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

A Western-style, high-fat diet promotes cardiovascular disease, in part because it is rich in choline, which is converted to trimethylamine (TMA) by the gut microbiota. However, whether diet-induced changes in intestinal physiology can alter the metabolic capacity of the microbiota remains unknown. Using a mouse model of diet-induced obesity, we show that chronic exposure to a high-fat diet escalates Escherichia coli choline catabolism by altering intestinal epithelial physiology. A high-fat diet impaired the bioenergetics of mitochondria in the colonic epithelium to increase the luminal bioavailability of oxygen and nitrate, thereby intensifying respiration-dependent choline catabolism of E. coli. In turn, E. coli choline catabolism increased levels of circulating trimethlamine N-oxide, which is a potentially harmful metabolite generated by gut microbiota.

High-fat diet–induced colonocyte dysfunction escalates microbiota-derived trimethylamine N-oxide

Microbiota-derived metabolites that elicit DNA damage can contribute to colorectal cancer (CRC). However, the full spectrum of genotoxic chemicals produced by indigenous gut microbes remains to be defined. We established a pipeline to systematically evaluate the genotoxicity of an extensive collection of gut commensals from inflammatory bowel disease patients. We identified isolates from divergent phylogenies whose metabolites caused DNA damage and discovered a distinctive family of genotoxins—termed the indolimines—produced by the CRC-associated species Morganella morganii. A non–indolimine-producing M. morganii mutant lacked genotoxicity and failed to exacerbate colon tumorigenesis in mice. These studies reveal the existence of a previously unexplored universe of genotoxic small molecules from the microbiome that may affect host biology in homeostasis and disease. Description A new class of bacterial genotoxins Individuals with inflammatory bowel disease are at increased risk of developing colorectal cancer compared with the general population. The gut microbiome is among the many factors that can influence tumorigenesis, in part by modulating the immune system and producing microbial metabolites. Cao et al. developed a functional screen to test whether gut bacteria from patients with inflammatory bowel disease have genotoxic effects (see the Perspective by Puschhof and Sears). The authors discovered a family of DNA damage–inducing microbial metabolites called indolimines, which were produced by the Gram-negative bacteria Morganella morganii. In a mouse model of colon cancer, M. morganii exacerbated tumor burden, but a mutant form of the bacteria unable to produce indolimine did not. This diverse series of genotoxic small molecules from the human microbiome may play a role in intestinal tumorigenesis. —PNK Functional screening of commensal gut microbiota reveals small-molecule genotoxins in patients with inflammatory bowel disease. INTRODUCTION Gut microbiota can potentially contribute to the development and progression of colorectal cancer (CRC) by producing small-molecule genotoxins. For example, select commensal Escherichia coli strains produce the canonical microbiota-derived genotoxin colibactin, which engenders the formation of DNA double-strand breaks (DSBs) in intestinal epithelial cells and exacerbates CRC in mouse models. Furthermore, human CRCs harbor colibactin-associated mutational signatures, implying a direct role for microbiota-induced DNA damage in CRC. However, the impacts of microbiota-derived genotoxins beyond colibactin remain largely unexplored. RATIONALE Given the extensive diversity of small-molecule metabolites produced by bacteria, we hypothesized that additional taxa from the human gut microbiome might produce previously undiscovered small molecules that cause DNA damage in host cells. Identifying and characterizing such genotoxins and their respective biosynthetic pathways may reveal causal roles of gut microbes in shaping host biology and disease susceptibility. Thus, we designed a large-scale electrophoresis-based DNA damage screening pipeline to evaluate the genotoxicity of a collection of more than 100 gut commensals isolated from patients with inflammatory bowel disease (IBD). RESULTS We identified diverse bacteria from the human microbiota whose small-molecule metabolites caused genotoxicity in both cell-free and cell-based DNA damage assays. For example, small-molecule metabolites from gram-positive bacteria (including Clostridium perfringens and Clostridium ramosum strains) and gram-negative bacteria (including multiple Morganella morganii strains) directly damaged DNA in cell-free assays and induced the expression of the DSB marker γ-H2AX and cell-cycle arrest in epithelial cells. However, the DNA damage patterns caused by these metabolites were distinct from colibactin-induced cross-links, and these isolates lacked the biosynthetic machinery to produce colibactin or other known genotoxins. These data thus implied the existence of previously unrecognized microbiota-derived genotoxins. M. morganii is enriched in the gut microbiota of both IBD and CRC patients. Using a combination of comparative metabolomics and bioactivity-guided natural product-discovery techniques, we discovered a family of M. morganii-derived small-molecule genotoxins—termed the indolimines—that elicited DNA damage in cell-based and cell-free assays. Furthermore, we identified a previously uncharacterized bacterial decarboxylase (annotated as an aspartate aminotransferase encoded by the aat gene) that was essential for indolimine synthesis and constructed an isogenic aat mutant M. morganii that lacked genotoxicity in both cell-free and cell-based DNA damage assays. Compared with the non–indolimine-producing mutant, wild-type M. morganii caused increased intestinal permeability and induced transcriptional signatures associated with abnormal DNA replication and intestinal epithelial cell proliferation in gnotobiotic mice. Furthermore, indolimine-producing M. morganii induced increased colonic tumor burden in the context of a mock microbial community in a mouse model of CRC. CONCLUSION By leveraging function-based assessments of the microbiome, we uncovered the existence of a broader universe of microbiota-derived small-molecule genotoxins. We found that diverse bacterial strains isolated from IBD patients exhibited DNA-damaging activities and discovered a previously undescribed family of genotoxins, termed the indolimines, produced by the IBD- and CRC-associated species M. morganii. Indolimine-producing M. morganii caused increased intestinal permeability and exacerbated colon tumorigenesis in gnotobiotic mice. Overall, these studies imply an expanded role for microbiota-derived genotoxins in shaping host biology and disease susceptibility. Human gut microbes isolated from IBD patients produce small-molecule genotoxins. Diverse gut microbes isolated from patients with IBD exhibit direct genotoxicity. M. morganii produces a family of genotoxic small molecule metabolites, termed the indolimines. Indolimine-producing M. morganii induces DNA damage in intestinal epithelial cells (IECs) and increased colon tumor burdens in gnotobiotic mouse models.

