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. Description 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 A review explains that high-fat diets impair gut oxygen control and nitrate exposure, resulting in changes to the gut microbiota. 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. Dysbiosis is linked to weakened host control over microbial growth. The composition of the gut microbiota is governed by diet and by host control over microbial growth, which includes high mitochondrial oxygen consumption in the colonic epithelium to maintain anaerobiosis. The transition between nursing (left) and adult-type diet (middle) shifts the microbiota composition, but both states represent homeostasis. Dysbiosis ensues only when host control of microbial growth is weakened because dietary factors, antibiotics, or underlying host conditions reduce oxygen consumption in the colonic epithelium, which drives dysbiosis by increasing the diffusion of oxygen into the intestinal lumen (right). FAs, fatty acids; O2, oxygen; CO2, carbon dioxide [created using BioRender.com].

The microbiome and gut homeostasis

Biomarker-activatable probes based on smart AIEgens for fluorescence and optoacoustic imaging

Reactive oxygen species (ROS) comprise the superoxide anion (O2•−), hydrogen peroxide (H2O2), hydroxyl radical (•OH), and singlet oxygen (1O2). ROS can damage a variety of macromolecules, including DNA, RNA, proteins, and lipids, and compromise cell viability. To prevent or reduce ROS-induced oxidative stress, bacteria utilize different ROS defense mechanisms, of which ROS scavenging enzymes, such as superoxide dismutases, catalases, and peroxidases, are the best characterized. Recently, evidence has been accumulating that some of the terminal oxidases in bacterial respiratory chains may also play a protective role against ROS. The present review covers this role of terminal oxidases in light of recent findings.

ROS Defense Systems and Terminal Oxidases in Bacteria

Ripened pu-erh tea has the biological activity of antioxidation and anti-inflammation, which inhibits the related parameters of colitis. However, the role of storage-induced changes in bioactive ingredients of ripened pu-erh tea in colitis remains unclear. In this study, 3.5% dextran sulfate sodium-induced colitis mice were treated with 10 mg/kg bw/day extracts, aged 14 years (P2006) and unaged (P2020) ripened pu-erh tea, respectively, for 1 week. We found that ripened pu-erh tea, especially P2006, inhibited the intestinal oxidative stress-mediated inflammation pathway (TLR4/MyD88/ROS/p38MAPK/NF-κB p65), upregulated the expression of intestinal tight junction proteins (Mucin-2, ZO-1, occludin), promoted M2 polarization of macrophages, and in turn, improved the intestinal immune barrier, which stemmed from the reshaping of intestinal microbiota (e.g., increased Lachnospiraceae_NK4A136_group and Akkermansia levels). Our results speculate that drinking aged ripe pu-erh tea (10 mg/kg bw/day in mice, a human equivalent dose of 7 g/60 kg bw/day) has a practical effect on alleviating and preventing the development of intestinal inflammation.

Aged Ripe Pu-erh Tea Reduced Oxidative Stress-Mediated Inflammation in Dextran Sulfate Sodium-Induced Colitis Mice by Regulating Intestinal Microbes.

Reactive oxygen species (ROS), such as the superoxide anion or hydrogen peroxide, have been established over decades of research as, on the one hand, important and versatile molecules involved in a plethora of homeostatic processes and, on the other hand, as inducers of damage, pathologies and diseases. Which effects ROS induce, strongly depends on the cell type and the source, amount, duration and location of ROS production. Similar to cellular pH and calcium levels, which are both strictly regulated and only altered by the cell when necessary, the redox balance of the cell is also tightly regulated, not only on the level of the whole cell but in every cellular compartment. However, a still widespread view present in the scientific community is that the location of ROS production is of no major importance and that ROS randomly diffuse from their cellular source of production throughout the whole cell and hit their redox-sensitive targets when passing by. Yet, evidence is growing that cells regulate ROS production and therefore their redox balance by strictly controlling ROS source activation as well as localization, amount and duration of ROS production. Hopefully, future studies in the field of redox biology will consider these factors and analyze cellular ROS more specifically in order to revise the view of ROS as freely flowing through the cell.

/pdf/reactive-oxygen-species-not-omnipresent-but-important-in-57ty8xzsl4.pdf

Reactive Oxygen Species: Not Omnipresent but Important in Many Locations

Epithelial-Derived Reactive Oxygen Species Enable AppBCX-Mediated Aerobic Respiration of Escherichia coli during Intestinal Inflammation.

Introduction Infection with nontyphoidal Salmonella strains, such as Salmonella enterica serovar Typhimurium (S. Typhimurium) commonly causes foodborne bacterial gastroenteritis. Studies on the pathogenesis of S. Typhimurium infection often focus on bona fide virulence factors. S. Typhimurium produces two distinct type III secretion systems that allow for the delivery of a sophisticated repertoire of effector proteins into host cells. These type III secretion systems are required for invasion of intestinal epithelial cells and subsequent replication inside professional phagocytes in the lamina propria and in deeper tissues. In immunocompetent individuals, detection of S. Typhimurium by the innate immune system results in a subacute, neutrophilic inflammatory response that confines the infection to the intestinal tract. In immunocompromised individuals, such as those with neutropenia, systemic dissemination and replication can occur. While we understand key strategies of how S. Typhimurium causes disease, we are only beginning to recognize the complex interplay of host and bacterial metabolism. Recent findings have revealed how S. Typhimurium adapts its diverse energy metabolism to mirror host metabolism and limit nutrient competition in various host niches.

/pdf/salmonella-finds-a-way-metabolic-versatility-of-salmonella-49rx6npd69.pdf

Salmonella finds a way: Metabolic versatility of Salmonella enterica serovar Typhimurium in diverse host environments

Intestinal inflammation disrupts the microbiota composition leading to an expansion of Enterobacteriaceae family members (dysbiosis). Associated with this shift in microbiota composition is a profound change in the metabolic landscape of the intestine. It is unclear how changes in metabolite availability during gut inflammation impact microbial and host physiology.We investigated microbial and host lactate metabolism in murine models of infectious and non-infectious colitis. During inflammation-associated dysbiosis, lactate levels in the gut lumen increased. The disease-associated spike in lactate availability was significantly reduced in mice lacking the lactate dehydrogenase A subunit in intestinal epithelial cells. Commensal E. coli and pathogenic Salmonella, representative Enterobacteriaceae family members, utilized lactate via the respiratory L-lactate dehydrogenase LldD to increase fitness. Furthermore, mice lacking the lactate dehydrogenase A subunit in intestinal epithelial cells exhibited lower levels of inflammation in a model of non-infectious colitis.The release of lactate by intestinal epithelial cells during gut inflammation impacts the metabolism of gut-associated microbial communities. These findings suggest that during intestinal inflammation and dysbiosis, changes in metabolite availability can perpetuate colitis-associated disturbances of microbiota composition. Video Abstract. 

/pdf/colonocyte-derived-lactate-promotes-e-coli-fitness-in-the-3st4euei.pdf

Savannah J. Taylor

Papers

Epithelial-Derived Reactive Oxygen Species Enable AppBCX-Mediated Aerobic Respiration of Escherichia coli during Intestinal Inflammation.

Salmonella finds a way: Metabolic versatility of Salmonella enterica serovar Typhimurium in diverse host environments

Colonocyte-derived lactate promotes E. coli fitness in the context of inflammation-associated gut microbiota dysbiosis