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Drugging the gut microbiota: toward rational modulation of bacterial composition in the gut
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Drugging the gut microbiota: toward rational modulation of bacterial composition in the gut Fernando Altamura1, Corinne F. Maurice2 and Bastien Castagner1 Abstract
The human gastrointestinal tract hosts almost a trillion microorganisms, organized in a complex community known as the gut microbiota, an integral part of human physiology and metabolism. Indeed, disease-specific alterations in the gut microbiota have been observed in several chronic disorders, including obesity and inflammatory bowel diseases. Correcting these alterations could revert the development of such pathologies or alleviate their symptoms. Recently, the gut microbiota has been the target of drug discovery that goes beyond classic probiotic approaches. This short review examines the promises and limitations of the latest strategies designed to modulate the gut bacterial community, and it explores the druggability of the gut microbiota by focusing on the potential of small molecules and prebiotics. Addresses 1 Department of Pharmacology & Therapeutics, McGill University, 3655 Prom. Sir-William-Osler, Montreal, Quebec, H3G 1Y6, Canada 2 Department of Microbiology & Immunology, McGill University, 3649 Prom. Sir-William-Osler, Montreal, Quebec, H3G 0B1, Canada Corresponding author: Castagner, Bastien (bastien.castagner@ mcgill.ca)
Current Opinion in Chemical Biology 2020, 56:10–15 This review comes from a themed issue on Next generation therapeutics €l Rodriguez Edited by Gonçalo Bernardes and Raphae For a complete overview see the Issue and the Editorial
https://doi.org/10.1016/j.cbpa.2019.09.005 1367-5931/© 2019 Elsevier Ltd. All rights reserved.
Keywords Gut microbiota, Probiotics, Prebiotics, Gut health, Drug discovery, Bacterial metabolism.
Why target the gut microbiota? Microorganisms colonize every surface of our body that communicates with the external environment, and the gastrointestinal tract is no exception. Our ‘forgotten organ’, the gut microbiota, is a complex microbial ecosystem that interacts with its host, while the term
Current Opinion in Chemical Biology 2020, 56:10–15
gut microbiome denotes its genetic pool (our ‘second genome’) [1e3]. Beyond training the immune system, the gut microbiota promotes health through the synthesis and release of several metabolites and vitamins. Short-chain fatty acids (SCFAs) result from the bacterial glycan fermentation and interact with the host via G-proteinecoupled receptors (GPCRs) and by inhibition of histone deacetylases (HDACs) [4,5]. However, bacterial enzymes can also release toxic metabolites such as trimethylamine, later oxidized by the liver to trimethylamine-N-oxide, which is linked to cardiovascular diseases [6]. They can also release the active form of drugs after glucuronide deconjugation of primary compounds, as in the case of the antineoplastic agent SN-38 [7**]. Disease-specific changes in bacterial community structure, loosely termed ‘dysbiosis’, have been observed in several human chronic disorders, including inflammatory bowel diseases (IBDs), obesity, and type 2 diabetes (T2D). Dysbiosis is typically also characterized by a loss in microbial biodiversity, allowing for the expansion of pathogens, such as Clostridioides difficile and enterohemorrhagic Escherichia coli [8]. Today, we witness the ongoing unraveling of new connections between the gut microbiota and other organ systems, hinting to its possible entanglement in pathologies beyond metabolic disorders, including Parkinson diseases and autism. Importantly, the links between these shifts in gut microbial composition and human disorders are stronger than mere correlations because numerous disease phenotypes can be transferred by microbiota transplantation to germ-free animals [9,10]. Therefore, the precise editing of the gut microbiota and/or the modulation of its metabolism could become a valuable strategy to promote human health, and several recent examples point toward exciting therapeutic opportunities.
Manipulating the microbiota with live therapeutics Live therapeutics use living organisms (mostly bacteria) for the treatment of a disease or for the alleviation of its symptoms. Several probiotic strains are reported to suppress pathogens, decrease toxins levels, improve lactose digestion, lower serum cholesterol, deconjugate www.sciencedirect.com
Drugging the Gut Microbiota Altamura et al.
