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Bile acid metabolism. Flow diagram showing the metabolism and fate of bile acids. In the liver (orange arrows), cholesterol is enzymatically converted to primary bile acids such as cholic acid. After conjugation of taurine or glycine to cholic acid by hepatocytes, the resulting glycocholic acid or taurocholic acid are stored in the gall bladder until released into the small intestine in response to food ingestion. In the small intestine (blue arrows), several commensals deconjugate and/or dehydroxylate bile acids, producing unconjugated deoxycholic acid and cholic acid. Alternatively, glycholic acid or taurocholic acid can be dehydroxylated to the conjugated secondary bile acids glycodeoxycholic acid or taurodeoxycholic acid. In a process called enterohepatic circulation, unconjugated bile acids are excreted with the feces or reabsorbed from the ileum back into the liver. Depending on the types of microbiota and nutrition ingested, bile acid composition may vary throughout the intestines. Therefore, the inhibitory effect identified in this study (red) of deoxycholic acid and the enhancing effect (green) of glycodeoxycholic acid or taurodeoxycholic acid on the T6SS of V. cholerae may vary depending on the microbiota present.
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The type six-secretion system (T6SS) is a molecular syringe that many Gram-negative pathogens use to kill other bacteria, including commensal bacteria of the human gut. We investigated how the environment of the intestine, specifically commensal bacteria, the mucus lining, and bile affect the T6SS of the bacterial pathogen Vibrio cho...
Citations
... Similarly, Bifidobacterium bifidum could metabolize GDCA, TDCA, and CA into DCA [59] . Punicalagin intervention reduced the abundance of BSH-producing bacteria (Clostridiaceae and Bifidobacteriaceae) and the activity of BSH enzymes, thereby reducing ileal FXR activation [24] . ...
... The activity of T6SSs from important intestinal pathogens such as Vibrio cholerae and S. Typhimurium has been shown to be activated by bile salts 14,15 , but the mechanism of such regulation is still elusive. Several studies indicate that c-di-GMP signaling regulates T6SS activity in pathogenic bacteria such as P. aeruginosa and Agrobacterium tumefaciens 16,17 , while our recent study demonstrated that bile salts induce intracellular accumulation of c-di-GMP in S. Typhimurium 4 , leading us to speculate that bile salts activate S. Typhimurium SPI-6-encoded T6SS via modulating intracellular c-di-GMP levels. ...
Cyclic di-GMP (c-di-GMP) is a second messenger that transduces extracellular stimuli into cellular responses and regulates various biological processes in bacteria. H-NS is a global regulatory protein that represses expression of many genes, but how H-NS activity is modulated by environmental signals remains largely unclear. Here, we show that high intracellular c-di-GMP levels, induced by environmental cues, relieve H-NS-mediated transcriptional silencing in Salmonella enterica serovar Typhimurium. We find that c-di-GMP binds to the H-NS protein to inhibit its binding to DNA, thus derepressing genes silenced by H-NS. However, c-di-GMP is unable to displace H-NS from DNA. In addition, a K107A mutation in H-NS abolishes response to c-di-GMP but leaves its DNA binding activity unaffected in vivo. Our results thus suggest a mechanism by which H-NS acts as an environment-sensing regulator in Gram-negative bacteria.
... In intestinal pathogens such as S. Typhimurium, V. cholerae and Shigella sonnei, the T6SS is important for host colonization via competition against the resident microbiota [67][68][69]. The T6SSs of these bugs is regulated by host-produced signals such as bile salts and mucins, which positively regulate the T6SS activity of S. Typhimurium and V. cholerae [68,70]. In a similar manner, V. cholerae is commonly associated with aquatic animals and its T6SS gene cluster is upregulated by chitin [71]. ...
Bacteria live in complex polymicrobial communities and are constantly competing for resources. The type VI secretion system (T6SS) is a widespread antagonistic mechanism used by Gram-negative bacteria to gain an advantage over competitors. T6SSs translocate toxic effector proteins inside target prokaryotic cells in a contact-dependent manner. In addition, some T6SS effectors can be secreted extracellularly and contribute to the scavenging scarce metal ions. Bacteria deploy their T6SSs in different situations, categorizing these systems into offensive, defensive and exploitative. The great variety of bacterial species and environments occupied by such species reflect the complexity of regulatory signals and networks that control the expression and activation of the T6SSs. Such regulation is tightly controlled at the transcriptional, posttranscriptional and posttranslational level by abiotic (e.g. pH, iron) or biotic (e.g. quorum-sensing) cues. In this review, we provide an update on the current knowledge about the regulatory networks that modulate the expression and activity of T6SSs across several species, focusing on systems used for interbacterial competition.
