Long Chain Fatty Acids and Virulence Repression in Intestinal Bacterial Pathogens

Abstract

When bacterial pathogens enter the gut, they encounter a complex milieu of signaling molecules and metabolites produced by host and microbial cells or derived from external sources such as the diet. This metabolomic landscape varies throughout the gut, thus establishing a biogeographical gradient of signals that may be sensed by pathogens and resident bacteria alike. Enteric bacterial pathogens have evolved elaborate mechanisms to appropriately regulate their virulence programs, which involves sensing and responding to many of these gut metabolites to facilitate successful gut colonization. Long chain fatty acids (LCFAs) represent major constituents of the gut metabolome that can impact bacterial functions. LCFAs serve as important nutrient sources for all cellular organisms and can function as signaling molecules that regulate bacterial metabolism, physiology, and behaviors. Moreover, in several enteric pathogens, including Salmonella enterica, Listeria monocytogenes, Vibrio cholerae, and enterohemorrhagic Escherichia coli, LCFA sensing results in the transcriptional repression of virulence through two general mechanisms. First, some LCFAs function as allosteric inhibitors that decrease the DNA binding affinities of transcriptional activators of virulence genes. Second, some LCFAs also modulate the activation of histidine kinase receptors, which alters downstream intracellular signaling networks to repress virulence. This mini-review will summarize recent studies that have investigated the molecular mechanisms by which different LCFA derivatives modulate the virulence of enteric pathogens, while also highlighting important gaps in the field regarding the roles of LCFAs as determinants of infection and disease.

Clinical Risk Factors and Microbiological and Intestinal Characteristics of Carbapenemase-Producing Enterobacteriaceae Colonization and Subsequent Infection

“…A matter of concern is that patient carriage of or infection with another MDRO has been shown to increase the risk of CRE colonization more than 9-fold ( 42 ). As in this and other studies ( 35 , 36 ), CRE colonization is commonly associated with low SCFA levels. Moreover, these SCFAs serve to enhance the mucosal barrier and inhibit intestinal inflammation ( 30 – 32 ).…”

“…These complicated activities involve microbe-microbe and microbe-host interactions, which include complex bacterial networks, the host immune system, and mucus and intestinal epithelial barrier integrity. A number of studies ( 30 – 32 , 35 , 36 ) have concluded that butyrate is able to recover barrier function through the positive regulation of the expression of claudin-1, ZO-1, and occludin in cdx2-transformed IEC-6 cells (cdx2-IEC) and Caco-2 cells, resulting in increased transepithelial electrical resistance. Thus, we conclude that, to a certain extent, lower SCFA levels were probably associated with downregulated TJ proteins in CRKP-colonized mice.…”

“…Colonization of the intestine by nonhost niche microorganisms can lead to a permeable gut through various mechanisms ( 30 – 38 ), by either being directly responsible for the features of inflammation ( 30 – 32 ) or favoring microbe-microbe and microbe-host interactions such as regulating the diversity and community composition of the cecal microbiome ( 33 , 34 ), manipulating bacterial metabolites ( 35 , 36 ), participating the innate and the adaptive immune responses ( 37 ), and penetrating host barriers ( 38 ), allowing colonizing microorganisms to invade the intestinal tissue and leading to subsequent translocated infection.…”

Salmonella Invasion Is Controlled by Competition among Intestinal Chemical Signals

“…These results imply that as Salmonella moves from the ileum toward environments with lower concentrations of formic acid, the invasion-rescuing effect of formic acid is lost. As the cecum and the colon have lower formic acid and higher fatty acid concentrations ( 14 ), the sequential exposure to these chemical cues may be utilized by Salmonella as a signal to switch from induction to repression of invasion. To test this hypothesis, we analyzed invasion gene expression in Salmonella under various conditions, using a hilA :: luxCDABE reporter fusion.…”

“…Bile functions by disrupting the HilD-DNA complex and mediates rapid degradation of the protein, thus preventing invasion ( 9 ). Similarly, the invasion event is avoided in the large intestine by using short- and long-chain fatty acids (S/LCFA), produced by a vast native microbiota ( 14 ). Fatty acids such as the propionic and oleic acids function to prevent invasion by disrupting the DNA-binding ability of HilD ( 6 , 7 ).…”