Regulation of bacterial pathogenesis by intestinal short-chain Fatty acids

Abstract

The human gut microbiota is inextricably linked to health and disease. One important function of the commensal organisms living in the intestine is to provide colonization resistance against invading enteric pathogens. Because of the complex nature of the interaction between the microbiota and its host, multiple mechanisms likely contribute to resistance. In this review, we dissect the biological role of short-chain fatty acids (SCFA), which are fermentation end products of the intestinal microbiota, in host-pathogen interactions. SCFA exert an extensive influence on host physiology through nutritional, regulatory, and immunomodulatory functions and can also affect bacterial fitness as a form of acid stress. Moreover, SCFA act as a signal for virulence gene regulation in common enteric pathogens. Taken together, these studies highlight the importance of the chemical environment where the biology of the host, the microbiota, and the pathogen intersects, which provides a basis for designing effective infection prevention and control.

Keywords: Gut microbiota; Short-chain fatty acids; Virulence gene regulation.

© 2013 Elsevier Inc. All rights reserved.

Figures

Figure 3.1

An overview of short-chain fatty acid (SCFA) production in the intestines. Primary fermenters such as Bacteroides species oxidize mono- and oligosaccharides and release SCFA that can be subsequently utilized by secondary fermenters to generate additional SCFA. Acetogens also utilize hydrogen released from fermentation reactions along with carbon dioxide to form acetate, thereby contributing to intestinal SCFA content.

Figure 3.2

A representative schematic of bacterial responses to weak organic acids. Nonionized organic acids, symbolized as “HA,” can diffuse across bacterial membrane and dissociate into protons (H+) and anions (A−) in the circumneutral cytoplasm. This influx of proton will induce the acid tolerance response (ATR) that functions to maintain intracellular pH homeostasis by removing cytoplasmic protons. ATR, in general, includes a glutamate decarboxylase system (GadD, glutamate decarboxylase; GadT, glutamate-GABA antiporter), an F0F1-ATPase, and a deamination system (e.g., AA, arginine; amine, ornithine). The organic anions accumulated in the cytoplasm can feed into metabolic pathways such as TCA cycle or membrane fatty acid synthesis after addition of coenzyme A.

Figure 3.3

A model depicting virulence functions of representative enteric pathogen in response to an intestinal gradient of short-chain fatty acids (SCFA). Ec, Enterohaemorrhagic Escherichia coli, upregulates flagella synthesis in response to butyrate. Lm, Listeria mono-cytogenes, reduces production of the pore-forming toxin, listeriolysin O, in response to butyrate. Se, Salmonella enterica, decreases production of Type III Secretion System in response to colonic mixtures of SCFA.