... The activity of T6SSs from important intestinal pathogens such as Vibrio cholerae and S. Typhimurium has been shown to be activated by bile salts 28, 35 , but the mechanism of such regulation is still elusive. Several studies indicate that c-di-GMP signaling regulates T6SS activity in pathogenic bacteria such as P. ...
The type VI secretion system (T6SS) is a widespread versatile machine that is encoded by many gram-negative bacteria and plays crucial roles in interbacterial competition and bacteria-host interactions. Histone-like nucleoid structuring protein (H-NS) is a global regulator that represses the expression of T6SS genes in various pathogens and environmental isolates. Bacteria appear to have evolved regulatory mechanisms to relieve the transcriptional repression mediated by H-NS when the T6SS activity is required, but the underlying molecular mechanism awaits elucidation. Here we show that elevated intracellular cyclic di-GMP (c-di-GMP) levels alleviate the H-NS–mediated repression of the T6SS in Salmonella enterica serovar Typhimurium.Mechanistically, c-di-GMP directly binds to the H-NS protein to abrogate its binding to the T6SS promoters, thus derepressing expression of the T6SS genes. Furthermore, we provide evidence that bile salts-induced increase in intracellular c-di-GMP levels leads to activation of the S . TyphimuriumT6SS within the host gut, facilitating its killing of commensal bacteria and successful colonization. The observations that c-di-GMP derepresses gene expression via targeting the H-NS or H-NS-like proteins in Vibrio parahaemolyticus , Pseudomonas aeruginosa and Pseudomonas putida suggest a general mechanism through which the H-NS family of proteins act as environment-sensing regulators in Gram-negative bacteria.
... In clinical isolates, high osmolarity and high cell density, involving the regulators oscR and hapR, respectively, are both required for secretion, even though the T6SS is constitutively expressed and produced (Ishikawa et al. 2009(Ishikawa et al. , 2012. Globally, the T6SS regulation also depends on other environmental signals, such as bile (Bachmann et al. 2015), nucleoside levels (Watve et al. 2015), and chitin (Meibom et al. 2005;Lo Scrudato and Blokesch 2013;Borgeaud et al. 2015;Metzger et al. 2016) through the chitin competence pathway. The global regulators LonA and TsrA also play a role in T6SS regulation. ...
The Type VI Secretion System (T6SS) is used by bacteria for virulence, resistance to grazing and competition with other bacteria. We previously demonstrated that the role of the T6SS in interbacterial competition and in resistance to grazing is enhanced in Vibrio cholerae in the presence of subinhibitory concentrations of polymyxin B. Here, we performed a global quantitative proteomic analysis and a targeted transcriptomic analysis of the T6SS known regulators in V. cholerae grown with and without polymyxin B. The proteome of V. cholerae is greatly modified by polymyxin B with more than 39 % of the identified cellular proteins displaying a difference in their abundance, including T6SS-related proteins. We identified a regulator whose abundance and expression are increased in the presence of polymyxin B, vxrB, the response regulator of the two-component system VxrAB (VCA0565-66). In vxrAB, vxrA and vxrB deficient mutants, the expression of both hcp copies (VC1415 and VCA0017), encoding an identical protein Hcp which is the major component of the T6SS syringe, although globally reduced, was not modified by polymyxin B. Thus, the upregulation of the T6SS in the presence of polymyxin B appears to be, at least in part, due to the two-component system VxrAB.
... Depending on the biotype or strain, V. cholerae can utilize multiple defenses against the gut microbiome. All V. cholerae strains have the type six secretion system (T6SS) which, if functional, directly injects toxic effectors into eukaryotic cells and bacteria (Bachmann et al., 2015). The T6SS is one method V. cholerae uses to interact with the host and its resident microbiota. ...
... These results did not occur in the gelatin control. This indicates a component of the mucin was necessary to activate a functional T6SS in C6706 (Bachmann et al., 2015). ...
... Resident gut bacteria can metabolize these bile acids via bile salt hydrolases (Hung and Mekalanos, 2005;Song et al., 2019). This bile acid deconjugation can inhibit V. cholerae T6SS expression, perhaps due to a carboxylic acid group present in a bile salt, although the mechanism of action is not known (Bachmann et al., 2015). The resident gut microbiome can also produce components against non-commensal bacteria. ...