bile acids, and supply nutrients to the host [11]. Despite all these effects, probiotics carry intrinsic limitations as a targeted approach to modulate the gut ecosystem. Indeed, most probiotic bacteria used to date belong to the Lactobacillus and Bifidobacterium genera because of their known resistance to the harsh gastrointestinal tract and the ease to culture them. Furthermore, Zmora et al. [12*] recently showed that exogenous bacteria colonize the human gut mucosa only transiently and in highly individualized patterns and therefore impact the indigenous microbiome and host gene-expression profile inconsistently across different healthy individuals. Notably, the use of probiotics after a course of antibiotics in healthy humans has recently been shown to delay the return of a diverse endogenous microbiota, casting doubt on the benefits of probiotics in this context [13**]. A fecal microbiota transplant (FMT) seems to overcome these limitations. Indeed, transferring a full community rather than a subset of a few strains can generate a more significant and long-lasting shift in the gut endogenous composition, and its beneficial effects appear to last longer, especially after antibiotic treatment. However, health concerns together with regulatory uncertainty regarding screening donors and logistics of delivery still prevent FMT from being the gold-standard method to treat disorders. Suez et al. [13] showed that autologous FMT, which uses samples taken from the patient before gut microbiota disruption by antibiotic treatment, induced a rapid and near-complete recovery within days of administration. Although laborious, this strategy could be useful to prevent long-term microbiota perturbations by antibiotic use. Fortunately, we are now witnessing a Renaissance within the world of live therapeutics, leaning toward more targeted approaches. As we link specific bacteria to downstream host functions, we can explore the probiotic potential of nonconventional strains such as Akkermansia muciniphila. Indeed, three groups independently demonstrated that the gut microbiota composition is linked to the response of immune checkpoint inhibitors for the treatment of cancer [14-16*]. More specifically, Routy et al. [14] found a correlation between clinical responses to the drug and the relative abundance of A. muciniphila. Interestingly, an oral supplementation of this bacterium in germ-free mice humanized with feces from patients not responding to the inhibitors could restore the treatment efficacy. Working toward the same goal, Tanoue et al. [17] isolated a consortium of 11 bacterial strains from healthy human donor feces capable of inducing interferon-geproducing CD8 T cells in the intestine. Mice colonized with the consortium showed enhanced host resistance against Listeria monocytogenes infection and improved efficacy of immune checkpoint inhibitors in syngeneic tumor models. This research shows that a rationally selected www.sciencedirect.com
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and well-defined consortium of bacteria could provide exciting alternatives to generic probiotic strains and FMT for the treatment of diseases ranging from cancer to C. difficile infection [18]. The possibility of genetically modified probiotics that could deliver compounds of therapeutic interest in situ or to maximize their probiotic quality is also an enticing possibility. However, the reception of this application will depend on the development of tighter safety systems, possibly including kill switch mechanisms. Another promising modulatory therapeutic strategy features the use of bacteriophages, but a better understanding of the dynamic interaction between phages and the gut bacteria will be necessary before it becomes a reality [19].
Can we drug it? Novel therapeutic targets in the gut microbiota emerge when precise molecular mechanisms of hoste microbiota interactions are unraveled. As mentioned previously, the reactivation of glucuronidated drug metabolites in the gut by bacterial glucuronidases can cause toxicity [20]. The selective inhibition of these bacterial enzymes offers an exciting strategy against dose-limiting side effect in irinotecan cancer treatment [7**] and intestinal adverse effect of the nonsteroidal anti-inflammatory drug diclofenac [21,22]. These interventions demonstrate the potential of inhibiting bacterial enzymes for human benefit and offer a clear path for drug discovery targeting the microbiota. In another recent example of inhibition of a bacterial enzyme, Roberts et al. [23*] have shown that administration of a covalent inhibitor of choline utilization (cut) gene cluster, iodomethylcholine, reduced the production of trimethylamine-N-oxide (normally produced from bacterial metabolism of dietary phosphatidyl choline) in vivo and rescued the choline diete induced formation of enhanced thrombi. More recently, Orman et al. [24] performed elegant structure-guided work on the choline TMA-lyase cutC that lead to the identification of betaine aldehyde as an inhibitor. The same group also characterized the gut microbiota metabolism of L-dopa, a drug prescribed for Parkinson disease, and rationally designed an effective inhibitor of this metabolism [25]. These approaches have the potential to ameliorate human health by targeted inhibition of deleterious metabolism of the gut microbiota, without overtly affecting its composition. Can we induce informed and targeted changes to the composition of the gut microbiota to benefit the host’s health? Recent work suggests that this might be the case. Maier et al. [26*] comprehensively screened more than 1000 marketed drugs (covering different therapeutic classes) against 40 representative bacterial Current Opinion in Chemical Biology 2020, 56:10–15
12 Next generation therapeutics
strains in vitro. They found that 24% of human-targeted drugs (therefore excluding antibiotics and antiseptics) could inhibit the growth of at least one strain. Similarly, multiple small molecules have been reported to impact the gut microbiota, for better or worse [27]. Although incidental and mostly unwanted, these interactions suggest that small-molecule drugs could have targeted effects on the gut microbiota, which could be exploited for the development of new therapeutic strategies. Recently, Sun et al. [28*] investigated the short-term impact of metformin, a drug used for the treatment of T2D, on the gut microbiota in treatment-naı¨ve patients. They observed increased production of the secondary bile acid glycoursodeoxycholic acid, resulting in inhibition of the intestinal farnesoid X receptor, concomitant with a reduction of the Bacteroides fragilis population. They suggest that metformin acts in part by this mechanism to improve obesity-induced glucose intolerance and insulin resistance. Importantly, the group showed the therapeutic effect of glycoursodeoxycholic acid administration in a mouse model, suggesting a new potential pathway for the treatment of metabolic diseases. Although serendipitous in the metformin case, the precise manipulation of the gut microbiota can be rationally designed, as demonstrated by Zhu et al. [29**]. They showed that the growth of aerotolerant Enterobacteriaceae during gut inflammation could be prevented by a tungstate treatment, which selectively inhibited molybdenum cofactoredependent microbial respiration. This treatment caused negligible shifts in composition under homeostatic conditions because these pathways are operative only in the event of inflammation. Remarkably, tungstate-mediated gut microbiota editing decreased the extent of intestinal inflammation in mouse models of colitis.
