Bile-tolerant Gram-Negative Bacteria

bile-resistant Gram-negative bacteria
SUMMARY
Bacterial pathogens have coevolved with humans in order to efficiently infect, replicate within, and be transmitted to new hosts to ensure survival and a continual infection cycle. For enteric pathogens, the ability to adapt to numerous host factors under the harsh conditions of the gastrointestinal tract is critical for establishing infection. One such host factor readily encountered by enteric bacteria is bile, an innately antimicrobial detergent-like compound essential for digestion and nutrient absorption. Not only have enteric pathogens evolved to resist the bactericidal conditions of bile, but these bacteria also utilize bile as a signal to enhance virulence regulation for efficient infection. This review provides a comprehensive and up-to-date analysis of bile-related research with enteric pathogens. From common responses to the unique expression of specific virulence factors, each pathogen has overcome significant challenges to establish infection in the gastrointestinal tract. Utilization of bile as a signal to modulate virulence factor expression has led to important insights for our understanding of virulence mechanisms for many pathogens. Further research on enteric pathogens exposed to this in vivo signal will benefit therapeutic and vaccine development and ultimately enhance our success at combating such elite pathogens.

INTRODUCTION
Enteric pathogenic bacteria represent a unique set of pathogens, as these bacteria must overcome numerous challenges in order to successfully establish infection in the small intestine or colon (Fig. 1). These challenges include pathogen-specific immune responses (1) and several bactericidal conditions of the gastrointestinal tract, including the low pH of the stomach (2), the presence of bile in the small intestine (3, 4), low iron availability (5, 6), and an established commensal microbiome consisting of billions of bacteria from hundreds of different species (7). The human gastrointestinal tract is a challenging environment that prevents many bacteria from surviving under these harsh conditions; however, enteric bacterial pathogens have evolved not only to survive these severe exposures but also to successfully colonize and establish infection in the host.

Given the length of the small intestine, bile is one of the more long-term exposures encountered by bacteria, both pathogenic and commensal, in the early part of the gastrointestinal tract. For the host, bile is essential for digestion and nutrient absorption and is composed of proteins (globulins and albumins), lipids (phospholipids, cholesterol, and fatty acids), carbohydrates, vitamins, mineral salts, and other trace elements (8). In the liver, the primary bile acids cholic acid and chenodeoxycholic acid are synthesized by hepatocytes and are further metabolized in the liver by conjugation to glycine or taurine through N-acyl amidation. Conjugated bile acids have reduced bile acid toxicity and increased solubility, are almost fully ionized at physiological pH, and are termed bile salts. Bile salts are maintained at high concentrations in the duodenum, jejunum, and proximal ileum to solubilize, digest, and absorb lipids and lipid-soluble vitamins (8, 9). The facultative and anaerobic commensal bacteria in the small intestine metabolize bile salts through deconjugation and hydroxy group oxidation, resulting in the production of secondary bile salt compounds. In the distal ileum, bile salts are absorbed into the bloodstream, complexed to plasma proteins, and returned to the liver (9). The majority of bile (95%) is recycled back into the small intestine and does not enter the colon (10). Concentrations of bile salts range from 0.2% to 2% (wt/vol), depending on the time of day, diet, and individual (11). As reviewed by Ridlon et al., bacterial colonization in the small intestine increases from ∼103 bacteria/ml in the duodenum to 104 bacteria/ml in the jejunum and 106 to 108 bacteria/ml in the ileum. Lactobacillus and Streptococcus are the predominant genera in the duodenum and jejunum, while Enterococcus, Bacteroides, Clostridium, and other commensals, in addition to Lactobacillus, are able to colonize the ileum (9). Human and rodent studies have demonstrated that the bactericidal properties of bile components likely prevent overgrowth of the commensal bacteria in the small intestine. The absence of this mechanism is problematic for individuals who have reduced bile output, such as patients with hereditary defects like intrahepatic cholestasis (12 – 15).
Depending on the organism and the site of infection, pathogenic bacteria have developed resistance mechanisms to counteract the bactericidal conditions of bile. In fact, a number of enteric pathogens use bile as a signal to regulate virulence gene expression to either colonize or maintain infection in the human gastrointestinal tract (Tables 1 and 2). For pathogens that colonize the small intestine, resistance to bile is critical to ensure long-term survival in the host. Here we review the bile-associated regulation of virulence mechanisms in enteric bacterial pathogens and provide an analysis of the bile-related research performed to date.
https://journals.asm.org/doi/10.1128/cmr.00031-16

https://journals.asm.org/doi/10.1128/cmr.00031-16

Bile-tolerant Gram-Negative Bacteria

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