Modulating gut microbes

doi:10.1126/science.abc3965

GSTDTAP > 气候变化

DOI	10.1126/science.abc3965
	Modulating gut microbes
	Jennifer A. Wargo
	2020-09-11
发表期刊	Science
出版年	2020
英文摘要	There are hundreds of trillions of microbes within the human body, which have a profound impact on modulating host function. Many of these microbes reside in the gastrointestinal tract and have been shown to influence normal physiology across all body systems ([ 1 ][1]). Disruptions in the delicate balance of microbes within the gut and other niches are associated with numerous disease states—including neurologic disorders, cardiovascular disease, gastrointestinal disorders, and even cancer ([ 2 ][2]). Accordingly, there is intense interest in targeting these microbes to promote overall health and to abrogate disease, with considerable advances made recently. Strategies to modulate gut microbes include fecal microbiota transplant (FMT), which involves the transfer of fecal material from one individual to another for a desired physiologic effect. This approach, among other gut microbiota modulation strategies, has shown promise in treating several disease conditions, although opportunities exist to iterate and build on these approaches. The idea that disruptions in the gastrointestinal tract could contribute to systemic disease was championed centuries ago by Hippocrates, a physician in ancient Greece. Strategies to modulate the composition of the gut have also been around for centuries, with the first reports of the use of FMT dating back to the fourth century BCE in China where fecal preparations were used to treat gastrointestinal disorders ([ 3 ][3]). Parallels have also been observed in the animal kingdom, where coprophagia (ingesting fecal material) is common and may confer an increase in gut microbial diversity and associated enhancements in host function for digestion and other physiologic processes. However, the first successful clinical application of FMT was not published until 1958 with the report of FMT from healthy donors used for patients with pseudomembranous enterocolitis from Clostridioides difficile infection (CDI) ([ 4 ][4]). Numerous clinical trials have since been undertaken, using FMT and other gut microbiota modulation strategies to treat diseases of the gut (such as CDI, and inflammatory bowel disease, IBD) as well as other systemic diseases—including metabolic syndrome, autism, multiple sclerosis, Parkinson's disease, and even cancer ([ 2 ][2]). ![Figure][5] Strategies to alter gut microbiota Fecal microbiota transplant (FMT) involves transfer of fecal microbiota from a donor to another individual . Alternatively, microbial consortia (targeted formulations used to augment host microbiota) are being developed. Diet, prebiotics, and postbiotics can also influence the microbial community. GRAPHIC: N. CARYI/ SCIENCE To date, many of the strategies to target gut microbes have involved the two extremes: either transfer of entire microbial communities (by using FMT) or transfer of a single microbial taxon. However, a growing number of approaches are now being developed as more is learned about the functional aspects and physiologic impact of microbes throughout the body. These iterative approaches transcend efforts that focus on taxonomic characterization of microbial niches through next-generation genomic sequencing, incorporating interrogation of functional characteristics of gut microbes (by metabolomic profiling and studies in preclinical models) to mediate the desired physiologic response. This has led to a host of therapeutic strategies from microbial consortia to pre-, pro-, and postbiotic interventions. Nonetheless, much still needs to be learned to implement true “precision” modulation of the gut microbiota. When considering strategies to modulate the gut microbiota, the indication for intervention in the intended population must be considered. Gut dysbiosis, an imbalance in the composition of commensal microbial communities, has been linked to numerous disease states, substantiating the use of FMT and other gut microbiota modulation strategies ([ 5 ][6]). This link is fortified by data demonstrating that although there has been a decrease in infectious diseases over the past several decades with the widespread use of antibiotics, there has been a concurrent increase in allergy and autoimmune diseases ([ 6 ][7]) presumably at least partially due to disruption of the gut microbiota. Notably, some of the diseases being treated by gut microbiota modulation have a profound dysbiosis (such as CDI), whereas others have a more subtle disruption of gut microbes, which has implications for choosing the appropriate strategy for gut microbiota modulation. Numerous other factors should be taken into account when contemplating modulation of the gut microbiota. These include the means of gut microbiota modulation, preparative regimen, measurement of engraftment of gut microbes and of the desired physiologic effect, and concurrent dietary intake ([ 7 ][8]). In general, the approach aims to restore a more “healthy” gut microbial community—although the definition of a “healthy” gut microbiota is not clearly established. However, data suggest that a diverse microbial community with a high degree of functional redundancy is associated with better overall health ([ 2 ][2]) and better outcomes in several disease states ([ 8 ][9], [ 9 ][10]). The most successful application of FMT thus far is in the treatment of refractory CDI, where treatment with FMT has been shown to be generally safe and highly effective ([ 2 ][2]). Nonetheless, guidelines for proper treatment and screening of donor stool are critical for safety and include screening for infectious diseases and disorders that are associated with perturbations of the gut microbiota, as well as the use of medications that can affect gut microbes such as antibiotics and proton pump inhibitors ([ 10 ][11]). Notably, these guidelines are iterative, as new recommendations are made to expand screening and testing of donors based on insights gained from ongoing trials. For example, screening of donors for multidrug-resistant organisms and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is now recommended. This follows reports of several patients with CDI who developed systemic infection with antibiotic-resistant bacterial infections following FMT ([ 11 ][12]), as well as concerns about possible infections with SARS-CoV-2. The use of FMT is being investigated across numerous other disease conditions, although most of these are associated with a less profound dysbiosis and greater heterogeneity in assessed endpoints and outcomes. However, there is clear evidence of success in some trials across a number of indications, including IBD, after hematopoietic stem cell transplant and in autism spectrum disorders ([ 5 ][6]). Limitations in measuring efficacy in FMT trials may