Prebiotics in drug discovery Dietary glycans are a major driver of gut microbiota diversity and composition [30,31]. Although continuously adapting to every dietary intake, the gut community remains a resilient ecosystem overall. However, more sustained perturbations, such as a change of dietary habits, will shift the composition to a different equilibrium state, as demonstrated in the gut microbiota seasonal variation of the Tanzanian Hadza community [32]. Our bacterial genetic diversity dictates the digestion of an array of complex dietary glycans. Indeed, the human genome encodes only a few carbohydrate-active enzymes (CAZymes) that can cleave complex polysaccharides found in food such as vegetables, plants, and grains. Therefore, most of these glycans reach the large intestine intact, where they are digested by the gut microbiota, which encodes a much wider repertoire of Current Opinion in Chemical Biology 2020, 56:10–15
CAZymes [33]. The microbiota-accessible carbohydrates (MACs) also include mucin glycans and represent the major source of carbon for the gut bacteria. In return, we obtain w10% of our calorie intake from the absorption of short-chain fatty acids produced by the bacterial glycan fermentation [34]. Interestingly, the host can use internal resources to maintain the integrity of the gut microbial community during a state of disease by shedding fucosylated proteins from intestine epithelial cells, with subsequent bacteria-mediated fucose hydrolysis and metabolism [35]. Beyond the benefit of a healthy vegetable and fiberrich diet, it should be possible to rationally alter the gut microbial community landscape with prebiotics: glycans or other molecules undigested by the host but metabolized by its bacteria [36]. In fact, nature already uses this strategy with human milk oligosaccharides (HMOs) to nurture the gut microbiota of developing infants. A few clinical trials performed over the last two years illustrate the strong potential of prebiotic-based therapeutics [37e40]. One study [41] investigated the effects of arabinoxylans on the physiology of patients who are overweight and obese. The prebiotic supplementation upregulated tight junction proteins including occludin and claudins, thereby improving intestinal permeability. Furthermore, it decreased the fecal pH as more SCFAs were produced and also reduced levels of tumor necrosis factor a, a marker of inflammation. In another study [42], children with autism following an exclusion diet (gluten and casein-free) were given galactooligosaccharides (B-GOSÒ) supplements resulting in an increase of fecal butyrate, a reduction of fecal amino acids (normally indicative of nutrients’ malabsorption), and even a significant improvement in antisocial behavior. New mechanistic insights into the effects of prebiotic sprout from recent animal studies, which are important to guide therapeutic approaches [43]. Indeed, Zou et al. [44*] investigated the mechanisms underlying the action of inulin on the gut microbiota in a mouse model where obesity was induced by a high-fat diet. They found that the prebiotic prevented obesity by reducing overall body weight, fat mass, size of white fat cells, cholesterol levels, blood glucose concentration, and appetite. It also increased colon length and weight, crypt length, enterocyte proliferation, and gut permeability through expression of tight junction proteins. In addition, it stimulated the proliferation of Paneth cells and secretion of glucagon-like peptide 1 from L-cells. At a community level, inulin impacted the gut microbiota by increasing the number of bacteria and alpha diversity, while reducing bacterial encroachment. The authors could trace all these beneficial effects to the ability of inulin to induce the production of interleukin-22. A www.sciencedirect.com
Drugging the Gut Microbiota Altamura et al.
different study [45] also used a diet-induced mouse model of obesity (high-fat high-sucrose diet) to investigate the effects of a crude extract of camu camu (Myrciaria dubia, an Amazonian fruit) on the composition of the gut microbiota and the host gastrointestinal physiology. They found that camu camu improved insulin sensitivity, metabolic inflammation, and endotoxemia, while reducing weight gain and fat mass. Treated mice also featured an expansion of A. muciniphila and drastic changes in metatranscriptomic profiles, including an upregulation of thermogenin in brown fat cells and the bile acid receptor TGR5. Another study [46] used an antibiotic-induced mouse model of C. difficile infection to study how prebiotics can impact the course of the infection. They demonstrate that diets rich in complex mixtures of microbial accessible carbohydrates or containing inulin as sole carbohydrate can change the microbiota composition, its metabolic output, and C. difficileemediated inflammation.
