The gut is home to a large and diverse community of bacteria and other microbes, known as the gut microbiota. The makeup of this community is important for the health of both the host and its residents. For instance, many gut bacteria help to digest food or keep disease-causing bacteria in check. In return, the host provides them with nutrients. When this balance is disturbed, the host is exposed to risks such as infections. In particular, treatments with antibiotics that kill gut bacteria can lead to side effects like diarrhea, because the gut becomes recolonized with harmful bacteria including Clostridium difficile and Salmonella.

Reese et al. have now investigated what happens to the gut environment after antibiotic treatment and how the gut microbiota recovers. Mice treated with broad-spectrum antibiotics showed an increase in the “redox potential” of their gut environment. Redox potential captures a number of measures of the chemical makeup of an environment, and provides an estimate for how efficiently some bacteria in that environment can grow. Some of the change in redox potential came from the host’s own immune system releasing chemicals as it reacted to the effects of the treatment. However, Reese et al. found that treating gut bacteria in an artificial gut – which has no immune system – also increased the redox potential. This experiment suggests that bacteria actively shape their chemical environment in the gut.

After the treatment, bacteria that thrive under high redox potentials, which include some disease-causing species, recovered first and fastest. This, in turn, helped to bring redox potential back to how it was before the treatment. Although the gut’s chemical environment recovered, some bacterial species were wiped out by the antibiotic treatment. The microbiota only returned to its previous state when the treated mice were housed together with non-treated mice. This was expected because mice that live together commonly exchange microbes, for instance by eating each other’s feces, and the treated mice received new species to replenish their microbiota.

These findings are important because they show that the chemical environment shapes and is shaped by the bacterial communities in the gut. Future research may investigate if altering redox potential in the gut could help to keep the microbiota healthier in infections and diseases of the digestive tract.

Mammalian gut microbial communities are likely to be structured by both host- and microbial-associated factors. Extensive research to date has focused on how host factors like diet (David et al., 2014; Claesson et al., 2012), genetics (Goodrich et al., 2014), geography (De Filippo et al., 2010; Yatsunenko et al., 2012; Arumugam et al., 2011), and immune state (Hooper et al., 2012) shape the gut microbiota. Yet, work in free-living microbial systems reveals that bacteria typically play active roles in shaping their own environment (Shi and Norton, 2000; Gobbetti, 1998; Goddard, 2008; Osono, 2005; Rui et al., 2009; Gerbersdorf et al., 2009). Identifying how these drivers interact is necessary both for a more complete understanding of the gut microbiota and for developing rational interventions. If ecological forces prove important, then compositional changes will likely be the result of feedbacks between the microbes and their environment.

Redox potential, a metric of the environmental capacity for reducing chemical reactions (i.e., those involving the gain of electrons) to occur, is a composite measurement of various factors that influence gut microbiota structure (Cowley et al., 2015; Friedman et al., 2017; Dhall et al., 2014). Much of our knowledge for how gut redox potentials are determined involves host-associated pathways (Spees et al., 2013; Rivera-Chávez et al., 2016). Passive diffusion of oxygen from the epithelium increases redox potential and stimulates growth of aerobic microbes (Espey, 2013; Albenberg et al., 2014). Secretion of redox-active immune molecules such as reactive oxygen species or nitrate is known to be a feature of inflammation that imposes oxidative stress on commensal microbes and can be exploited by select pathogens to colonize the intestine (Winter et al., 2010; 2013; Faber et al., 2016; Spees et al., 2013; Rivera-Chávez et al., 2016; Kelly et al., 2015; David et al., 2015). Maintenance of redox homeostasis in host tissue can also have spillover effects on luminal redox state (Circu and Aw, 2011).

Yet, redox potential is likely to also be shaped by microbial metabolism. In free-living microbial communities, variation in available electron acceptors dictates where microbes that employ respiration can thrive; the differential microbial metabolism that follows can produce further changes in electron acceptor availability (Morris and Schmidt, 2013; Chen et al., 2017; Noll et al., 2005; Orcutt et al., 2011). Moreover, microbial metabolism has been proposed as a mechanism for low redox potential states in the lung of cystic fibrosis patients (Cowley et al., 2015).

