The microbiome and gut homeostasis

Abstract

Changes in the composition of the gut microbiota are associated with many human diseases. So far, however, we have failed to define homeostasis or dysbiosis by the presence or absence of specific microbial species. The composition and function of the adult gut microbiota is governed by diet and host factors that regulate and direct microbial growth. The host delivers oxygen and nitrate to the lumen of the small intestine, which selects for bacteria that use respiration for energy production. In the colon, by contrast, the host limits the availability of oxygen and nitrate, which results in a bacterial community that specializes in fermentation for growth. Although diet influences microbiota composition, a poor diet weakens host control mechanisms that regulate the microbiota. Hence, quantifying host parameters that control microbial growth could help define homeostasis or dysbiosis and could offer alternative strategies to remediate dysbiosis.

Regulating the redox swamp

The diversity and abundance of organisms that live in the human gut are well known. We also have some idea of associations between microbial taxa and host disease, but we have failed to consistently translate this understanding into therapeutic options. Redox reactions, which are governed by the availability of respiratory electron acceptors, are the drivers of bacterial community composition. Lee et al . reviewed the literature on bacterial colonization of regions of the gut and concluded that colonization is primarily regulated by host physiology controlling electron acceptor availability rather than by microbial activity. Although diet shapes microbiota composition, its effects are largely mediated by its effect on host homeostasis. Intervening with host gut physiology could thus offer a more tractable route to translational solutions for gut dysbiosis than trying to manipulate the microbiota. —CA

Abstract

A review explains that high-fat diets impair gut oxygen control and nitrate exposure, resulting in changes to the gut microbiota.

Abstract

BACKGROUND

Changes in the composition of gut-associated microbial communities (gut microbiota) are linked to a wide spectrum of human diseases, such as cancer, obesity, and even neurological disorders. Understanding the factors that shape the gut microbiota is therefore a primary objective of microbiome research. One factor governing the composition of the gut microbiota is diet. Weaning marks an abrupt shift in diet, which is associated with phylum-level changes in the fecal microbiota composition. But the fecal microbiota of healthy adults and that of breastfed infants before weaning are both homeostatic communities. Thus, diet-induced changes in the composition of the gut microbiota are not always associated with disease. Furthermore, large variation in the species composition of the gut microbiota between individuals makes it impossible to define homeostasis or dysbiosis by the presence or absence of specific microorganisms. Limited information on the ecological causes of dysbiosis and the causative effects of dysbiosis on disease makes it difficult to translate research into medical interventions.

ADVANCES

In this Review, we explore whether homeostasis and dysbiosis can be better defined by looking at a second factor that governs gut microbiota composition and function: the host environment. Bacterial growth requires energy in the form of adenosine triphosphate (ATP). Microbes that can maximize energy production in a specific environment will accelerate their growth and dominate microbial communities. Because respiration yields more energy than fermentation, bacteria that respire will dominate a microbial community when respiratory electron acceptors, such as oxygen, are present in the environment. The host uses these principles of bacterial community composition to shape its gut microbiota. Our body maintains a high luminal oxygen concentration in the small intestine to drive the microbial community composition to be dominated by bacteria that use respiration for energy production. By contrast, through maintaining the epithelium in a state of physiological hypoxia, the host limits access to oxygen in the lumen of the large intestine, which drives a dominance of bacteria that use fermentation for energy production. Recent insights into the ecological drivers of dysbiosis suggest that a disruption of homeostasis is generally associated with a weakening of host control mechanisms that regulate the microbiota. Host control mechanisms that limit the availability of oxygen for bacteria in the colon become weakened in mouse models of colorectal cancer, ulcerative colitis, antibiotic treatment, or enteric infection. The resulting increase in the availability of oxygen increases the abundance of bacteria that respire oxygen in the colonic microbiota. Similarly, negative health effects of a Western-style high-energy, low-fiber diet are associated with a weakening of host factors that control the microbial environment in the gut. These mechanistic insights suggest that dysbiosis is associated with a state of weakened host control over the microbial environment. Conversely, gut homeostasis represents a state where host functions that control microbial growth are normal (i.e., characteristic of a healthy or normally functioning individual).

OUTLOOK

The idea that dysbiosis is characterized by an underlying impairment of host functions that regulate the gut microbiota and microbial metabolism suggests that measurements of these host functions could provide a more quantitative insight into the state of microbiome homeostasis than current microbe-centric approaches. For example, measurements of oxygen concentrations along the longitudinal axis of the intestine could be used to determine a normal range that is characteristic of a healthy or normally functioning individual. Measurements within the normal range might indicate homeostasis, whereas values outside this range would indicate dysbiosis. Furthermore, targeting the host functions that regulate the gut microbiota with therapeutic approaches could fuel the conception of new strategies to remediate dysbiosis with drugs that restore host control over the microbiota.