Challenges in developing effective prebiotics Two factors prevent the development of effective prebiotics: (1) our limited understanding of who eats what? in the gut microbiota and (2) the large diversity of glycan structures with the associated CAZymes able to digest them. Indeed, most clinical trials focussed only on a few structures including galactooligosaccharides, fructooligosaccharides, and resistant starch, in contrast to the large diversity of complex glycan structures contained in our diet. Furthermore, although a number of elegant studies [47e49] continue to shed light on the complex mechanisms of glycan metabolism beyond the well-characterized starch utilization system of B. thetaiotaomicron [50], the bacterial consumers of a myriad of potential prebiotic glycans remain unidentified. In addition, we are in tremendous need of studies that also provide mechanistic insights between a prebiotic and a downstream phenotype. This
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task is particularly challenging, given the complexity of the gut microbial community and its many channels bridging it to host physiological organ systems. Indeed, manipulating blindly the gut microbiota can be dangerous. For example, Singh et al. [51] found that incorporating soluble inulin into a compositionally defined diet induced a gut microbiota-dependent hepatocellular carcinoma, featuring early onset of cholestasis and hepatocyte death, followed by neutrophilic liver inflammation. Natural modulations of the gut bacteria linked to age, diet, drug interactions, lifestyle, and geographical location also hinder the development of prebiotic therapeutics. A recent study [52] showed differential effects of the same inulin-type fructan based on dietary habits. The prebiotic supplementation was significantly more effective in patients who maintained a high-fiber diet than in those on a low-fiber diet. Another study demonstrated interpersonal differences in postmeal glucose response that was in part due to dissimilarities in the gut microbiota [53]. These studies suggest that a personalized approach might be necessary and should be systematically addressed if we intend to exploit the benefits of prebiotic supplements [54].
Concluding remarks In the last decade, gut microbiota research changed our perception of what it means to be human by better characterizing our forgotten organ and drawing its connections to our health and disease. The druggability of the gut microbiota leads the way to a very challenging, yet exciting trail for drug discovery, aiming to treat human pathologies by an informed and precise editing of its microorganisms. Recently, several groups have achieved promising results by targeting microbial enzymes involved either in the production of toxic metabolites or the modulation of drug activity. Beside the emergence of new and creative approaches directly targeting endogenous or exogenous pathogens, a better
Figure 1
Various strategies targeting the microbiota. A disease-associated microbiota state, termed ‘dysbiosis,’ may be corrected with selective antibiotics targeting facultative anaerobes, FMT, probiotics, or prebiotics. Furthermore, a microbiota may be steered toward a desired altered state that produces more useful metabolites or has a positive immune system modulation by drugs, probiotics, or prebiotics. Alternatively, direct microbial enzyme inhibition may be used to prevent unwanted metabolism. FMT, fecal microbiota transplant; SCFA, short-chain fatty acids; TMA, trimethylamine. www.sciencedirect.com
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understanding of glycan metabolism by the gut microbiota and its consequence for the host is likely to contribute to additional promising strategies (see Figure 1 for a schematic summary of modulatory approaches). The gut remains an attractive organ for drug discovery. Indeed, the design of nonabsorbable molecules that can reach the large intestine in high concentrations bypasses the issues related to absorption, distribution, and metabolism that typically plague drug discovery and significantly expands the chemical space available. Finally, new exciting methods will complement the essential but laborious humanized mouse models. Chemostat-type in vitro culture systems capable of maintaining complex communities can be perturbed by different xenobiotics in a controlled and precise fashion, as was shown by Guzman-Rodriguez et al. [55]. In addition, microscopic spherical intestinal organoids derived from primary tissues that include cell lineage and polarization that recapitulate more closely the gut epithelium can be inoculated with defined microbial communities or the whole gut microbiota, offering targeted approaches to interrogate bacteriaehost interactions [56,57]. These models offer exciting screening and testing platforms with a higher throughput than previously possible, leading us to believe that gut microbiotaetargeting therapeutics will soon be part of our medical arsenal.
Conflict of interest statement Nothing declared.
Role of the funding source This work is supported by the Canadian Glycomics Network. BC is a Tier II Canada Research Chair in Therapeutic Chemistry. CFM is a Tier II Canada Research Chair in Gut Microbial Physiology.