Here, we investigated the nature of redox potential dynamics under antibiotic treatment to assess the importance of host and microbial processes in structuring gut bacterial communities. Antibiotics directly disturb the microbiota but are also expected to alter host biology related to redox potential. Specifically, antibiotics have been found to increase gut epithelium oxygenation as a result of altered microbial composition and metabolic signaling to the host (Kelly et al., 2015; Rivera-Chávez et al., 2016). Increases in luminal oxygen due to diffusion from the microvasculature supplying the epithelium would lead to a higher redox potential under antibiotic treatment. In addition, host inflammation responses to antibiotic treatment and antibiotic-associated pathogen colonization have been shown to produce electron acceptors and other redox active molecules that cause oxidative stress (Faber et al., 2016; Winter et al., 2010; 2013; Spees et al., 2013). While these pathways have been demonstrated previously, their overall impact on redox potential has not been measured. Furthermore, the contribution of microbial metabolism to gut redox potential has not been tested, although it is known that a wide range of resident gut bacteria can respire aerobically and anaerobically (Ravcheev and Thiele, 2014). Antibiotic-driven bacterial inhibition could increase the availability of electron acceptors and thus serve as another mechanism for antibiotic induced changes in gut redox potential. On the other hand, antibiotic inhibition could limit bacterial production of oxidizing agents thereby resulting in an overall decrease in redox potential under antibiotics.

Changes in redox potential under antibiotics would in turn be expected to yield insight into the forces structuring the composition and function of the microbiota. Elevated redox potential due to a host immune response could restrict the microbiota beyond direct antibiotic mortality as inflammation would introduce additional oxidative stress into microbial ecosystems. By contrast, elevated redox potential due to the accumulation of oxygen or anaerobic electron acceptors would foster the growth of respiring bacteria. Antibiotic disturbance produces reproducible community succession in the gut following treatment—most notably, a transient bloom in Enterobacteriaceae (Antonopoulos et al., 2009; David et al., 2015; Young and Schmidt, 2004; Theriot et al., 2014; Peterfreund et al., 2012; Dethlefsen et al., 2008; Jakobsson et al., 2010; Looft and Allen, 2012), which has been ascribed to an increase in oxygen availability (David et al., 2015). But, the role of redox potential during this successional process has not previously been studied. If redox potential changes due to antibiotic treatment, we would predict that redox state recovery would be necessary for community resilience, that is for compositional recovery to a pre-disturbance state to occur (Shade et al., 2012). Furthermore, we expect that feedback between the community (i.e. the biotic component of the system) and their environment (i.e., the abiotic component) would drive further redox potential changes during the successional period. Such a pattern would highlight the potential of manipulating redox potential to alter community dynamics after disturbance.

Here, we combined in vivo and ex vivo antibiotic studies to isolate the effects of host and microbial pathways on redox state in the mammalian gut. We confirmed that redox potential increased during antibiotic treatment in association with some changes in host immune state. However, multiple lines of evidence in both mice and an artificial human gut model suggested that antibiotic-induced changes in microbial metabolism were sufficient to cause an increase in redox potential. After antibiotic treatments ended, we observed redox recovery within a week. A successional return to conventional community composition only occurred, though, when mice were co-housed and shared gut microbiota, indicating that microbial dispersal is necessary above and beyond environmental recovery for the return of normal microbiota community structure.

Here, we found that a key feature of the microbial environment, redox potential, can be rapidly and dramatically altered in the gut under antibiotic treatment. This shift was accompanied by changes in electron acceptor availability. The direction and timing of the redox potential shift was associated with microbial dynamics and could be reproduced with an ex vivo model of the human gut absent host effects. Moreover, we found evidence that redox potential kinetics were driven by shifts in microbial load and metabolism, specifically among facultative anaerobes from the family Enterobacteriaceae. Although there was evidence of increases in certain host pathways of electron acceptor production, we did not find persistent and significant changes in host inflammation. Therefore, we propose microbial respiration of host sourced electron acceptors acts as a major determinant of redox potential in the gut, in addition to the host production itself. Redox potential consequently shaped successional dynamics following the cessation of treatment, but return to control redox conditions was insufficient to produce community recovery. Dispersal was required for community structure to exhibit full resilience to antibiotic disturbance.

Our findings imply that electron acceptors are a critical resource normally competed over by the resident bacteria and, as such, are key factors structuring gut microbial ecology. The ability to respire a broad range of electron acceptors is already known to be crucial for pathogens to colonize the intestine (Winter et al., 2010; 2013; Faber et al., 2016). Yet, ecological research to date on commensal microbiota has primarily focused on substrate availability (Donaldson et al., 2016 and references therein, Pereira and Berry, 2017) or, to a lesser extent, oxygen (Espey, 2013). Our results here support the hypothesis that the availability of other electron acceptors is an important ecological factor driving the structure of resident bacterial populations as well (Jones et al., 2007; 2011). If true, this hypothesis would imply that pathogen colonization resistance by commensal microbes could be mediated by bacterial competition involving respiratory pathways.