Commensal microbiota from patients with inflammatory bowel disease produce genotoxic metabolites

A balanced gut microbiota contributes to health, but the mechanisms maintaining homeostasis remain elusive. Microbiota assembly during infancy is governed by competition between species and by environmental factors, termed habitat filters, that determine the range of successful traits within the microbial community. These habitat filters include the diet, host-derived resources, and microbiota-derived metabolites, such as short-chain fatty acids. Once the microbiota has matured, competition and habitat filtering prevent engraftment of new microbes, thereby providing protection against opportunistic infections. Competition with endogenous Enterobacterales, habitat filtering by short-chain fatty acids, and a host-derived habitat filter, epithelial hypoxia, also contribute to colonization resistance against Salmonella serovars. However, at a high challenge dose, these frank pathogens can overcome colonization resistance by using their virulence factors to trigger intestinal inflammation. In turn, inflammation increases the luminal availability of host-derived resources, such as oxygen, nitrate, tetrathionate, and lactate, thereby creating a state of abnormal habitat filtering that enables the pathogen to overcome growth inhibition by short-chain fatty acids. Thus, studying the process of ecosystem invasion by Salmonella serovars clarifies that colonization resistance can become weakened by disrupting host-mediated habitat filtering. This insight is relevant for understanding how inflammation triggers dysbiosis linked to noncommunicable diseases, conditions in which endogenous Enterobacterales expand in the fecal microbiota using some of the same growth-limiting resources required by Salmonella serovars for ecosystem invasion. In essence, ecosystem invasion by Salmonella serovars suggests that homeostasis and dysbiosis simply represent states where competition and habitat filtering are normal or abnormal, respectively.

Salmonella versus the microbiome

5-Aminosalicylic acid (5-ASA), a peroxisome proliferator-activated receptor gamma (PPAR-γ) agonist, is a widely used first-line medication for the treatment of ulcerative colitis, but its anti-inflammatory mechanism is not fully resolved. Here, we show that 5-ASA ameliorates colitis in dextran sulfate sodium (DSS)-treated mice by activating PPAR-γ signaling in the intestinal epithelium. DSS-induced colitis was associated with a loss of epithelial hypoxia and a respiration-dependent luminal expansion of Escherichia coli, which could be ameliorated by treatment with 5-ASA. However, 5-ASA was no longer able to reduce inflammation, restore epithelial hypoxia, or blunt an expansion of E. coli in DSS-treated mice that lacked Pparg expression specifically in the intestinal epithelium. These data suggest that the anti-inflammatory activity of 5-ASA requires activation of epithelial PPAR-γ signaling, thus pointing to the intestinal epithelium as a potential target for therapeutic intervention in ulcerative colitis.IMPORTANCE An expansion of Enterobacterales in the fecal microbiota is a microbial signature of dysbiosis that is linked to many noncommunicable diseases, including ulcerative colitis. Here, we used Escherichia coli, a representative of the Enterobacterales, to show that its dysbiotic expansion during colitis can be remediated by modulating host epithelial metabolism. Dextran sulfate sodium (DSS)-induced colitis reduced mitochondrial activity in the colonic epithelium, thereby increasing the amount of oxygen available to fuel an E. coli expansion through aerobic respiration. Activation of epithelial peroxisome proliferator-activated receptor gamma (PPAR-γ) signaling with 5-aminosalicylic acid (5-ASA) was sufficient to restore mitochondrial activity and blunt a dysbiotic E. coli expansion. These data identify the host's epithelial metabolism as a potential treatment target to remediate microbial signatures of dysbiosis, such as a dysbiotic E. coli expansion in the fecal microbiota.

