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Published in final edited form as: Curr Opin Microbiol. 2014 Dec 2;0:121–125. doi: 10.1016/j.mib.2014.11.010

The rest of the story: the microbiome and gastrointestinal infections

Jhansi L Leslie a, Vincent B Young a,b,#
PMCID: PMC4324160  NIHMSID: NIHMS643395  PMID: 25461582

Abstract

Bacterial infectious diseases are studied primarily as a host-pathogen dyad. However it is increasingly apparent that the gut microbial community is an important participant in these interactions. The gut microbiota influences bacterial infections in a number of ways, including via bacterial metabolism, stimulation of host immunity and direct bacterial antagonism. This review focuses on recent findings highlighting the interplay between the gastrointestinal microbiota, its host and bacterial pathogens; and emphasizes how these interactions ultimately impact our understanding of infectious diseases.

Introduction

Classically, infectious diseases are viewed as a two-way interaction between a host and an invading pathogen. However, recent studies increasingly demonstrate that this perception is an over simplification. Appreciation that most organisms are colonized with distinct polymicrobial communities, collectively termed the microbiota, has lead to a reexamination of the concept of microbes in the context of health and disease [1]. Experiments in germ-free organisms, which lack a microbiota, show that the acquisition of symbiotic microbes is critical for normal development of the host [2,3]. In addition to host development, there is increasing appreciation that the microbiota plays a role in determining susceptibility and outcome of infections (Table 1).

Table 1.

The Effect of the Microbiome on Infection

Type of Interaction Pathogen Outcome of Infection Reference
Direct
Production of bacteriocins C. perfringens
C. difficile 		Decreased colonization [35] [36]
Competition for nutrients S. Typhimurium Decreased colonization [37]
Cross-feeding (eg. H2, Salic acid) S. Typhimurium
C. difficile 		Increased colonization [38] [39]
Conversion of host derived metabolites (eg. Bile acids) C. difficile Decreased colonization [11••]
Indirect
Production of immunomodulatory molecules (e.g. butyrate) --- --- [16] [17] [19•]
Stimulation of hematopoiesis L. monocytogenes Increased myelopoiesis and protection from systemic infection [21•]
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This review focuses on studies exploring interactions between the microbiota and either a host or a pathogen and endeavors to highlight how integration of the microbiota in to the investigation of host-pathogen interactions can ultimately lead to a more complete understanding of infectious diseases.

Host-Microbiota interactions: more than the sum of the parts

While it is becoming evident that few, if any, sites within the human body are truly sterile, the gastrointestinal tract is the most densely colonized site in the human body [4,5]. The adult gastrointestinal tract is primarily colonized by anaerobic bacteria that broadly belong to two phyla; Firmicutes and Bacteroidetes [6]. The presence and composition of the gut microbiota are important determinates of host physiology and health, while ‘dysbiosis’ or an altered gut microbial community is associated with states of disease [7,8]. Understanding the interplay between the gut microbiota and the host is an important topic of investigation.

Metabolic interactions

The symbioses between a host and associated communities are integral to the physiology of both. At the core of these interactions is metabolism as the gut bacterial community is important to the metabolic potential of the host. While therapeutic doses of antibiotics are known to alter the microbiome, low doses of antibiotics given early in life lead to lasting effects in composition of the gut microbial community [9]. These changes are associated with long-term alterations in host metabolism, which may predispose the host to diet dependent obesity [10].

Host-microbiota metabolism is tightly linked; disruption of the microbiota shifts the gastrointestinal metabolic profile towards one that supports the growth of bacterial pathogens. In the context of C. difficile infection, a study correlating colonization resistance to community structure demonstrates that communities that are drastically different in terms of membership can provide resistance to colonization by C. difficile [11••]. Rather than the community structure, the commonality between these resistant communities was their metabolic profile. Specifically, the susceptible community had a significant increase in key metabolites utilized by C. difficile such as carbon sources and primary bile acids like taurocholate.

Bile acid metabolism is a process that depends on both the host and the microbiota. The host synthesizes and secretes primary bile acids. Bile not actively recovered in the distal ileum is conjugated by the colonic microbiota into secondary bile acids which are then absorbed by the host in the colon (the role microbiota and bile acid metabolism is reviewed here [12]). However, antibiotic mediated alterations of the microbiota disrupts host-microbiota bile acid metabolism leading to increased levels of primary bile acids in the large bowel, setting up an advantageous environment for germination of C. difficile spores [13]. The importance of bile acids in the pathogenesis of C. difficile is underscored by findings that suggest that Clostridium scindens, a bacterium that can convert primary to secondary bile acids, partially restores colonization resistance to C. difficile [14,15].

