Frenemies: Signaling and Nutritional Integration in Pathogen-Microbiota-Host Interactions

Abstract

The mammalian gastrointestinal (GI) microbiota is highly adapted to thrive in the GI environment and performs key functions related to host nutrition, physiology, development, immunity, and behavior. Successful host-bacterial associations require chemical signaling and optimal nutrient utilization and exchange. However, this important balance can be severely disrupted by environmental stimuli, with one of the most common insults upon the microbiota being infectious diseases. Although the microbiota acts as a barrier toward enteric pathogens, many enteric pathogens exploit signals and nutrients derived from both the microbiota and host to regulate their virulence programs. Here we review several signaling and nutrient recognition systems employed by GI pathogens to regulate growth and virulence. We discuss how shifts in the microbiota composition change host susceptibility to infection and how dietary changes or manipulation of the microbiota could potentially prevent and/or ameliorate GI infections.

Fig 1

Microbiota-derived nutrients feed pathogenic bacteria. Black arrows indicate production of a particular nutrient, blue arrows indicate consumption of the indicated nutrient. Members of the intestinal microbiota stimulate (green arrow) mucosal sugar production by the host as well as produce glycosidic enzymes that liberate mucosal sugars (galactose, fucose, sialic acid etc) from host mucin glycoproteins. Liberated mucosal sugars can directly feed invading pathogen populations. Fermentation of dietary and host-derived sugars by the microbiota leads to production of SCFA, hydrogen and organic acids like succinate, which can also serve as nutrient sources for pathogens during infection. Epithelial cell turnover releases ethanolamine into the lumen of the gut, where it can serve as a selective nutrient for pathogen proliferation during inflammation.

Fig. 2

Modulation of virulence by commensal Bacteroides. Commensal Bacteroides affect virulence and progression of disease by AE pathogens in several ways. A. Bacteroides produce a significant amount of succinate as a by-product of carbohydrate fermentation. Succinate is sensed by EHEC and C. rodentium and upregulates expression of the LEE PAI. B. L-fucose is liberated from host mucin glycoproteins by fucosidases expressed by members of the microbiota such as Bacteroides thetaiotaomicron. Free fucose is sensed by EHEC and represses the LEE PAI to prevent early activation of this virulence factor before reaching the epithelium. C. Nutrient competition between Bacteroides spp. and pathogenic enterobacteriaceae significantly affects the progression of disease. When only simple sugars (mono and di-saccharides) are present commensal Bacteroides and pathogens are forced to compete for nutrients, which limits growth and eventually leads to clearance of the pathogen. When both simple sugars and complex carbohydrates are present Bacteroides will preferentially utilize polysaccharides, and pathogenic enterobacteriacae are able to utilize simple sugars to proliferate and persist in the intestine.

Fig. 3

Adrenergic and nutrient signals intersect to control expression of the EHEC LEE. Host hormones Epinephrine (Epi) and Norepinephrine (NE), whose intestinal availability is modulated by the microbiota, are recognized by two sensor histidine kinases, QseC and QseE. QseC also recognizes the microbiota-derived quorum sensing molecule AI-3. QseC and QseE phosphorylate their cognate response regulators (RR) QseB and QseE respectively and QseC also phosphorylates RRs KdpE and QseF. KdpE interacts with the master regulator of carbon metabolism Cra to activate Ler, which Cra also activates under gluconeogenic conditions (ex: low glucose levels, high levels of succinate). The mucosal sugar fucose, whose liberation is microbiota dependent, is recognized by another HK FusK. FusR, the cognate RR of FusK, represses activation of the LEE. Expression of FusKR is repressed by the QseC/QseE signalling cascade.