Future work will be needed to comprehensively chart the dynamics and chemical landscape across which bacteria in the gut compete for electron acceptors. While any redox active molecule could contribute to redox potential changes (hence testing all possible chemical drivers of redox is infeasible), we focused here on three relevant electron acceptor species (oxygen, nitrate, and fumarate) that derive from independent pathways and may be representative of overall dynamics. Our data lead us to conjecture that oxygen availability transiently increased due to the decreased respiration capacity of an antibiotic-constrained bacterial community. But, as oxygen grew increasingly available, the remaining facultative anaerobes switched to aerobic respiration leaving other host-sourced electron acceptors, such as nitrate, to accumulate. Accrued electron acceptors, especially nitrate, may also have been contributed by changes in host physiology as evidenced by an upregulation of the Nos2 gene, which is linked to reactive nitrogen species levels (Dedon and Tannenbaum, 2004; Winterbourn, 2008). Still, not all electron acceptors accumulated during antibiotic treatment. Notably, our data suggest that ones produced by the microbiota rather than the host, like fumarate, were less available under antibiotic pressure.

Our data also support a model where consumption by specific bacterial taxa shape redox homeostasis in the gut. We observe that facultative anaerobes like the Enterobacteriaceae behave as pioneer taxa whose dynamics inversely track redox dynamics after antibiotic treatment, providing new understanding of the deterministic mechanism driving the consistent bloom of these bacteria following antibiotic treatment (Antonopoulos et al., 2009; David et al., 2015; Young and Schmidt, 2004; Theriot et al., 2014; Peterfreund et al., 2012; Dethlefsen et al., 2008; Jakobsson et al., 2010; Looft and Allen, 2012). Enterobacteriaceae are especially suited to exploiting electron acceptor availability because their diverse repertoire of respiration pathways (Ravcheev and Thiele, 2014; Jones et al., 2007; 2011) allow for fast growth rates under a high redox regime. Enterobacteriaceae and respiration pathway genes more generally are also more prevalent in inflamed mouse guts (Hughes et al., 2017), another environment where heightened redox potential is expected. Under experimental inflammation, though, Enterobacteriaceae expansion can be prevented by treatment with tungstate, a respiration inhibitor (Zhu et al., 2018). This result corroborates our model that members of the Enterobacteriaceae use respiration to bloom under disturbed conditions, and it highlights the potential for manipulating electron acceptor availability or usability to engineer the microbiota.

An increase in resource availability is common following ecological disturbance and can promote the growth of pioneer taxa, which are best suited to quickly respond to a resource spike but which draw down the resource thereby bringing about their own displacement (Connell and Slatyer, 1977; Peet and Christensen, 1980; Tilman, 1985). Here, as in many cases of ecological succession, the Enterobacteriaceae were eventually replaced by more conventional community members that typically grow better under more limiting conditions; in fact, the relationship between change in Enterobacteriaceae abundance and change in redox state is consistent with these taxa facilitating the success of secondary colonizers. However, why redox recovery was ultimately hysteretic (i.e., the gut temporarily became a reducing environment following the end of treatment) remains unclear. It has previously been shown that members of the Enterobacteriaceae will produce reducing agents, such as H₂S, in response to antibiotic treatment (Shatalin et al., 2011), but this theory requires further investigation in a community and host-associated context.

Beyond identifying a role for microbiota in shaping gut redox potentials, our results more broadly illustrate how microbial factors can be important in addition to host factors for determining abiotic conditions in the gut through the balancing of production and consumption of resources. While the host is ultimately the source of all substrates in the gut, microbial action determines the realized environment which shapes community composition and function. Such microbial ecosystem engineering (Jones et al., 1994; Wright and Jones, 2006) is consistent with our understanding of how microbes can shape their environments in free-living systems (Gerbersdorf et al., 2009; Goddard, 2008). The altered resource availabilities that result from microbial action then contribute to structuring the microbial community itself. Such feedbacks may contribute to a number of phenomena in host-associated systems. Common constituents of the gut (i.e., the phyla Firmicutes and Bacteroidetes) could perpetuate similar hospitable environments for themselves regardless of host biology leading to the broad, phylum-level consistency of composition seen between humans regardless of diet, geography, or genetics (David et al., 2014; Claesson et al., 2012; Goodrich et al., 2014; De Filippo et al., 2010; Yatsunenko et al., 2012; Arumugam et al., 2011). Variations in how the gut environment is dictated by microbes may also help explain inter-individual differences in response to interventions in the absence of consistent host effects (e.g., Venkataraman et al., 2016). Microbial metabolic signaling additionally can alter host production of substrates including redox active molecules. Most notably reduced butyrate levels, a change observed here, have been demonstrated to increase gut nitrate levels (Byndloss et al., 2017) and host epithelial oxygenation (Rivera-Chávez et al., 2016).