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ScienceDirect
Drugging the gut microbiota: toward rational modulation of bacterial composition in the gut Fernando Altamura1, Corinne F. Maurice2 and Bastien Castagner1 Abstract
The human gastrointestinal tract hosts almost a trillion microorganisms, organized in a complex community known as the gut microbiota, an integral part of human physiology and metabolism. Indeed, disease-specific alterations in the gut microbiota have been observed in several chronic disorders, including obesity and inflammatory bowel diseases. Correcting these alterations could revert the development of such pathologies or alleviate their symptoms. Recently, the gut microbiota has been the target of drug discovery that goes beyond classic probiotic approaches. This short review examines the promises and limitations of the latest strategies designed to modulate the gut bacterial community, and it explores the druggability of the gut microbiota by focusing on the potential of small molecules and prebiotics. Addresses 1 Department of Pharmacology & Therapeutics, McGill University, 3655 Prom. Sir-William-Osler, Montreal, Quebec, H3G 1Y6, Canada 2 Department of Microbiology & Immunology, McGill University, 3649 Prom. Sir-William-Osler, Montreal, Quebec, H3G 0B1, Canada Corresponding author: Castagner, Bastien (bastien.castagner@ mcgill.ca)
Current Opinion in Chemical Biology 2020, 56:10–15 This review comes from a themed issue on Next generation therapeutics €l Rodriguez Edited by Gonçalo Bernardes and Raphae For a complete overview see the Issue and the Editorial
https://doi.org/10.1016/j.cbpa.2019.09.005 1367-5931/© 2019 Elsevier Ltd. All rights reserved.
Keywords Gut microbiota, Probiotics, Prebiotics, Gut health, Drug discovery, Bacterial metabolism.
Why target the gut microbiota? Microorganisms colonize every surface of our body that communicates with the external environment, and the gastrointestinal tract is no exception. Our ‘forgotten organ’, the gut microbiota, is a complex microbial ecosystem that interacts with its host, while the term
Current Opinion in Chemical Biology 2020, 56:10–15
gut microbiome denotes its genetic pool (our ‘second genome’) [1e3]. Beyond training the immune system, the gut microbiota promotes health through the synthesis and release of several metabolites and vitamins. Short-chain fatty acids (SCFAs) result from the bacterial glycan fermentation and interact with the host via G-proteinecoupled receptors (GPCRs) and by inhibition of histone deacetylases (HDACs) [4,5]. However, bacterial enzymes can also release toxic metabolites such as trimethylamine, later oxidized by the liver to trimethylamine-N-oxide, which is linked to cardiovascular diseases [6]. They can also release the active form of drugs after glucuronide deconjugation of primary compounds, as in the case of the antineoplastic agent SN-38 [7**]. Disease-specific changes in bacterial community structure, loosely termed ‘dysbiosis’, have been observed in several human chronic disorders, including inflammatory bowel diseases (IBDs), obesity, and type 2 diabetes (T2D). Dysbiosis is typically also characterized by a loss in microbial biodiversity, allowing for the expansion of pathogens, such as Clostridioides difficile and enterohemorrhagic Escherichia coli [8]. Today, we witness the ongoing unraveling of new connections between the gut microbiota and other organ systems, hinting to its possible entanglement in pathologies beyond metabolic disorders, including Parkinson diseases and autism. Importantly, the links between these shifts in gut microbial composition and human disorders are stronger than mere correlations because numerous disease phenotypes can be transferred by microbiota transplantation to germ-free animals [9,10]. Therefore, the precise editing of the gut microbiota and/or the modulation of its metabolism could become a valuable strategy to promote human health, and several recent examples point toward exciting therapeutic opportunities.
Manipulating the microbiota with live therapeutics Live therapeutics use living organisms (mostly bacteria) for the treatment of a disease or for the alleviation of its symptoms. Several probiotic strains are reported to suppress pathogens, decrease toxins levels, improve lactose digestion, lower serum cholesterol, deconjugate www.sciencedirect.com
Drugging the Gut Microbiota Altamura et al.
