthesis [86], glucose uptake [70,84,87], adaptation to noxious environments [88,89], and production of secondary metabolites [90]. Interestingly, QS can occur within species and between species [90,91], as well as between kingdoms (e.g., eucaryotic host cells and bacteria) [92,93,94,95,96]. Therefore, the term “quorum sensing” can be expanded to encompass multimodal communication networks including the intraspecies, interspecies, and interkingdom signaling cascades.
4. Different Quorum Sensing Signals in the Gut
4.1. Autoinducing Peptides
Different AIs are employed by Gram-positive and Gram-negative bacteria. The Gram-positive bacteria utilize oligopeptides, commonly referred to as autoinducing peptides (AIPs), for their communication [97]. These AIPs are of various types, differing in sequence and structural organization [97,98]. Following their synthesis, AIPs are immediately processed. Since peptides are unable to traverse lipid-bilayer membranes, specialized transporters move the processed AIPs outside the cell [64]. The AIPs’ processing by posttranslational modification produces a number of products with sizes ranging from 5 to 17 amino acids in linear or cyclical structural organization [97,98]. The extracellular AIPs bind to a two-component histidine kinase receptor on the bacterial membrane and activate the kinase activity of the receptor. This results in autophosphorylation and the subsequent relay of the phosphate group to a response regulator downstream [99,100]. The phosphorylated response regulator activates the operon, creating an autoinducing feed-forward looping that synchronizes the QS response [64].
Figure 1. Cross-communication in the gut, showing bacteria–bacteria, bacteria–host, and host–bacteria communication. In the bacteria–bacteria communication, elevated AI-2 induces the growth of native gut bacterial residents such as Firmicutes and Bifidobacteria but suppresses the expansion of pathogens such as V. cholera. 3-Oxo-C12:2 is positively associated with Firmicutes. Indole enhances the proliferation of beneficial bacteria. In the bacteria–host communication, 3-oxo-C12:2 protect tight junction integrity. Indoles enhances epithelial barrier function via the aryl hydrocarbon receptor (AhR). While AI-3 induces pro-inflammatory reactions by stimulating the expression of cytokines IL-8, 3-oxo-C12:2-HSL reduces inflammation by repressing the expression of IL-1, IL-8, and TNF. 3-Oxo-C12 exacts a negative impact on the epithelial barrier by disrupting the tight junctions. Gram-positive signal peptides, such as competence and sporulation factor (CSF) bind to the cation transporter (OCTN2), and subsequently activate heat shock protein (HSP), p38 MAP, and protein kinase B (Akt), to protect intestinal barriers from oxidative stress damage, and impairment. The QS peptide, EntF*, promotes colorectal cancer (CRC) metastasis through interference with the epithelial cells’ integrity. The host–bacteria communication means, from the host end, the microenvironment in the lumen (pH, Temperature, Osmotic pressure, and Bile acids) which inactivates QS signals such as AI-2 is modulated. Also, paraoxonases (PONs) exert lactonase-like activity against AHLs signals. AI-2 mimics, and catecholamines (epinephrine (EPI)/norepinephrine (NE)) are recognized by the bacterial QS receptors to modulate gut microbial balance (created using BioRender.com, accessed on 12 December 2022).
4.2. N-Acyl Homoserine Lactones
In Gram-negative bacteria, the most prevalent group of AIs are the N-acyl homoserine lactones (AHLs) [71,115]. Different bacterial species produce AHLs with different acyl chain lengths or substitutions [102,103], but with the same essential homoserine lactone moiety. The LuxI protein family is responsible for producing the AHLs from S-adenosyl methionine (SAM) and an acylated-acyl carrier protein (ACP) [116]. The AHLs can freely move across the cell membrane [75,80].
4.3. Autoinducer-2
Before the discovery of autoinducer-2 (AI-2), QS was thought to occur just within species employing AIP or AHL (collectively known as autoinducer-1 or AI-1). However, bacteria in mixed populations have different mechanisms by which they can sense, recognize, and interact with one another [68,104,105]. AI-2 is the “universal” QS molecule that mediates interspecies communication and was first identified in the marine bacterium Vibrio harveyi which, together with AHL, regulates bioluminescence [104,105]. Produced by S-ribosylhomocysteinase (LuxS), AI-2 is conserved in both Gram-positive and Gram-negative bacteria [91,119,120,121]. Using S-adenosylmethionine (SAM), bacterial cells produce S-adenosylhomocysteine (SAH) which is then broken down by the nucleosidase Pfs into adenine and S-ribosylhomocysteine (SRH) [122,123]. LuxS cleaves SRH at the thioether bond to produce homocysteine and 4,5-dihydroxy-2,3-pentanedione (DHPD), the latter of which cyclizes and rearranges spontaneously into AI-2 [68]. For bacteria, the step catalyzed by LuxS has at least two uses: SAH detoxification and AI-2 production [124].
4.4. Autoinducer-3
Autoinducer-3 (AI-3) consists of various products belonging to the pyrazinone family synthesize through a chain of reactions. Two of these reactions—the production of the AI-3 by the action of threonine dehydrogenase (Tdh) and the spontaneous cyclization by aminoacyl-tRNA synthetase—are crucial [79]. Studies have shown that the production of AI-3 is not dependent on AI-2 synthase (LuxS) [106,107]. AI-3 is responsible for the pathogenesis of enteropathogenic Escherichia coli (EPEC) [79,106,107,125,126]. QseC, a histidine kinase receptor, senses AI-3 to modulate gene expression [127]. QseC is conserved among different kinds of bacteria. Bacterial species such as E. coli, V. cholerae, Salmonella sp., Shigella sp., and C. violaceium possess QseC sensors [127,128].