Regulation of immune response

Many aspects of host immune function are regulated by signals produced by the microbiome, such as metabolites. Butyrate, one short chain fatty acid produced by members of the microbiota, facilitates the development of localized immunity in the form of populations of peripheral anti-inflammatory T regulatory cells [16,17]. The immunomodulatory aspect of Tregs has been shown to play a role in persistent bacterial infections [18]. Since phylogenetically diverse members of the microbial community are able to elicit the differentiation of peripheral Tregs, this suggests that there is likely functional redundancy in composition of the gut microbial communities, such that different community structures provide the same function [19,20].

In addition to altering local immune response, microbiome-derived signals regulate immune function at primary immune sites [21•]. In mice, the presence of a gut microbial community enhances levels of myelopoiesis. Compared to germ-free or antibiotic treated mice, mice with intact microbiota had increased myeloid cells and were protected from systemic infection with the pathogen Listeria monocytogenes. Notably in this model, myelopoiesis was only achieved in the context of colonization with live bacteria, administration of MAMPs or SCFAs was not sufficient to restore germ-free mice to levels comparable to mice with intact communities. This suggests that diverse bacterial signals modulate host immunity, tuning the immune system to respond to a given situation such as bacterial or viral infections [22,23].

While microbial products alter the host, changes in host physiology can also alter the microbiota. Due to the abundance of anaerobes in the intestines it has been assumed that the lumen is strictly anaerobic. Characterization of the structure of the GI tract has shown that there are distinct communities associated with the mucosa compared to the lumen [24]. These distinct community structures are arranged in concordance with the radial oxygen gradient that exists within the gut [25,26]. Microbial communities are not immutable and changes in oxygen maybe a key driver. Notably, exogenous oxygen exposure such as hyperbaric oxygen therapy can shift the composition of the fecal microbiota [26••]. Inflammation can also alter oxygen homeostasis in the gut via the release of reactive oxygen and nitrogen species. While obligate anaerobes are incapable of detoxifying reactive oxygen species, some facultative anaerobes thrive in the inflamed gut [27]. Bacteria from the family Enterobacteriaceae, such as Escherichia coli are able to utilize host-derived nitrate as an alternative electron receptor during anaerobic respiration thereby gaining a competitive edge to expand within the gut [28]. Interestingly, antibiotic therapy, a risk factor for infections by non-typhoid Salmonella, decreases colonization resistance to E. coli by increasing inflammation in the gut [29]. Thus the interplay between a host and its microbiota is central to a host’s predisposition to infection.

Pathogen-Microbiota interactions: context matters

Another critical function of the microbiota is colonization resistance, or the capacity of the microbes that colonize our body to exclude pathogens. While some aspects of colonization resistance are mediated by bacterial modulation of immune response, bacteria-bacteria interactions also play a role. Unraveling how these direct bacterial interactions affect the pathogenesis of an infection has been the focus of many recent studies.

Direct bacterial inhibition

Bacteria are constantly competing for space and nutrients. One way that bacteria gain a competitive advantage is via production of microbial products such as bacteriocins [30,31]. Bacteriocins are ribosomal synthesized microbial peptides that typically have a narrow range of bactericidal activity. While lactic acid bacteria production of bacteriocins has received much focus, many bacteria are believed to be capable of producing bacteriocins (for a comprehensive review please see [32]). Recently, bacteriocins have been appreciated as a means by which members of the gut microbiota might exclude bacterial pathogens. Human stool has been shown to contain many strains capable of producing bacteriocins [33,34]. Recently, Thuricin CD, a bacteriocin produced by a strain of Bacillus thuringiensis isolated from a human fecal sample, was demonstrated to have activity against C. difficile in a mouse model of infection [35].

As an added wrinkle of complexity in microbiota-pathogen interactions, production of bacteriocins may be driven by the context of the surrounding microbial community. In the setting of a four-strain consortium of fecal isolates that excluded Clostridium perfringens colonization, an isolate of Ruminococcus gnavus produced an anti-bacterial product only when specific members of the consortia were present [36]. The anti-bacterial substance was detected in Ruminococcus gnavus mono-associated mice or when it was present with the two Clostridia members of consortia, however addition of Bacteroides thetaiotaomicron to the community suppressed the expression of this molecule.

