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Microbial management

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Science  10 Jul 2020:
Vol. 369, Issue 6500, pp. 153
DOI: 10.1126/science.abc5619

The human colon is home to a complex microbial ecosystem (microbiota), composed mostly of anaerobic organisms. Recent data suggest that gut microbes and their metabolites can affect human health through multiple mechanisms including altering the immune response (1), changing host cell metabolic states (2), and even affecting the response to immunotherapies (3).

The potential causative role of gut microbiota in health and disease is one of the most extraordinary findings of the past decade. Yet we are only starting to understand the multitude of mechanisms by which microbes promote changes in intestinal physiology, and how changes in the symbiotic relationship between the host and the resident microbiota contribute to the pathogenesis of both infectious and noninfectious diseases.


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In the healthy colon, Enterobacteriaceae are a minor constituent of microbiota (4). However, a wide range of human diseases are associated with a severe disruption of the balanced gut microbial ecosystem, often characterized by an expansion of facultative anaerobic Enterobacteriaceae (5) (Fig. 1A). Indeed, a disturbance of the intestinal microbial community by antibiotic treatment results in Enterobacteriaceae outgrowth (610). An intestinal bloom of Enterobacteriaceae is also observed in humans with severe intestinal inflammation, including patients with inflammatory bowel disease (1114), colorectal cancer (15, 16), necrotizing enterocolitis (17), and during conditions of low-level intestinal inflammation, such as irritable bowel syndrome (18, 19) and obesity (20, 21). These studies suggest that Enterobacteriaceae expansion may play an important role in the pathogenesis of human diseases and should be considered a microbial signature of intestinal dysbiosis.

I have leveraged my background in microbiology, immunology, and veterinary medicine to determine the mechanisms by which the host and the microbiota interact to prevent disease-associated Enterobacteriaceae expansion (10). An important benefit we derive from the obligate anaerobic microbes that inhabit our colon is their ability to digest complex dietary carbohydrates (fiber) into fermentation products that contribute to host nutrition (22), immune development (2326), and niche protection against pathogens (10, 27). In contrast, facultative anaerobic bacteria, such as Enterobacteriaceae, do not provide such benefits and instead may be capable of diverting nutrients away from the host by metabolizing fermentation products when oxygen is present (2830). Thus, it is likely that the host has evolved strategies to help maintain a diverse intestinal microbial community dominated by obligate anaerobic bacteria that generate fermentation products from fiber, a strategy also known as “microbiota-nourishing immunity” (31, 32).

My recent work highlights the central role of colonic epithelial cells (colonocytes) in shaping a beneficial microbiota and promoting microbiota-nourishing immunity (Fig. 1B). Colonocyte maturation and differentiation requires PPAR-γ (peroxisome proliferator–activated receptor–γ) (33), a nuclear receptor highly expressed in differentiated colonocytes of mice and humans (34). PPAR-γ activates mitochondrial β-oxidation of long-chain and short-chain fatty acids (SCFAs), resulting in oxygen consumption through oxidative phosphorylation (3537). Mature colonocytes consume high levels of oxygen to maintain their oxidative metabolic state, resulting in an oxygen partial pressure of less than 7.6 mmHg (<1% oxygen), a condition known as physiologic epithelial hypoxia (38). I established that the highly oxidative metabolic state of mature colonocytes plays a critical role in limiting the amount of oxygen diffusing from the mucosal surface, which helps to maintain an anaerobic environment in the lumen of the large bowel (Fig. 1B) (10, 39). Through this mechanism, the colonic epithelium ensures the dominance of beneficial anaerobic microorganisms, thereby maintaining gut homeostasis.

The role of colonocytes in maintaining homeostasis in the colon suggests that an imbalance in the microbial community could be caused by an underlying defect in epithelial metabolic function. To gain insights into mechanisms of gut homeostasis disruption, I employed an antibiotic model of microbiota disturbance (Fig. 1B), which alters epithelial metabolism via depletion of the microbial-derived SCFAs butyrate, propionate, and acetate. Butyrate activates PPAR-γ signaling in human epithelial cells (40) to drive the metabolism of surface colonocytes toward mitochondrial β-oxidation (3537), which is important for maintaining physiologic hypoxia (10).

