The gut microbiome outlook LEWIS HOUGHTON/SPL A researcher tests donor stool before it is used for faecal microbiota transplantation. Engineering the microbiome Modified bacteria and carefully formulated microbial communities could form the basis of new living treatments. By Claire Ainsworth lthough it happened almost a decade transplants were proving so successful that aspects of our physiology — from conditions ago, Willem de Vos still vividly remem- it was no longer ethical to continue to give such as obesity to how the immune system bers his colleagues being told to halt people in the control group the conventional functions and even mental health. The suc- the clinical trial they had been run- antibiotic treatment with which the trans- cess of FMT in treating C. difficile also shows ning. De Vos was part of the team plants were being compared. “That showed that, in principle, the ecology of the gut can be Aconducting the first randomized clinical trial us that it worked and why it worked,” says manipulated to treat disease. Now, scientists of faecal microbiota transplantation (FMT) de Vos, a microbiologist at the University of are attempting to engineer gut microbiota that — faeces from healthy donors were used as a Wageningen in the Netherlands and the Uni- will allow them to do just that. last-resort treatment for people with a dev- versity of Helsinki in Finland. The antibiot- Synthetic biologists are working at the level astating, recurrent gut infection caused by ic-treated patients who relapsed were given of individual species, engineering gut bacteria the bacterium Clostridium difficile. About a the transplant, which cured them. not only to deliver therapeutic payloads but year in, the data and safety monitoring board The C. difficile story is one of a growing list of also to monitor and respond to conditions overseeing the trial had seen enough: the examples of how the gut microbiome shapes inside the body. Meanwhile, synthetic ecol- trial needed to end. But it wasn’t because the our biology. The community of microbes that ogists are looking at the gut as an ecosystem therapy didn’t work — quite the opposite. The lives in the gut has been associated with many and assembling communities of microbes that S20 | Nature | Vol 577 | 30 January 2020 ©2020 Spri nger Nature Li mited. All ri ghts reserved. ©2020 Spri nger Nature Li mited. All ri ghts reserved. interact to produce substances or behaviours signal can be detected in stool samples, rais- from organisms acting alone. for medical benefit. Both approaches are in ing the possibility of using the bacterium as a These emerging properties of the gut micro- their infancy, and there are challenges to get- living diagnostic test for inflammatory bowel biome have a profound effect on our biology, ting them into the clinic. Yet the technologies disease — which is often transient in nature such as by producing vitamins or molecules are already proving to be powerful tools, allow- and, therefore, hard to detect in the clinic. that modulate our immune responses. To ing scientists to explore the complex microbial The bacteria formed a stable colony in the understand these interactions and to devise interactions in our internal ecosystem. guts of mice for six months and responded to new therapies, researchers are building com- experimentally induced gut inflammation3. binations of different bacteria known as syn- Bespoke bacteria Importantly, engineered bacteria that can thetic ecosystems. For the most part, these Engineering individual microbes has an remember other kinds of environmental signal ecosystems are made up of naturally occurring impressive array of potential applications. would allow researchers to explore conditions bacterial strains, although some scientists are Gut bacteria have been altered to produce in different regions of the gut — something that experimenting with ecosystems containing therapeutic molecules to treat metabolic con- is hard to do with conventional stool samples. genetically engineered microbes. ditions, kill pathogens and trigger immune “What we really would like is the bacteria to be From a therapeutic point of view, synthetic responses to cancers. A strain of Escherichia like detectives and tell us what’s going on as ecosystems have a number of potential advan- coli engineered to produce the proteins they pass through,” says Silver. tages. FMT currently relies on faecal matter needed to correct rare metabolic deficien- Getting a genetic circuit to work in the lab provided by donors. Stool samples contain cies is now in clinical trials. And in 2018, a is hard enough. Translating that to the messy, team in Singapore revealed gut bacteria that competitive environment of the gut microbi- “What we really would it had engineered to stick to colon cancer cells ome presents an even greater challenge. Any like is the bacteria to be and secrete an enzyme that converts a sub- modification that imposes an extra burden stance naturally found in vegetables such as — say, extra protein production — on a bacte- like detectives and tell us broccoli into a molecule that inhibits tumour rium puts it at a disadvantage, resulting in that what’s going on.” growth. When given to mice with colon cancer, organism either being out-competed or ditch- the treatment shrank tumours and reduced ing its engineered function to survive. Partly recurrence1. Bacteria can even be engineered for this reason, researchers have struggled to highly complex mixtures of microbes that to sense signs of disease and respond by pro- get many engineered bacteria to make the leap vary from donor to donor, and each must be ducing therapeutic molecules. For example, in from test tube to animal models. Scientists screened for pathogenic microbes. If FMTs 2017, researchers took a gut bacterium com- are now working on ways around this; Silver, could be stripped down to just the key spe- monly used as a probiotic and gave it the ability for example, is using genetic elements that cies needed to treat people, simplified path- to detect communication signals produced naturally place a minimal burden on the cell. ogen-free mixtures of these selected microbes by pathogenic bacteria. The probiotic bacte- The final hurdle will be showing that engi- could be grown in the lab. Synthetic commu- rium then produces an antimicrobial molecule neered bacteria are effective and safe. What’s nities would offer a standardized therapeutic in response. The researchers showed that it more, unlike conventional drugs, engineered with a known composition, and would lift the helped clear infections in worms and mice2. bacteria could spread into the environment reliance on finding suitable donors. Studies such as this show the potential of and share their DNA with other bacteria. Research, including a few studies in people, live therapeutics, but so far the engineered Although the chances of them surviving in suggest that this approach could work. Mix- bacteria are comparatively straightforward the wild are thought to be low, the possibility tures of selected bacteria isolated from stool systems — they produce a therapeutic mole- of unforeseen consequences (not to mention samples have shown promise in treating peo- cule either at a constant rate or in response to the need to secure public acceptance and regu- ple with C. difficile. And it’s not just infections an environmental signal. Now, researchers are latory approval) has led researchers to explore that could be tackled, but also conditions such looking to broaden the scope of engineered a number of options to contain engineered as inflammatory bowel disease. In 2013, a team microbes and engineer bacteria with DNA con- bacteria, including kill switches that force led by scientists in Japan identified a commu- taining more complex elements designed to bacteria to kill themselves with a toxin if their nity of human gut microbes that could pro- work like electronic circuits. This is the realm engineered circuits turn faulty or if they leave mote the activity of inflammation-damping of synthetic biology, a discipline that aims to the body. immune cells called regulatory T cells, and apply engineering principles — such as stand- showed that this could ameliorate inflamma- ardized, modular components — to biological Constructing communities tory bowel disease in mice4. As well as devel- systems. While some researchers engineer individual oping therapies, stripping down conventional These complex feats of engineering are bacteria, others are turning their attention to FMTs is allowing scientists to work out which allowing bacteria to do simple computational groups of microbes. Just as a city functions bacteria in stool transplants are exerting a tasks, such as remembering a one-off stimulus as a result of many people doing different therapeutic effect — something that de Vos and long after it has passed. For example, a team jobs, the gut is a hive of interactions between his colleagues are exploring in conditions such of synthetic biologists led by Pamela Silver at myriad microbes carrying out different func- as inflammatory bowel disease and metabolic the Wyss Institute for Biologically Inspired tions. Some interactions are metabolic — one syndrome. Engineering at Harvard University in Bos- bacterium might produce something that One drawback of this stripping-down ton, Massachusetts, engineered a bacterium another consumes, for instance. Others approach is that it limits the applications of the to detect a chemical produced by inflamed are ecological, such as when one microbe synthetic community to functions that already gut cells. In response, the bacteria secrete a inhibits the growth of another. By working exist. There might be situations in which you molecular signal, and continue to secrete it together, communities of microbes produce would want to create a community with a even if the gut inflammation dies down. The molecules or behaviours that would not arise new function, such as producing a vitamin Nature | Vol 577 | 30 January 2020 | S21 ©2020 Spri nger Nature Li mited.