The aquatic bacterium Vibrio cholerae is the etiological agent of the diarrheal disease cholera, which has plagued the world for centuries. This pathogen has been the subject of studies in a vast array of fields, from molecular biology to animal models for virulence activity to epidemiological disease transmission modeling. V. cholerae genetics and the activity of virulence genes determine the pathogenic potential of different strains, as well as provide a model for genomic evolution in the natural environment. While animal models for V. cholerae infection have been used for decades, recent advances in this area provide a well-rounded picture of nearly all aspects of V. cholerae interaction with both mammalian and non-mammalian hosts, encompassing colonization dynamics, pathogenesis, immunological responses, and transmission to naïve populations. Microbiome studies have become increasingly common as access and affordability of sequencing has improved, and these studies have revealed key factors in V. cholerae communication and competition with members of the gut microbiota. Despite a wealth of knowledge surrounding V. cholerae, the pathogen remains endemic in numerous countries and causes sporadic outbreaks elsewhere. Public health initiatives aim to prevent cholera outbreaks and provide prompt, effective relief in cases where prevention is not feasible. In this review, we describe recent advancements in cholera research in these areas to provide a more complete illustration of V. cholerae evolution as a microbe and significant global health threat, as well as how researchers are working to improve understanding and minimize impact of this pathogen on vulnerable populations.
... The gut microbial deconjugation of bile acids plays a significant role in their bile tolerance and circulation, thus providing colonization resistance against V. cholerae. Deconjugation of taurocholate by B. obeum was reported in a recent study to affect the colonization potential of V. cholerae, due to the poor expression of virulence genes, and this can be explained as taurocholate is critically involved in the activation of virulence genes, and hence aid in colonization [115][116][117]. These studies concluded that the commensal microbiota, B. obeum, plays a crucial role in driving V. cholerae colonization resistance via deconjugation of taurocholate, and the BSH activity affects the pathogenesis of the V. cholerae the most at the early stage of infection. ...
... Hung et al. reported that when V. cholerae is not in biofilm form in response to the toxicities of deconjugated bile salts, it activates the transcriptional activator of vps and vpsR genes and hence the formation of biofilm structure against bile toxicities [120]. However, more reports are indicating the poor activation of virulence in the presence of deconjugated bile [57,[112][113][114][115][116][117][118], therefore, future studies are required to fully understand the effect of BSH activity on V. cholerae. ...
Vibrio cholerae is a non-invasive enteric pathogen known to cause a major public health problem called cholera. The pathogen inhabits the aquatic environment while outside the human host, it is transmitted into the host easily through ingesting contaminated food and water containing the vibrios, thus causing diarrhoea and vomiting. V. cholerae must resist several layers of colonization resistance mechanisms derived from the host or the gut commensals to successfully survive, grow, and colonize the distal intestinal epithelium, thus causing an infection. The colonization resistance mechanisms derived from the host are not specific to V. cholerae but to all invading pathogens. However, some of the gut commensal-derived colonization resistance may be more specific to the pathogen, making it more challenging to overcome. Consequently, the pathogen has evolved well-coordinated mechanisms that sense and utilize the anti-colonization factors to modulate events that promote its survival and colonization in the gut. This review is aimed at discussing how V. cholerae interacts and resists both host- and microbe-specific colonization resistance mechanisms to cause infection.
... In addition, the relative proportion of secondary and deconjugated secondary bile salts in the intestinal lumen can impact V. cholerae colonization. Secondary bile salts activate CT expression as well as a suite of other virulence factors (61), while deconjugated bile salts inhibit pathogen virulence and growth (50,62). The gut commensal bacterium Blautia obeum produces bile salt hydrolase that deconjugates bile salts and lowers the concentrations of secondary bile salts in the gut, reducing virulence of V. cholerae (50). ...
In order for successful fecal-oral transmission, enteric bacterial pathogens have to successfully compete with the intestinal microbiota and reach high concentrations during infection. Vibrio cholerae requires cholera toxin (CT) to cause diarrheal disease, which is thought to promote the fecal-oral transmission of the pathogen. Besides inducing diarrheal disease, the catalytic activity of CT also alters host intestinal metabolism, which promotes the growth of V. cholerae during infection through the acquisition of host-derived nutrients. Furthermore, recent studies have found that CT-induced disease activates a niche-specific suite of V. cholerae genes during infection, some of which may be important for fecal-oral transmission of the pathogen. Our group is currently exploring the concept that CT-induced disease promotes the fecal-oral transmission of V. cholerae by modulating both host and pathogen metabolism. Furthermore, the role of the intestinal microbiota in pathogen growth and transmission during toxin-induced disease merits further investigation. These studies open the door to investigating whether other bacterial toxins also enhance pathogen growth and transmission during infection, which may shed light on the design of novel therapeutics for intervention or prevention of diarrheal diseases.
