Gut cell metabolism shapes the microbiome

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Science  11 Aug 2017:
Vol. 357, Issue 6351, pp. 548-549
DOI: 10.1126/science.aao2202

Gut microbes are key partners in host defense against potential pathogens (1). This might be achieved through cross-talk between gut bacteria, epithelial cells lining the gut (colonocytes), and immune cells (2). Part of this cross-talk involves metabolites derived from the bacteria, such as the short-chain fatty acid butyrate. This can bind to specific G protein-coupled receptors in colonocytes and immune cells, leading to antimicrobial immune responses (3). However, what if this cross-talk were not the full story? On page 570 of this issue, Byndloss et al. (4) show that butyrate instructs colonocytes to consume oxygen through the β-oxidation metabolic pathway and consequently protects the host against the expansion of potentially pathogenic bacteria that can lead to inflammatory bowel diseases.

Colonocytes are exposed to numerous microbial antigens (molecules that activate immune cells) and metabolites. Yet, colonocytes and microbes are usually in a state of symbiosis, whereby inflammation is not induced and a mucous barrier lines the epithelium. This symbiosis occurs particularly with obligate anaerobic bacteria, which survive only in low-oxygen conditions (hypoxia). Some of these bacteria produce butyrate, which is an essential energy source for colonocytes, allowing them to maintain a healthy gut (5). In addition, butyrate decreases immune cell recruitment and proinflammatory signals (6).

Colonocyte metabolism determines gut health

On treatment with antibiotics, colonocytes exhibit altered metabolism, which changes the environment of the gut lumen and the types of bacteria that can thrive.


Conversely, potentially pathogenic bacteria, such as Enterobacteriaceae family members, can populate the gut—particularly after treatment with antibiotics—and cause inflammation, known as dysbiosis. Dysbiosis-inducing bacteria are often facultative anaerobes, which can survive with or without oxygen. Dysbiosis is considered a contributing factor that leads to inflammatory bowel diseases (7).

Symbiosis is maintained by ensuring that conditions are right for the growth of obligate anaerobes and not facultative anaerobes. Hypoxia in the gut lumen is required to prevent the expansion of facultative anaerobic bacteria such as pathogenic Escherichia and Salmonella (7). Colonocytes consume oxygen to β-oxidize butyrate, which contributes to luminal hypoxia by limiting oxygen diffusion into the gut lumen (7). Nitrate is an important energy source for facultative anaerobes and can be produced by the enzyme nitric oxide synthase 2 (NOS2) that is expressed in colonocytes. Therefore, regulating host-derived nitrate and oxygen are key to symbiosis. Recent discoveries suggest that obligate anaerobes also prevent expansion of facultative anaerobes by limiting host production of nitrate and oxygen (8). However, the molecular mechanisms were unknown.

Byndloss et al. treated mice with the antibiotic streptomycin, which alters the microbiota composition, decreases butyrate concentration, and increases nitrate and oxygen in the lumen. How and why do both nitrate and oxygen increase upon streptomycin treatment? This study unequivocally demonstrates that Escherichia coli (a surrogate marker for dysbiosis) requires nitrate for energy production and thus proliferation. The authors also found that butyrate elicits a response in colonocytes that is important for limiting nitrate production. They demonstrate that butyrate activates the nuclear receptor peroxisome proliferator-activated receptor-γ (PPAR-γ) in colonocytes, which in turn repressed the expression of NOS2 and reduced luminal nitrate levels (see the figure).

Immune cells also respond to butyrate through G protein-coupled receptors (6). Moreover, PPAR-γ activates mitochondrial β-oxidation in macrophages (9), thus also consuming oxygen. Additionally, immune cells, such as regulatory T cells (Tregs) that suppress inflammation, are decreased on antibiotic treatment and during intestinal inflammation, altered gut barrier function, or dysbiosis (10). So, how do we know that modulation of colonocytes, rather than immune cells, explains the outgrowth of pathogenic bacteria?

Byndloss et al. investigated this conundrum and dissected the role of PPAR-γ by generating a mouse model lacking PPAR-γ in intestinal epithelial cells that also had reduced numbers of Tregs (by treatment with CD25 antibodies). Colonocyte PPAR-γ loss was associated with higher NOS2 expression and luminal nitrate. In addition, these mice did not respond to butyrate or streptomycin, and were more sensitive to chemically induced intestinal inflammation.

These findings offer an essential contribution to the understanding of numerous pathological situations associated with dysbiosis (11). Indeed, a higher abundance of butyrate-producing bacteria in the gut is associated with a lower risk of intestinal inflammation (12) and gut barrier dysfunction, but also a lower risk of obesity and type 2 diabetes mellitus (13, 14). However, this does not mean that we can target intestinal PPAR-γ to treat such diseases, because there are other butyrate receptors and PPAR-γ has numerous roles.

Several important questions remain unanswered. Can we directly extrapolate such findings to humans? Additionally, we know that numerous types of dysbiosis exist according to the type of antibiotic used. Thus, it is unclear whether all antibiotics affect butyrate-PPAR-γ signaling, or if enough evidence exists to directly link luminal oxygen and nitrate levels to dysbiosis and pathologies. For instance, metformin (used to treat type 2 diabetes mellitus) or gastric bypass surgery (to treat obesity) are associated with increased butyrate-producing bacteria and improved health, but also a higher abundance of Enterobacteriaceae (13). Therefore, an increase in Enterobacteriaceae is not always a risk factor for poor health, due to antibiotic use, or reduced butyrate abundance in the gut (13).

The study by Byndloss et al. highlights a unique mechanism of symbiosis between host and microbes, which directly interferes with the metabolic capacities of both bacterial and host cells. Therefore, this study starts to decipher the complex interactions between host and microbes, which may help identify future therapeutic strategies targeting the gut microbiota.

References and Notes

  1. Acknowledgments: P.D.C. is a recipient of grants from Fonds de la Recherche Scientifique, European Research Council Starting grant 2013 (336452-ENIGMO), Fund for Strategic Fundamental Research-WELBIO, and the Funds Baillet Latour (Grant for Medical Research 2015).

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