bile acids, and supply nutrients to the host [11]. Despite all these effects, probiotics carry intrinsic limitations as a targeted approach to modulate the gut ecosystem. Indeed, most probiotic bacteria used to date belong to the Lactobacillus and Bifidobacterium genera because of their known resistance to the harsh gastrointestinal tract and the ease to culture them. Furthermore, Zmora et al. [12*] recently showed that exogenous bacteria colonize the human gut mucosa only transiently and in highly individualized patterns and therefore impact the indigenous microbiome and host gene-expression profile inconsistently across different healthy individuals. Notably, the use of probiotics after a course of antibiotics in healthy humans has recently been shown to delay the return of a diverse endogenous microbiota, casting doubt on the benefits of probiotics in this context [13**]. A fecal microbiota transplant (FMT) seems to overcome these limitations. Indeed, transferring a full community rather than a subset of a few strains can generate a more significant and long-lasting shift in the gut endogenous composition, and its beneficial effects appear to last longer, especially after antibiotic treatment. However, health concerns together with regulatory uncertainty regarding screening donors and logistics of delivery still prevent FMT from being the gold-standard method to treat disorders. Suez et al. [13] showed that autologous FMT, which uses samples taken from the patient before gut microbiota disruption by antibiotic treatment, induced a rapid and near-complete recovery within days of administration. Although laborious, this strategy could be useful to prevent long-term microbiota perturbations by antibiotic use. Fortunately, we are now witnessing a Renaissance within the world of live therapeutics, leaning toward more targeted approaches. As we link specific bacteria to downstream host functions, we can explore the probiotic potential of nonconventional strains such as Akkermansia muciniphila. Indeed, three groups independently demonstrated that the gut microbiota composition is linked to the response of immune checkpoint inhibitors for the treatment of cancer [14-16*]. More specifically, Routy et al. [14] found a correlation between clinical responses to the drug and the relative abundance of A. muciniphila. Interestingly, an oral supplementation of this bacterium in germ-free mice humanized with feces from patients not responding to the inhibitors could restore the treatment efficacy. Working toward the same goal, Tanoue et al. [17] isolated a consortium of 11 bacterial strains from healthy human donor feces capable of inducing interferon-geproducing CD8 T cells in the intestine. Mice colonized with the consortium showed enhanced host resistance against Listeria monocytogenes infection and improved efficacy of immune checkpoint inhibitors in syngeneic tumor models. This research shows that a rationally selected www.sciencedirect.com
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and well-defined consortium of bacteria could provide exciting alternatives to generic probiotic strains and FMT for the treatment of diseases ranging from cancer to C. difficile infection [18]. The possibility of genetically modified probiotics that could deliver compounds of therapeutic interest in situ or to maximize their probiotic quality is also an enticing possibility. However, the reception of this application will depend on the development of tighter safety systems, possibly including kill switch mechanisms. Another promising modulatory therapeutic strategy features the use of bacteriophages, but a better understanding of the dynamic interaction between phages and the gut bacteria will be necessary before it becomes a reality [19].
Can we drug it? Novel therapeutic targets in the gut microbiota emerge when precise molecular mechanisms of hoste microbiota interactions are unraveled. As mentioned previously, the reactivation of glucuronidated drug metabolites in the gut by bacterial glucuronidases can cause toxicity [20]. The selective inhibition of these bacterial enzymes offers an exciting strategy against dose-limiting side effect in irinotecan cancer treatment [7**] and intestinal adverse effect of the nonsteroidal anti-inflammatory drug diclofenac [21,22]. These interventions demonstrate the potential of inhibiting bacterial enzymes for human benefit and offer a clear path for drug discovery targeting the microbiota. In another recent example of inhibition of a bacterial enzyme, Roberts et al. [23*] have shown that administration of a covalent inhibitor of choline utilization (cut) gene cluster, iodomethylcholine, reduced the production of trimethylamine-N-oxide (normally produced from bacterial metabolism of dietary phosphatidyl choline) in vivo and rescued the choline diete induced formation of enhanced thrombi. More recently, Orman et al. [24] performed elegant structure-guided work on the choline TMA-lyase cutC that lead to the identification of betaine aldehyde as an inhibitor. The same group also characterized the gut microbiota metabolism of L-dopa, a drug prescribed for Parkinson disease, and rationally designed an effective inhibitor of this metabolism [25]. These approaches have the potential to ameliorate human health by targeted inhibition of deleterious metabolism of the gut microbiota, without overtly affecting its composition. Can we induce informed and targeted changes to the composition of the gut microbiota to benefit the host’s health? Recent work suggests that this might be the case. Maier et al. [26*] comprehensively screened more than 1000 marketed drugs (covering different therapeutic classes) against 40 representative bacterial Current Opinion in Chemical Biology 2020, 56:10–15
12 Next generation therapeutics
strains in vitro. They found that 24% of human-targeted drugs (therefore excluding antibiotics and antiseptics) could inhibit the growth of at least one strain. Similarly, multiple small molecules have been reported to impact the gut microbiota, for better or worse [27]. Although incidental and mostly unwanted, these interactions suggest that small-molecule drugs could have targeted effects on the gut microbiota, which could be exploited for the development of new therapeutic strategies. Recently, Sun et al. [28*] investigated the short-term impact of metformin, a drug used for the treatment of T2D, on the gut microbiota in treatment-naı¨ve patients. They observed increased production of the secondary bile acid glycoursodeoxycholic acid, resulting in inhibition of the intestinal farnesoid X receptor, concomitant with a reduction of the Bacteroides fragilis population. They suggest that metformin acts in part by this mechanism to improve obesity-induced glucose intolerance and insulin resistance. Importantly, the group showed the therapeutic effect of glycoursodeoxycholic acid administration in a mouse model, suggesting a new potential pathway for the treatment of metabolic diseases. Although serendipitous in the metformin case, the precise manipulation of the gut microbiota can be rationally designed, as demonstrated by Zhu et al. [29**]. They showed that the growth of aerotolerant Enterobacteriaceae during gut inflammation could be prevented by a tungstate treatment, which selectively inhibited molybdenum cofactoredependent microbial respiration. This treatment caused negligible shifts in composition under homeostatic conditions because these pathways are operative only in the event of inflammation. Remarkably, tungstate-mediated gut microbiota editing decreased the extent of intestinal inflammation in mouse models of colitis.