... We first tested the robustness of susceptibility values by computing them from five mNODE models trained with different initial parameters for the PRISM + NLIBD dataset and found that susceptibility values from five training repeats are highly correlated (Extended Data Fig. 9). Here we focused on the bile acid metabolism, which is relatively well studied [44][45][46][47][48] and is shown to be associated with human gastrointestinal diseases such as gastrointestinal cancers 47 and IBD 49,50 . Bacteroides vulgatus ATCC 8482 has large positive susceptibilities for cholate and chenodeoxycholate. ...
Characterizing the metabolic profile of a microbial community is crucial for understanding its biological function and its impact on the host or environment. Metabolomics experiments directly measuring these profiles are difficult and expensive, whereas sequencing methods quantifying the species composition of microbial communities are well developed and relatively cost-effective. Computational methods that are capable of predicting metabolomic profiles from microbial compositions can save considerable efforts needed for metabolomic profiling experimentally. Yet, despite existing efforts, we still lack a computational method with high prediction power, general applicability and great interpretability. Here we develop a method called metabolomic profile predictor using neural ordinary differential equations (mNODE), based on a state-of-the-art family of deep neural network models. We show compelling evidence that mNODE outperforms existing methods in predicting the metabolomic profiles of human microbiomes and several environmental microbiomes. Moreover, in the case of human gut microbiomes, mNODE can naturally incorporate dietary information to further enhance the prediction of metabolomic profiles. Furthermore, susceptibility analysis of mNODE enables us to reveal microbe–metabolite interactions, which can be validated using both synthetic and real data. The results demonstrate that mNODE is a powerful tool to investigate the microbiome–diet–metabolome relationship, facilitating future research on precision nutrition.
... The toxic effector proteins that diversify this conserved complex have been identified as covalent modifications to the VgrG spike, cargo effectors loaded onto the spike with adaptor proteins, or loaded within the lumen of the Hcp tube (Pukatzki et al. 2007;Brooks et al. 2013;Unterweger et al. 2015;Wood et al. 2019;. Cargo effectors with either DUF4123 chaperone proteins or PAAR repeat motif proteins specialized to their specific effectors attach onto the VgrG spike (Unterweger et al. 2015;Wood et al. 2019;. ...
... The toxic effector proteins that diversify this conserved complex have been identified as covalent modifications to the VgrG spike, cargo effectors loaded onto the spike with adaptor proteins, or loaded within the lumen of the Hcp tube (Pukatzki et al. 2007;Brooks et al. 2013;Unterweger et al. 2015;Wood et al. 2019;. Cargo effectors with either DUF4123 chaperone proteins or PAAR repeat motif proteins specialized to their specific effectors attach onto the VgrG spike (Unterweger et al. 2015;Wood et al. 2019;. Loading effector proteins onto the T6SS is an essential step for efficient assembly and firing of the apparatus (Liang et al. 2019); cells expressing catalytically-inactive effectors assemble and fire the T6SS normally, while effector deletion strains are T6SS defective. ...
... Conversion from G to T at this site, dubbed SNP45, is sufficient to confer constitutive T6SS activity upon pandemic strains of V. cholerae, but the regulators affected by SNP45 are unknown. Common laboratory Wave 1 El Tor strains such as N16961, C6706, and A1552 do not express their T6SS under laboratory conditions but activate the system upon passage through infant mice, rabbits, and human volunteers (Lombardo et al. 2007;Mandlik et al. 2011;Fu et al. 2013;Bachmann et al. 2015). Multiple host signals have been shown to directly regulate the O1 El Tor T6SS directly. ...
The Vibrionaceae is a highly diverse family of aquatic bacteria. Some members of this ubiquitous group can cause a variety of diseases in humans ranging from cholera caused by Vibrio cholerae, severe septicemia caused by Vibrio vulnificus, to acute gastroenteritis by Vibrio parahaemolyticus. Planet Earth is experiencing unprecedented changes of planetary scale associated with climate change. These environmental perturbations paired with overpopulation and pollution are increasing the distribution of pathogenic Vibrios and exacerbating the risk of causing infections. In this chapter, we discuss various aspects of Vibrio infections within the context of the twenty-first century with a major emphasis on the aforementioned pathogenic species. Overall, we believe that the twenty-first century is posed to be both one full of challenges due to the rise of these pathogens, and also a catalyst for innovative and groundbreaking discoveries.KeywordsVibrio infectionsClimate changeCholeraGlobal warming
Vibrio parahaemolyticus
Vibrio vulnificus