Competition for nutrients

Another facet of the interplay between the microbiota and invading pathogens is nutrient base interactions. In addition to microbiota-host metabolioic interactions mentioned earlier, the metabolism of microbiota plays a role in colonization resistance, as pathogens must compete with resident microbes for the nutrients they need to grow. An example of nutrient based bacterial antagonism was recently described in the case of E. coli strain Nissle 1917 mediated colonization resistance to infection by Salmonella enterica serovar Typhimurium (S. Typhimurium) [37••]. E. coli strain Nissle is a well studied probiotic originally isolated in 1917 from a solider who was protected from infectious gastroenteritis. During infection with S. Typhimurium, inflammation limits the availability of key nutrients like iron. Since E. coli strain Nissle has many redundant iron transporters, it was hypothesized that it would be a suitable competitor for S. Typhimurium, during infection. A single dose of E. coli strain Nissle after infection with S. Typhimurium, lead to persistent colonization by E. coli strain Nissle and decreased levels of S. Typhimurium, colonization. Furthermore, reduced S. Typhimurium colonization was dependent on the presence of E. coli Nissle iron transport and independent of its immunemodulatory effect.

While some gut microbiota -pathogen relations can be detrimental to the pathogen, pathogens can also scavenge nutrients from the gut microbiota. S. Typhimurium, can utilize molecular hydrogen derived from the microbiota as an alternative electron source in order to colonize an intact gut microbial community [38]. In addition, recent work has highlighted bacterial cross-feeding during colonization by enteric pathogens [39]. Using a gnotobiotic mouse colonized with B. thetaiotaomicron as a model of an antibiotic treated gut, the authors found that levels of C. difficile were increased in these mice compared to infected germ-free mice. Notably, increased levels of C. difficile colonization is dependent on the ability of B. thetaiotaomicron to cleave host sialic acid, which is source of nutrition for C. difficile.

The significance of the microbiota in the context of this infection is underscored by findings which demonstrate that transplant of stool from healthy uninfected individuals can reduce colonization by diverse bacterial pathogens such as C. difficile or Vancomycin-resistant enterococci (VRE) [40–42]. A better understanding of the physiology of members of the gut microbiota will enable the rational selection of bacteria that best compete with specific enteric pathogens.

Host-microbiota-pathogen interactions: a systems approach to infection

While there is still much to be learned regarding the basic interactions within the gut microbiome itself, thinking about the microbiome in the context of infection can provide a more complete story in the study of host-pathogen interactions.

In many bacterial infections, such as those caused by VRE or Citrobacter rodentium, the cytokine IL-22 is protective [43,44]. Yet surprisingly, when comparing salmonella infection in wild-type versus IL-22 deficient mice, S. Typhimurium, colonization was enhanced in the presence of IL-22 [45••]. After exploring possible factors such as the pre-infection gut microbial community structure or post-infection levels of inflammation the authors found no major differences between the two strains of mice. However, the authors noticed that following S. Typhimurium infection, the intestine of IL-22 deficient mice experienced a ‘bloom’ of bacteria from the family Enterobacteriaceae. Further work demonstrated that commensal Enterobacteriacea were suppressed by antimicrobial peptides upregulated by IL-22, however in the absence of IL-22 the Enterobacteriacea were not suppressed and thus were able to compete with S. Typhimurium, reducing levels of colonization.

Concluding remarks

Gastrointestinal infections are more than host-pathogen interactions; rather they represent the culmination of dynamic exchanges between a host, its microbiome and a pathogen. The microbiota affects the outcome of infections both directly and indirectly. Studying the gastrointestinal microbiota within the framework of infectious diseases provides context to the narrative of an infection. Experiments cataloging structural differences in the microbiome during disease have paved the way for future studies, which should strive to understand the functional result of these changes.

Highlights.

  • The gut microbiome is a critical component in many gastrointestinal infections.

  • The microbiota modulates infections through both direct and indirect interactions.

  • Appropriate development of host immunity is dependent on the microbiome.

  • Dissimilar microbial communities may provide similar functions.

Acknowledgments

This work was funded by NIH grants T32 AI007528 (JLL) U19 AI09871 AND P30 DK034933 (VBY).

Footnotes

Address of Institution:

University of Michigan Medical School, 1500 E Medical Center Dr., Ann Arbor, MI 48109 USA

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