arise from “true negative” results, or from numerous other confounding factors, including features not dependent on gut microbes that contribute to the development and persistence of disease in the recipient, as well as variability in trial design and outcome measures. Additionally, there may be factors inherent to the FMT donor that may affect efficacy (such as composition and functional aspects of the transplanted microbiota); however, such “donor effects” may be less prominent for indications in which a more profound dysbiosis is present, such as in CDI and even IBD ([ 12 ][13]). Optimal dosing and route of delivery for FMT are also incompletely understood and may be context dependent. Additional studies are critically needed to interrogate the success (or failure) of this approach for these indications and to develop optimal strategies for use of FMT. One attribute of FMT not possessed by other strategies to modulate the gut microbiota is the diversity of microbes that may be administered (including not only bacteria, but also viruses, fungi, and archaea) (see the figure). This provides potential functional redundancy for favorable impact on host physiology. In a profoundly dysbiotic state, this diversity represents a potential advantage over strategies that administer minimal-complexity microbial consortia, which may not engraft and may not be sufficient in reestablishing a “favorable” gut microbiota. However, the same attribute of increased diversity and complexity of FMT is also a limitation that creates issues with reproducibility and scalability. There are also concerted efforts under way to develop consortia of microbes that can be reliably and consistently manufactured and administered to favorably modulate the gut microbiota to address gastrointestinal and systemic disease, offering improved scalability over FMT. This includes commercially available probiotics, which are live microorganism preparations with presumed health benefits. The impact of administration of many of these formulations across disease indications has been studied in clinical trials with mixed results, and to date none of these commercially available formulations are approved for use by major regulatory bodies such as the U.S. Food and Drug Administration ([ 13 ][14]). However, next-generation live biotherapeutics (live microorganisms developed as therapeutic agents with defined clinical benefit claims) are now being developed based on insights gained from sequencing data in human cohorts and from studies in preclinical models ([ 13 ][14])—with many now in clinical trials. The first wave of these next-generation live biotherapeutics focused mainly on taxonomy—incorporating single or several bacterial taxa within a consortia based on insights gained from profiling gut microbial species in human cohort studies and in preclinical models. An example of this is in cancer immunotherapy: Clinical trials are now under way using modulation of the gut microbiota through administration of microbial consortia ([ 7 ][8]). These formulations range from simple (monoclonal microbial formulations) to complex (involving consortia of 50 or more bacterial taxa and strains). However, there is a growing appreciation that focusing on the functional aspects of these microbes may be far more important than simply focusing on taxonomy, and genetically modified organisms are now being developed with a wide range of functional attributes ([ 13 ][14]). Although overall these formulations are generally well-tolerated, safety still needs to be taken into account because there are reports of bacterial translocation of these organisms from the gut into the bloodstream in critically ill patients receiving gut microbiota modulation through administration of commercially available probiotics ([ 14 ][15]). Another strong consideration in gut microbiota modulation is the role of diet and prebiotics, as these can profoundly influence existing commensal gut microbes and those administered for therapeutic intent. These may ultimately serve as a stand-alone intervention in appropriate individuals with more subtle gut dysbiosis. Short-term studies have shown that large changes in diet can have a marked impact on gut microbes and associated physiology in the short term ([ 15 ][16]). However, this reliably reverts to a preintervention state if the instituted change in diet is not sustained. Nonetheless, numerous dietary intervention studies are currently under way ([ 7 ][8]), ranging from a somewhat simple intervention of adding one cup of canned beans per day to existing diets (NCT02843425) to extended (or longer-term) dietary interventions, where meals are prepared for (and shipped to) participants (NCT03950635). Such dietary modifications have potential relevance even if recipients are also treated with other gut microbiota modulation strategies such as FMT or live biotherapeutics, as they may sustain and promote optimal function of the transferred gut microbes, although optimal approaches of dietary intervention in these scenarios has yet to be defined. The use of prebiotic supplementation (such as resistant starches, polyphenols, and polyunsaturated fatty acids) is also being studied, because these compounds may provide optimal substrate to beneficial commensal (or administered) microbes. It is becoming evident that modulation of gut microbes will be increasingly employed to promote overall health and to help treat disease, although optimal strategies for “precision” gut microbiota modulation remain incompletely understood. It is probable that a personalized approach will be needed, incorporating strategies such as FMT, administration of live biotherapeutics, dietary strategies, and prebiotics—although it is not inconceivable that an ideal “one-size-fits-all” approach could be identified. Through additional research and collaborative efforts, the true definition of dysbiosis in the gut microbiota as it relates to disease states can be better understood, as well as what constitutes an optimal gut microbiota to promote overall health, which could have broad impact for public health. 1. [↵][17]1. I. Cho, 2. M. J. Blaser , Nat. Rev. Genet. 13, 260 (2012). [OpenUrl][18][CrossRef][19][PubMed][20] 2. [↵][21]1. J. R. Allegretti, 2. B. H. Mullish, 3. C. Kelly, 4. M. Fischer , Lancet 394, 420 (2019). [OpenUrl][22][CrossRef][23][PubMed][24] 3. [↵][25]1. F. Zhang et al ., Am. J. Gastroenterol. 107, 1755 (2012). [OpenUrl][26][CrossRef][27][PubMed][28] 4. [↵][29]1. B. Eiseman, 2. W. Silen, 3. G. S. Bascom, 4. A. J. 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领域	气候变化 ; 资源环境
URL	查看原文
引用统计
文献类型	期刊论文
条目标识符	http://119.78.100.173/C666/handle/2XK7JSWQ/294088
专题	气候变化资源环境科学
推荐引用方式 GB/T 7714	Jennifer A. Wargo. Modulating gut microbes[J]. Science,2020.
APA	Jennifer A. Wargo.(2020).Modulating gut microbes.Science.
MLA	Jennifer A. Wargo."Modulating gut microbes".Science (2020).