/pdf/5-aminosalicylic-acid-ameliorates-colitis-and-checks-4t8odvwlg4.pdf

5-Aminosalicylic Acid Ameliorates Colitis and Checks Dysbiotic Escherichia coli Expansion by Activating PPAR-γ Signaling in the Intestinal Epithelium

Intestinal inflammation is a risk factor for colorectal cancer formation, but the underlying mechanisms remain unknown. Here, we investigated whether colitis alters the colonic microbiota to enhance its cancer-inducing activity. Colitis increased epithelial oxygenation in the colon of mice and drove an expansion of Escherichia coli within the gut-associated microbial community through aerobic respiration. An aerobic expansion of colibactin-producing E. coli was required for the cancer-inducing activity of this pathobiont in a mouse model of colitis-associated colorectal cancer formation. We conclude that increased epithelial oxygenation in the colon is associated with an expansion of a prooncogenic driver species, thereby increasing the cancer-inducing activity of the microbiota.IMPORTANCE One of the environmental factors important for colorectal cancer formation is the gut microbiota, but the habitat filters that control its cancer-inducing activity remain unknown. Here, we show that chemically induced colitis elevates epithelial oxygenation in the colon, thereby driving an expansion of colibactin-producing Escherichia coli, a prooncogenic driver species. These data suggest that elevated epithelial oxygenation is a potential risk factor for colorectal cancer formation because the consequent changes in the gut habitat escalate the cancer-inducing activity of the microbiota.

Increased Epithelial Oxygenation Links Colitis to an Expansion of Tumorigenic Bacteria.

Handle everyday research tasks with reliable, citation-backed results

Your personal Research Agent to handle research tasks with citation-backed results

Popular Tasks used by Researchers

How can I help with your research?

Meet SciSpace

Get more enhanced response by uploading the PDFs you want me to reference.

No relevant PDFs in your library

SciSpace is the AI research assistant for academics. Run systematic literature reviews on 280M+ papers, and write papers with cited sources. Trusted by 1M+ students, PhDs & researchers.

SciSpace | AI for Research

Analyze PDFs

Code & Manuscripts

Funding & Grants

Literature & Patents

Medical & Clinical Data

Systematic Review

Visualize & Present

Web & Data

Build a Google Scholar-like website for your research.

Build a website

Create charts and images for your research

Create a Chart

Write a paper for submission to a journal

Draft a manuscript

Patent Search

Design eye-catching scientific posters in minutes.

Scientific Poster Generation

Systematic Literature Review

One task is running at the moment. Your messages will be shown right after.

Drag and drop or click here to browse

Loved by <highlight>1 million+</highlight> researchers

Extract a list of specific topics and their sources from unstructured text

Topics

Compare and analyze relevant papers that matches with your search

Papers

Get insights from PDFs and bookmarked papers from your library

My library

Recent searches

Try searching for:

Catch AI-generated content in scholarly and non-scholarly content

{ai} Detector

Ai Writer

Get PDF Summaries, highlighted text explanations 

Chat with PDF

Effortlessly create in-text citations and bibliographies in APA and 2,500 other formats

Citation generator

Get explanations, summaries, and answers on academic papers

Ease up your research workflow with {scispace}'s cohort of exciting AI tools

Elevate your academic writing skills and convey your ideas the way you want

Paraphraser

Explore our range of reading and writing tools

Your file is being prepared and should be ready in a few minutes. If it's a large file, it might take a bit longer. You can close this window, and we'll email you the file when it's done.

You have reached a maximum limit of <strong>{limit}</strong> columns in the table. Remove at least <strong>1</strong> column to add or create another one.

Luana Johnston

Author Tools

Chat about Author

Papers

Increased Epithelial Oxygenation Links Colitis to an Expansion of Tumorigenic Bacteria.