Sequencing data have been deposited in the European Nucleotide Archive under Primary Accession Number (PRJEB26446).

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Author details

1. Aspen T Reese

   1. Department of Biology, Duke University, Durham, United States
   2. Department of Molecular Genetics and Microbiology, Duke University, Durham, United States

   Contribution

   Conceptualization, Data curation, Formal analysis, Funding acquisition, Validation, Investigation, Visualization, Methodology, Writing—original draft, Writing—review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-9004-9470

2. Eugenia H Cho

   Department of Bioengineering, University of Pennsylvania, Philadelphia, United States

   Contribution

   Investigation, Methodology, Writing—review and editing

   Competing interests

   No competing interests declared

3. Bruce Klitzman

   Department of Surgery, Duke University Medical Center, Durham, United States

   Contribution

   Methodology, Writing—review and editing

   Competing interests

   Duke University has received support from Profusa, Inc. as an NIH subaward and additional corporate support for research. Dr. Klitzman has no equity ownership. He now has a consulting agreement and has received professorial sponsorship through Duke University from Profusa, Inc.

4. Scott P Nichols

   Profusa, Inc., South San Francisco, United States

   Contribution

   Software, Investigation, Methodology, Writing—review and editing

   Competing interests

   Is the Director of Pre-Clinical and Advanced Technologies at Profusa, Inc.

5. Natalie A Wisniewski

   Profusa, Inc., South San Francisco, United States

   Contribution

   Software, Methodology, Writing—review and editing

   Competing interests

   Is a Co-Founder and Chief Technology Officer of Profusa, Inc.

6. Max M Villa

   Department of Molecular Genetics and Microbiology, Duke University, Durham, United States

   Contribution

   Validation, Investigation, Methodology, Writing—review and editing

   Competing interests

   No competing interests declared

7. Heather K Durand

   Department of Molecular Genetics and Microbiology, Duke University, Durham, United States

   Contribution

   Investigation, Writing—review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-4059-8484

8. Sharon Jiang

   Department of Molecular Genetics and Microbiology, Duke University, Durham, United States

   Contribution

   Investigation, Writing—review and editing

   Competing interests

   No competing interests declared

9. Firas S Midani

   Program in Computational Biology and Bioinformatics, Duke University, Durham, United States

   Contribution

   Formal analysis, Methodology, Writing—review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-2473-7758

10. Sai N Nimmagadda

    Department of Biomedical Engineering, Duke University, Durham, United States

    Contribution

    Investigation, Writing—review and editing

    Competing interests

    No competing interests declared

    "This ORCID iD identifies the author of this article:" 0000-0003-1837-4054

11. Thomas M O'Connell

    Department of Otolaryngology-Head and Neck Surgery, Indiana University School of Medicine, Indianapolis, United States

    Contribution

    Data curation, Software, Investigation, Methodology, Writing—review and editing

    Competing interests

    No competing interests declared

12. Justin P Wright

    Department of Biology, Duke University, Durham, United States

    Contribution

    Conceptualization, Supervision, Funding acquisition, Writing—review and editing

    Competing interests

    No competing interests declared

13. Marc A Deshusses

    Department of Civil and Environmental Engineering, Duke University, Durham, United States

    Contribution

    Conceptualization, Writing—review and editing

    Competing interests

    No competing interests declared

14. Lawrence A David

    1. Department of Molecular Genetics and Microbiology, Duke University, Durham, United States
    2. Program in Computational Biology and Bioinformatics, Duke University, Durham, United States
    3. Department of Biomedical Engineering, Duke University, Durham, United States
    4. Center for Genomic and Computational Biology, Duke University, Durham, United States

    Contribution

    Conceptualization, Formal analysis, Supervision, Funding acquisition, Project administration, Writing—review and editing

    For correspondence

    lawrence.david@duke.edu

    Competing interests

    No competing interests declared

    "This ORCID iD identifies the author of this article:" 0000-0002-3570-4767

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