5. Role of QS in Normobiosis
5.1. Intraspecies QS and Normobiosis
Gut bacteria were initially thought to be eavesdropping on AHLs synthesized within the complex gut microbial ecosystem [131]. However, available evidence, recently obtained using highly sensitive and sophisticated technologies, indicates the existence of AHL signaling among native gut residents [58,59,132,133]. The discovery of AHL signaling in the gut which is linked to normobiosis is one of the significant findings in understanding the human gut. In the human fecal samples from patients with inflammatory bowel disease (IBD) and healthy individuals, 14 distinct AHLs were profiled, one of which was prominent, identified as 3-oxo-C12:2-HSL [93].
5.2. Interspecies QS and Normobiosis
A growing body of knowledge shows that interspecies interactions mediated by Al-2 play a vital role in gut bacterial composition and balance. By using engineered E. coli strains that manipulate AI-2 levels by either raising or lowering the concentration of AI-2 in the gut, Thompson et al. evaluated the effect of the QS molecule on gut microbiota equilibrium [145]. In their studies, the researchers found that the antibiotic treatment lowered Firmicutes and other members carrying the luxS gene, indicating that AI-2 levels were reduced. Bacteroidetes were shown to dominate the microbiota following antibiotic-induced dysbiosis, possibly due to competitive advantage acquired from resistance caused by spontaneous mutations [146].
Gut microbiota functions also include the suppression of pathogen expansion, a phenomenon known as colonization resistance. Direct interactions between gut microbial communities appear to be crucial in colonization resistance. In a study using fecal microbiota of adults living in a region with a high cholera burden, Hsiao et al. showed that the production of AI-2 by commensal bacteria conferred colonization resistance against Vibrio cholerae infection [151].
One of the crucial interspecies QS molecules produced by some bacteria is indole, an amino acid-derived metabolite [108,130]. At indole concentrations below 1 mM, E. coli was reported to only exhibit a repellent response, but switched to an attraction response when the indole concentration was at 1 mM or more [158]. Yang et al. suggest that indole may prevent pathogen invasion with a repulsion mechanism while bringing beneficial resident bacterial species together and enhancing their proliferation [158]. Through differential adaptation, gut bacteria in the presence of indole can suppress pathogen expansion. Enteropathogenic E. coli (EPEC) motility, epithelial cell adhesion, biofilm formation, and virulence gene expression were all reported to be reduced in the presence of indole [159,160,161]. Usually, co-infections with two or more infectious agents, such as V. cholerae and EPEC, have been observed in diarrheal samples [162].
5.3. Interkingdom QS and Normobiosis
The most documented inter-kingdom communications (host–bacteria interactions) are the ones driven by AHL molecules from pathogens [166]. Hosts adjust accordingly by monitoring AHLs within the gut ecosystem and resisting infection by interfering with QS signal transduction [92]. Enteric bacterial pathogens use host stress hormones to their advantage. Although the exact mechanisms behind microbiota and hormonal signaling are as yet unknown, hormones released during host stress can affect the host–bacteria interactions, bacterial pathogenicity, and vulnerability to infection [51]. These stress hormones may be exploited by enteric pathogens as signaling molecules to modulate their virulence genes [52]. The growth and motility of pathogenic bacteria like Helicobacter pylori [167], Vibrio spp. [128,168], Klebsiella pneumoniae, P. aeruginosa, E. coli, and Staphylococcus aureus [169] have been found to be modulated by catecholamines. Catecholamines have also been reported to increase bacterial virulence [170]. In P. aeruginosa PA14, virulence appears to be induced via the las QS pathway following norepinephrine treatment [171].Another important finding is the release of AI-2 mimics by human epithelial cells that are recognized by bacterial AI-2 receptors [95]. Although the mechanism of AI-2 mimic synthesis is still poorly understood, the data currently available indicate that AI-2 mimic activity is stimulated when epithelial cells are exposed to bacteria, either directly or indirectly, suggesting that one or more secreted bacterial components induce AI-2 mimic synthesis [95]. One can compare pathogen interactions with their host as an “arms race” in which each player continuously responds to the other’s changing tactics [92]. The human aryl hydrocarbon receptor (AhR), a protein well-known for its function in mediating toxicity [184], has been shown to interact with several QS molecules (such as 3-oxo-C12-HSL, C4-HSL, and PQS) produced by P. aeruginosa to keep track of the bacterial infection at various stages [92]. Such eavesdropping helps the host adapt to changes in the gut flora.
Compared to other QS signaling molecules, much less research has been done on the impact of AIP on gut microbiota balance. However, available data suggest the importance of host–bacteria interaction via AIP in gut microbial balance (Figure 1). An AIP from Bacillus subtilis, also known as competence and sporulation factor (CSF), was shown to contribute to normobiosis by mediating inter-kingdom signaling [193]. B. subtilis was previously thought to be just soil bacteria, however, it is now confirmed to be a member of the human gut and evolved to exist there [194,195].
6. Conclusions
Today, QS is broadened to include multimodal communication, encompassing intraspecies, interspecies, and interkingdom signaling. The role of QS in normobiosis is undeniable. Via QS, gut microbiota maintains balance by suppressing pathogen expansion through enhancing biofilm formation and fitness of resident gut bacteria, mobilizing native members to reestablish balance following substance-induced dysbiosis, exerting anti-inflammatory response as well as preserving the tight junction integrity. Although gut microbiota research has just scratched the surface, exciting prospects exist for QS-based therapeutic interventions. With the advancement in technology, more and more tools are made available to further clarify the role of QS in normobiosis and elucidate the connection between QS inhibition and dysbiosis.
This entry is adapted from the peer-reviewed paper 10.3390/ijms24043722
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