Prebiotics in drug discovery Dietary glycans are a major driver of gut microbiota diversity and composition [30,31]. Although continuously adapting to every dietary intake, the gut community remains a resilient ecosystem overall. However, more sustained perturbations, such as a change of dietary habits, will shift the composition to a different equilibrium state, as demonstrated in the gut microbiota seasonal variation of the Tanzanian Hadza community [32]. Our bacterial genetic diversity dictates the digestion of an array of complex dietary glycans. Indeed, the human genome encodes only a few carbohydrate-active enzymes (CAZymes) that can cleave complex polysaccharides found in food such as vegetables, plants, and grains. Therefore, most of these glycans reach the large intestine intact, where they are digested by the gut microbiota, which encodes a much wider repertoire of Current Opinion in Chemical Biology 2020, 56:10–15
CAZymes [33]. The microbiota-accessible carbohydrates (MACs) also include mucin glycans and represent the major source of carbon for the gut bacteria. In return, we obtain w10% of our calorie intake from the absorption of short-chain fatty acids produced by the bacterial glycan fermentation [34]. Interestingly, the host can use internal resources to maintain the integrity of the gut microbial community during a state of disease by shedding fucosylated proteins from intestine epithelial cells, with subsequent bacteria-mediated fucose hydrolysis and metabolism [35]. Beyond the benefit of a healthy vegetable and fiberrich diet, it should be possible to rationally alter the gut microbial community landscape with prebiotics: glycans or other molecules undigested by the host but metabolized by its bacteria [36]. In fact, nature already uses this strategy with human milk oligosaccharides (HMOs) to nurture the gut microbiota of developing infants. A few clinical trials performed over the last two years illustrate the strong potential of prebiotic-based therapeutics [37e40]. One study [41] investigated the effects of arabinoxylans on the physiology of patients who are overweight and obese. The prebiotic supplementation upregulated tight junction proteins including occludin and claudins, thereby improving intestinal permeability. Furthermore, it decreased the fecal pH as more SCFAs were produced and also reduced levels of tumor necrosis factor a, a marker of inflammation. In another study [42], children with autism following an exclusion diet (gluten and casein-free) were given galactooligosaccharides (B-GOSÒ) supplements resulting in an increase of fecal butyrate, a reduction of fecal amino acids (normally indicative of nutrients’ malabsorption), and even a significant improvement in antisocial behavior. New mechanistic insights into the effects of prebiotic sprout from recent animal studies, which are important to guide therapeutic approaches [43]. Indeed, Zou et al. [44*] investigated the mechanisms underlying the action of inulin on the gut microbiota in a mouse model where obesity was induced by a high-fat diet. They found that the prebiotic prevented obesity by reducing overall body weight, fat mass, size of white fat cells, cholesterol levels, blood glucose concentration, and appetite. It also increased colon length and weight, crypt length, enterocyte proliferation, and gut permeability through expression of tight junction proteins. In addition, it stimulated the proliferation of Paneth cells and secretion of glucagon-like peptide 1 from L-cells. At a community level, inulin impacted the gut microbiota by increasing the number of bacteria and alpha diversity, while reducing bacterial encroachment. The authors could trace all these beneficial effects to the ability of inulin to induce the production of interleukin-22. A www.sciencedirect.com
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different study [45] also used a diet-induced mouse model of obesity (high-fat high-sucrose diet) to investigate the effects of a crude extract of camu camu (Myrciaria dubia, an Amazonian fruit) on the composition of the gut microbiota and the host gastrointestinal physiology. They found that camu camu improved insulin sensitivity, metabolic inflammation, and endotoxemia, while reducing weight gain and fat mass. Treated mice also featured an expansion of A. muciniphila and drastic changes in metatranscriptomic profiles, including an upregulation of thermogenin in brown fat cells and the bile acid receptor TGR5. Another study [46] used an antibiotic-induced mouse model of C. difficile infection to study how prebiotics can impact the course of the infection. They demonstrate that diets rich in complex mixtures of microbial accessible carbohydrates or containing inulin as sole carbohydrate can change the microbiota composition, its metabolic output, and C. difficileemediated inflammation.
