Gut microbiota play both versatile and critical roles in the human body. Not only do they help in immune responses, but also contribute to energy metabolism by degrading complex carbohydrates for which humans do not possess the enzymes.1 These symbiotic microorganisms can degrade glycans and polysaccharides, producing short-chain fatty acids (SCFAs) that can be used by the body and are beneficial to the epithelium of the colon, as we learned in BCM441.
Although the characterization of the gut microbiome remains incomplete, it is estimated that over half of microorganisms residing in healthy human GI tracts belong to the Bacteroidetes phylum. Bacteria in this phylum can degrade starch using the starch utilization system. The starch utilization system (Sus) and Sus-like systems consist of several proteins that work to bind, degrade, and import starch into the cell via a multiprotein system (Fig. 1).2
Alteration of gut microbiota composition is implicated in a number of human diseases, including inflammatory bowel disease, colorectal cancer, and obesity, some of which have no cure, like Crohn’s disease. Dysbiosis describes abnormalities in gut microbiota populations that are associated with various disorders. Antibiotics are common therapeutics against bacterial infections. However, antibiotics tend to be indiscriminate in their attack against bacteria, sometimes leading to dysbiosis and potential consequences for the human host. Secondary opportunistic bacterial infections have been known to arise following antibiotic use that leads to dysbiosis, and these opportunistic infections are facilitated by alterations in carbohydrate availability.3 Additionally, past work has demonstrated that glycan availability affects microbiota composition. As presented in BCM441, a 2014 Nature paper showed that alteration of gut microbiota, prompted by artificial sweeteners, had systemic consequences, namely due to the development of glucose intolerance.4
Because of its implication in various human diseases, gut microbiota have become a new potential therapeutic target, departing from classical antibiotics and biochemical techniques. Composition of microbiota is readily changeable, unlike the human genome, which makes targeting of microbiota a potential strategy.1 Recent work has explored tungstate as a selective inhibitor of pathogenic bacteria that relieved symptoms of the bowel disease colitis in mice models, although, tungstate should not be ingested by humans.5 A new study by Santilli, et.al., published in ACS Chemical Biology, describes the potential of targeting gut microbiota as a therapeutic agent for human diseases, particularly using small molecule nonmicrobicidal inhibitors.6
From the eight proteins (SusRABCDEFG) that comprise Bacteroides Sus, the protein SusG is an α-amylase located on the outer cellular surface that breaks α1,4-glycosidic bonds in starch-based polysaccharides. SusG is vital to Bacteroides thetaiotamicron growth on starch, even though other amylases are present.4
Santilli, et.al. used two species of bacteria from the Bacteroides phylum, B. thetaiotamicron (Bt) and B. fragilis (Bf) to investigate the effect of known human α-amylase inhibitors on growth and survival of these species. Bt and Bf were incubated in an anaerobic chamber with 100 µM of one of three human α-glucosidase inhibitors (acarbose, miglitol, and vogilbose), and one of four polysaccharides (potato starch, pullulan, chondroitin sulfate, and levan) in minimal media. By measuring optical density, the researchers found that acarbose can inhibit metabolism of potato starch and pullulan and thus bacterial growth. Bt and Bf could grow in the presence of miglitol and vogilbose and could metabolize chondroitin sulfate and levan even when treated with acarbose, the two of which are metabolized using not Sus, but Sus-like systems. Acarbose selectively acts on the Sus and does not actually kill the bacterial cells, as confirmed by the presence of viable cells in acarbose-treated cultures.
Acarviosin is essentially acarbose without the maltose component (Fig. 2). A similar study as mentioned above investigated the effects of this small molecule on the growth of Bf and Bt in minimal media containing either potato starch or pullulan. This small molecule inhibits potato starch metabolism but exerts no inhibitory effects on Bt and Bf grown in pullulan-containing media. Not only does this show the selectivity of these small molecules for the Sus, but also the potential ability to target specific starches through chemical modification of acarbose. For both acarbose and acarviosin, a higher concentration of the small molecule leads to increased inhibition of Bacteroides growth.
Acarbose is selective not only considering the targeted system but also bacterial species. Activity of other prominent members of the gut microbiome, namely Ruminococcus bromii from the Firmicutes phylum, E.coli, and Lactobacillus reuteri, were assessed in the presence of acarbose. E. coli and L. reuteri do not metabolize starch and thus were not negatively impacted by acarbose, as expected. In contrast, R. bromii does degrade starch but uses a different protein system in the metabolic process and lacks homologs of Sus proteins. Although there was a small amount of inhibition in pullulan media, R. bromii growth was not affected in media containing either potato starch, fructose, or maltose. Acarbose selectively acts against Bacteroides growth, which differs from antibiotics that may harm more than one type of bacteria.
Gut microbiota composition is dynamic, flexible, and can change within a host’s lifetime, depending on diet and condition. This study contributes to the growing idea of targeting gut microbiota composition as a potential therapeutic avenue. Looking forward, the authors aim to identify the targets within Bt Sus responsible for acarbose inhibition of starch metabolism. Application of this strategy to other gut microbes and using different small molecules are also currently being investigated. Moreover, researchers can study the effects of acarbose, acarviosin, and other derivatives on gut microbes in both healthy and diseased animal models. Instead of using antibiotics and for conditions that involve detrimental alterations in gut microbiota composition, the use of small molecules that selectively inhibit growth of specific bacterial species is a potential option for therapeutic strategies.
1.Jia, W., Li, H., Zhao, L. & Nicholson, J. K. Gut microbiota: a potential new territory for drug targeting. Nature Reviews Drug Discovery 7, 123–129 (2008).
2. Koropatkin, N. M. & Smith, T. J. SusG: A Unique Cell-Membrane-Associated α-Amylase from a Prominent Human Gut Symbiont Targets Complex Starch Molecules. Structure 18, 200–215 (2010).
3. Ng, K. M. et al. Microbiota-liberated host sugars facilitate post-antibiotic expansion of enteric pathogens. Nature 502, 96–99 (2013).
4. Suez, J. et al. Artificial sweeteners induce glucose intolerance by altering the gut microbiota. Nature 514, 181–186 (2014).
5. Zhu, W. et al. Precision editing of the gut microbiota ameliorates colitis. Nature 553, 208–211 (2018).
6. Santilli, A. D., Dawson, E. M., Whitehead, K. J. & Whitehead, D. C. Nonmicrobicidal Small Molecule Inhibition of Polysaccharide Metabolism in Human Gut Microbes: A Potential Therapeutic Avenue. ACS Chemical Biology 13, 1165–1172 (2018).