Intestinal epithelial dysfunction is a key driver of dysbiosis-associated expansion of Enterobacteriaceae. (A) In the healthy gut, the intestinal microbiota is dominated by obligate anaerobic bacteria (teal). An important feature of multiple human diseases is inflammation-induced gut dysbiosis characterized by a shift in the microbial community structure from obligate to facultative anerobic bacteria (red) such as Enterobacteriaceae. (B) During gut homeostasis (left), β-oxidation of microbiota-derived butyrate causes epithelial hypoxia, which supports an anaerobic environment in the lumen of the large intestine. Lack of luminal oxygen drives a dominance of beneficial obligate anaerobic bacteria (teal) in the gut microbiota. During gut dysbiosis (right), colonocytes decrease their oxidative capacity, either due to antibiotic-mediated decreases in butyrate-dependent PPAR-γ signaling (pictured) or due to expansion of immature colonocytes during repair responses. The resulting epithelial dysfunction disrupts anaerobiosis in the lumen and increases the availability of alternative electron acceptors, driving an expansion of facultative anaerobic Enterobacteriaceae by aerobic and anaerobic respiration. ANGPTL4, Angiopoietin-like protein 4.

GRAPHIC: ADAPTED FROM M. X. BYNDLOSS BY N. DESAI/SCIENCE

SCFAs also play a role in inhibiting intestinal inflammation by maintaining the regulatory T cell pool in the mucosa (2326). My work established that antibiotic treatment increases the intestinal inflammatory tone (41) by down-regulating epithelial PPAR-γ signaling and decreasing the number of regulatory T cells in the colonic mucosa (10, 41). The resulting up-regulation of inflammatory signals caused a shift in the metabolism of differentiated colonocytes toward anaerobic glycolysis, a metabolism characterized by low oxygen consumption (10, 42), leading to loss of epithelial hypoxia. An important consequence of elevated epithelial oxygenation is an increase in the amount of oxygen emanating from the mucosal surface, which promoted the expansion of Enterobacteriaceae via aerobic respiration in our animal models.

PPAR-γ can inhibit transcription of proinflammatory genes, including the iNOS gene (Nos2) (43). Dysbiosis-dependent down-regulation of PPAR-γ signaling in colonocytes resulted in elevated synthesis of iNOS, an enzyme that generates nitric oxide (NO), which reacts to form nitrate (NO3) in the gut lumen, thereby promoting Enterobacteriaceae expansion via anaerobic nitrate respiration (10).

Insights into the role of the intestinal epithelium in maintaining gut homeostasis have also come from my work in colitis models (44). Here, I revealed that epithelial injury caused by dextran sodium sulfate (DSS) results in activation of the intestinal repair response, resulting in loss of differentiated colonocytes. Oxygen levels emanating from the mucosal surface then drive growth of carcinogenic Enterobacteriaceae through aerobic respiration, which increases disease severity (44).

Taken together, my research reveals that colonocyte metabolism plays a central role in balancing the gut microbiota by “suffocating” harmful bacteria (31, 45). We now know that a disruption of epithelial hypoxia, and a subsequent increase in the amount of oxygen emanating into the colonic lumen, can cause the bloom of facultative anaerobic bacteria, a group associated with intestinal dysbiosis and inflammatory diseases. Additionally, my work has established that changes in the physiology of the colonic epithelium can also lead to increased levels of alternative electron acceptors, which can be used by Enterobacteriaceae for anaerobic respiration (10). My hope is that insights gained from my work will help elucidate novel targets for therapies that prevent colonization by microorganisms associated with an increased risk for the development of various human diseases (Fig. 1A).


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PHOTO: VANDERBILT UNIVERSITY MEDICAL CENTER

FINALIST

Mariana X. Byndloss

Mariana X. Byndloss received her D.V.M. and a Ph.D. from Universidade Federal de Minas Gerais in Brazil. After completing her postdoctoral fellowship at the University of California, Davis, Mariana started her laboratory in the Department of Pathology, Microbiology, and Immunology at Vanderbilt University Medical Center in 2018. Her research aims to understand how inflammation-mediated changes in gut epithelial metabolism lead to gut dysbiosis and increased risk of infectious gastroenteritis by Salmonella Typhimurium and noncommunicable diseases, namely obesity-associated cardiovascular disease and colon cancer. www.sciencemag.org/content/369/6500/153.1

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