Review
The impact of intestinal inflammation on the nutritional environment of the gut microbiota

https://doi.org/10.1016/j.imlet.2014.04.014Get rights and content

Highlights

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    Metal withholding mechanisms of the host alter the contest rules for microbes.

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    Exogenous electron acceptors are produced as a by-product of the host response.

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    New metabolic opportunities created by the host response guide microbiota changes.

Abstract

The intestinal epithelium is a single cell barrier separating a sterile mucosal tissue from a large microbial community dominated by obligate anaerobic bacteria, which inhabit the gut lumen. To maintain mucosal integrity, any breach in the epithelial barrier needs to be met with an inflammatory host response designed to repel microbial intruders from the tissue, protect the mucosal surface and repair injuries to the epithelium. In addition, inflammation induces mechanisms of nutritional immunity, which limit the availability of metals in the intestinal lumen, thereby imposing new selective forces on microbial growth. However, the inflammatory host response also has important side effects. A by-product of producing reactive oxygen and nitrogen species aimed at eradicating microbial intruders is the luminal generation of exogenous electron acceptors. The presence of these electron acceptors creates a new metabolic niche that is filled by facultative anaerobic bacteria. Here we review the changes in microbial nutrient utilization that accompany intestinal inflammation and the consequent changes in the composition of gut-associated microbial communities.

Introduction

During intestinal inflammation the epithelium plays an important role in mounting responses that are aimed at clearing the mucosal surface from microbes. For example, production of IFN-γ during inflammation results in the activation of DUOX2 (dual function NADPH oxidase 2) [1], NOX1 (NADPH oxidase 1) [2] and iNOS (inducible nitric oxide synthase) [3] in epithelial cells. Reactive oxygen species (ROS) produced by DUOX2 and NOX1 and reactive nitrogen species (RNS) generated by iNOS create a hostile environment in close proximity to the mucosal surface. Furthermore, the pro-inflammatory cytokine interleukin (IL)-22 induces the luminal release of the antimicrobial proteins lipocalin-2, calprotectin, RegIIIβ (regenerating islet-derived 3 beta) and RegIIIγ from epithelial cells [4], [5], [6].

These epithelial defenses can be augmented by the transmigration of neutrophils into the intestinal lumen as the severity of intestinal inflammation increases. Upon transmigration, the phagocyte NADPH oxidase (PHOX), superoxide dismutase (SOD) and myeloperoxidase (MPO) of neutrophils generate additional ROS in the gut lumen. Subsequent lysis of neutrophils in the intestinal lumen releases calprotectin, which constitutes approximately 40% of their cytoplasmic content [7]. As a result, neutrophils are the main sources of luminal calprotectin during severe intestinal inflammation [8].

Some of the antimicrobials released into the intestinal lumen are bacteriocidal, thereby protecting the mucosa from infection. For instance, release of the C-type lectin RegIIIγ contributes to luminal clearance of opportunistic pathogens, such as Listeria monocytogenes or vancomycin-resistant Enterococcus feacium, which are both members of the class Bacilli within the phylum Firmicutes [9], [10]. Chronic granulomatous disease, an illness caused by PHOX-deficiency, illustrates that the generation of ROS by phagocytes is essential for preventing recurrent bacterial infections [11], [12], [13]. It is thus likely that upon transmigration into the lumen, the respiratory burst of neutrophils aids in clearing bacteria from the vicinity of the mucosal surface. However, recent evidence suggests that in addition to its bacteriocidal effects, the inflammatory host response has also a profound impact on the nutritional environment in the gut lumen, which can lead to alterations in the composition of gut-associated microbial communities (microbiota). Here we review these novel hypotheses and the underlying mechanisms.

Section snippets

Nutritional immunity changes the rules for microbial contestants

One subset of antimicrobial proteins released into the intestinal lumen during inflammation functions in limiting the availability of trace elements required for bacterial growth, such as iron and zinc, a host defense mechanism known as nutritional immunity. Bacteria acquire ferric iron (Fe3+) by releasing high-affinity iron chelators, termed siderophores (reviewed in [14]). Enterobactin, a cyclic trimer of N-(2,3-dihydroxybenzoyl)-l-serine, is the siderophore produced by most members of the

Microbial metabolism in the healthy large intestine

In addition to conferring nutritional immunity by lowering the availability of metals in the intestinal lumen, the host response changes the luminal environment by generating inflammation-derived nutrients as a by-product. The resulting bloom of bacterial species that can utilize inflammation-derived nutrients can alter the composition of gut-associated microbial communities. To understand how inflammation-derived nutrients alter the growth conditions in the large bowel, it is important to

By-products of the host response support anaerobic respiration

Inflammation causes a dramatic change in the nutritional environment in the large intestine by generating exogenous electron acceptors. This concept was first established by showing that a by-product of neutrophils mounting a respiratory burst in the gut lumen is the oxidation of thiosulfate to tetrathionate (S4O62−) [40] (Fig. 1B). S. enterica can use tetrathionate as a respiratory electron acceptor, a property that has been used empirically in clinical laboratories since 1923 to enrich for

Why inflammation-derived electron acceptors favor Enterobacteriaceae

Exogenous electron acceptors enable Enterobacteriaceae to use strategies for maintaining redox balance, generating energy and acquiring carbon for biosynthesis of primary metabolites that are fundamentally different from those employed by Bacteroidia and Clostridia, thereby creating a new metabolic niche for these facultative anaerobic bacteria (Fig. 1). There are three advantages the metabolic strategy of Enterobacteriaceae has over that employed by Bacteroidia and Clostridia.

First, anaerobic

Conclusions

Intestinal inflammation has an impact on microbial metabolism through two different mechanisms. The first is related to the activity of antimicrobial proteins, which are released into the intestinal lumen during inflammation. The presence of these antimicrobial proteins favors growth of bacteria that are resistant against host nutrient withholding mechanisms [5], [8]. As a result, nutritional immunity can alter the outcome of a competition between individual microbes [30]. A mechanistic

Acknowledgements

Work in A.J.B.’s laboratory is supported by Public Health Service grants AI107393 and AI096528.

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