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<\/picture>\nBertrand Routy earned a lamentable reputation with Parisian oncologists in 2015. A doctoral student at the nearby Gustave Roussy cancer centre, Routy had to go from hospital to hospital collecting stool samples from people who had undergone cancer treatments. The doctors were merciless. \u201cThey made fun of me,\u201d Routy says. \u201cMy nickname was Mr Caca.\u201d<\/p>\n
But the taunting stopped after Routy and his colleagues published evidence that certain gut bacteria seem to boost people\u2019s response to treatment1<\/a><\/sup>. Now, those physicians are eager to analyse faecal samples from their patients in the hope of predicting who is likely to respond to anticancer drugs. \u201cIt was an eye-opener for a lot of people who couldn\u2019t see the clinical relevance of gut microbes,\u201d says Routy, who is now at the University of Montreal Health Centre in Canada.<\/p>\n Cancer has been a late bloomer in the microbiome revolution that has surged through biomedicine. Over the past few decades, scientists have linked the gut\u2019s composition of microbes to dozens of seemingly unrelated conditions \u2014 from\u00a0depression<\/a>\u00a0to\u00a0obesity<\/a>. Cancer has some provocative connections as well: inflammation is a contributing factor to some tumours and a few types of cancer have infectious origins. But with the explosive growth of a new class of drug \u2014 cancer immunotherapies \u2014 scientists have been taking a closer look at how the gut microbiome might interact with treatment and how these interactions might be harnessed.<\/p>\n After preliminary findings in mice and humans revealed that gut bacteria can sway responses to such drugs, scientists started trying to decipher the mechanisms involved. And researchers are launching a handful of clinical trials that will test whether the gut microbiome can be manipulated to improve outcomes.<\/p>\n Some proponents say that strategies to mould the microbiome could be game-changing in cancer treatment. \u201cIt\u2019s a smart place to be,\u201d says Jennifer Wargo, a surgeon\u2013scientist at MD Anderson Cancer Center in Houston, Texas. But others are worried that\u00a0the move to the clinic is premature<\/a>. William Hanage, an epidemiologist at the Harvard T. H. Chan School of Public Health in Boston, Massachusetts, calls the idea \u201cphenomenally interesting\u201d, but adds: \u201cI have some anxiety about the notion that only beneficial effects are possible.\u201d<\/p>\n Intriguing link<\/b><\/p>\n Although the excitement about microbes and immunotherapy has emerged only in the past three years, some researchers have been exploring connections between gut bacteria and cancer for much longer. Scientists first linked the infectious bacterium\u00a0Helicobacter pylori<\/i>to gastric cancer back in the 1990s, for example. And since then, other bacteria have been associated with cancer initiation and progression. Some of these microbes activate inflammatory responses and disrupt the mucus layers that protect the body from outside invaders, creating an environment that supports tumour growth. In other cases, they promote cancer survival by making cells resistant to anticancer drugs.<\/p>\n But gut bacteria can\u00a0also help fight tumours<\/a>. In 2013, a group led by Laurence Zitvogel2<\/a><\/sup>\u00a0at Gustave Roussy and one led by immunologists Romina Goldszmid and Giorgio Trinchieri3<\/a><\/sup>\u00a0at the National Cancer Institute in Bethesda, Maryland, showed that some cancer treatments rely on the gut microbiome activating the immune system.<\/p>\n Zitvogel\u2019s team found that the chemotherapy drug cyclophosphamide damages the mucus layer that lines the intestine, allowing some gut bacteria to travel into the lymph nodes and spleen, where they activate specific immune cells. For mice raised without microbes in their guts or given antibiotics, the drug largely lost its anticancer effects.<\/p>\n Following this observation, Zitvogel decided to explore whether bacteria in the gut might influence responses to a class of immunotherapy drugs called checkpoint inhibitors. These drugs, typically antibodies to cell-surface molecules such as CTLA4 and PD1, unleash a person\u2019s immune system against tumour cells, and are used to treat several types of cancer (see \u2018A little help from their friends\u2019). But only 20\u201340% of people respond to treatment4<\/a><\/sup>.<\/p>\n <\/p>\n <\/p>\n In 2015, Zitvogel and her team showed that microbe-free mice failed to respond to one such drug, and mice given a particular bacterium,\u00a0Bacteroides fragilis<\/i>, responded better than did mice without it5<\/a><\/sup>.<\/p>\n The idea started to spread. Thomas Gajewski, a cancer clinician at the University of Chicago in Illinois, reported that\u00a0Bifidobacterium<\/i>\u00a0microbes increased the response to cancer immunotherapy in mice6<\/a><\/sup>. These gut-dwelling bacteria acted by boosting the ability of some immune cells to initiate a response against tumours.<\/p>\n Wargo saw these results presented at a meeting in 2014, and on returning to Texas, immediately started to collect stool samples from people with skin cancer who were about to undergo immunotherapy at her institution. Last November, Wargo7<\/a><\/sup>, Gajewski8<\/a><\/sup>\u00a0and Zitvogel1<\/a><\/sup>\u00a0all published results in\u00a0Science<\/i>\u00a0linking positive immunotherapy responses in people to specific varieties of gut bacteria. The samples that Routy had collected in Paris helped Zitvogel\u2019s team to also show that people who had taken antibiotics for unrelated infections tended to respond poorly to immunotherapy.<\/p>\n To solidify the relationships, the researchers transferred bacteria from the human participants into the intestines of mice with comparable cancers. Rodents who got \u2018beneficial\u2019 bacteria developed smaller tumours than did mice that received microbes from people who hadn\u2019t responded to treatment. \u201cAll of this work has been very exciting,\u201d says Neeraj Surana, a microbiologist at Boston Children\u2019s Hospital. \u201cThey\u2019ve opened up the possibility for a clear therapeutic application of microbiome science.\u201d<\/p>\n Heading to the clinic<\/b><\/p>\n Researchers are now running with that possibility. Hassane Zarour, an immunologist at the University of Pittsburgh in Pennsylvania, partnered with the global pharmaceutical company Merck to collect faecal bacteria from people who respond to treatment with a checkpoint inhibitor and transfer them into the intestine of non-responders, a process called faecal microbiome transplant. Merck has invested about US$900,000 into this trial, which is set to start in the next few weeks.<\/p>\n Wargo is planning a similar trial. Together with the Parker Institute for Cancer Immunotherapy in San Francisco, California, and the biotech company Seres Therapeutics in Cambridge, Massachusetts, she expects to test whether faecal transplants can reshape the gut microbiome of non-responders in a beneficial way.<\/p>\n![\"\"](\"https:\/\/media.nature.com\/w800\/magazine-assets\/d41586-018-05208-8\/d41586-018-05208-8_15780934.jpg\")
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