Challenges in developing effective prebiotics Two factors prevent the development of effective prebiotics: (1) our limited understanding of who eats what? in the gut microbiota and (2) the large diversity of glycan structures with the associated CAZymes able to digest them. Indeed, most clinical trials focussed only on a few structures including galactooligosaccharides, fructooligosaccharides, and resistant starch, in contrast to the large diversity of complex glycan structures contained in our diet. Furthermore, although a number of elegant studies [47e49] continue to shed light on the complex mechanisms of glycan metabolism beyond the well-characterized starch utilization system of B. thetaiotaomicron [50], the bacterial consumers of a myriad of potential prebiotic glycans remain unidentified. In addition, we are in tremendous need of studies that also provide mechanistic insights between a prebiotic and a downstream phenotype. This
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task is particularly challenging, given the complexity of the gut microbial community and its many channels bridging it to host physiological organ systems. Indeed, manipulating blindly the gut microbiota can be dangerous. For example, Singh et al. [51] found that incorporating soluble inulin into a compositionally defined diet induced a gut microbiota-dependent hepatocellular carcinoma, featuring early onset of cholestasis and hepatocyte death, followed by neutrophilic liver inflammation. Natural modulations of the gut bacteria linked to age, diet, drug interactions, lifestyle, and geographical location also hinder the development of prebiotic therapeutics. A recent study [52] showed differential effects of the same inulin-type fructan based on dietary habits. The prebiotic supplementation was significantly more effective in patients who maintained a high-fiber diet than in those on a low-fiber diet. Another study demonstrated interpersonal differences in postmeal glucose response that was in part due to dissimilarities in the gut microbiota [53]. These studies suggest that a personalized approach might be necessary and should be systematically addressed if we intend to exploit the benefits of prebiotic supplements [54].
Concluding remarks In the last decade, gut microbiota research changed our perception of what it means to be human by better characterizing our forgotten organ and drawing its connections to our health and disease. The druggability of the gut microbiota leads the way to a very challenging, yet exciting trail for drug discovery, aiming to treat human pathologies by an informed and precise editing of its microorganisms. Recently, several groups have achieved promising results by targeting microbial enzymes involved either in the production of toxic metabolites or the modulation of drug activity. Beside the emergence of new and creative approaches directly targeting endogenous or exogenous pathogens, a better
Figure 1
Various strategies targeting the microbiota. A disease-associated microbiota state, termed ‘dysbiosis,’ may be corrected with selective antibiotics targeting facultative anaerobes, FMT, probiotics, or prebiotics. Furthermore, a microbiota may be steered toward a desired altered state that produces more useful metabolites or has a positive immune system modulation by drugs, probiotics, or prebiotics. Alternatively, direct microbial enzyme inhibition may be used to prevent unwanted metabolism. FMT, fecal microbiota transplant; SCFA, short-chain fatty acids; TMA, trimethylamine. www.sciencedirect.com
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14 Next generation therapeutics
understanding of glycan metabolism by the gut microbiota and its consequence for the host is likely to contribute to additional promising strategies (see Figure 1 for a schematic summary of modulatory approaches). The gut remains an attractive organ for drug discovery. Indeed, the design of nonabsorbable molecules that can reach the large intestine in high concentrations bypasses the issues related to absorption, distribution, and metabolism that typically plague drug discovery and significantly expands the chemical space available. Finally, new exciting methods will complement the essential but laborious humanized mouse models. Chemostat-type in vitro culture systems capable of maintaining complex communities can be perturbed by different xenobiotics in a controlled and precise fashion, as was shown by Guzman-Rodriguez et al. [55]. In addition, microscopic spherical intestinal organoids derived from primary tissues that include cell lineage and polarization that recapitulate more closely the gut epithelium can be inoculated with defined microbial communities or the whole gut microbiota, offering targeted approaches to interrogate bacteriaehost interactions [56,57]. These models offer exciting screening and testing platforms with a higher throughput than previously possible, leading us to believe that gut microbiotaetargeting therapeutics will soon be part of our medical arsenal.
Conflict of interest statement Nothing declared.
Role of the funding source This work is supported by the Canadian Glycomics Network. BC is a Tier II Canada Research Chair in Therapeutic Chemistry. CFM is a Tier II Canada Research Chair in Gut Microbial Physiology.
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