Credit: Jane Hurd
Credit: Jane Hurd

Three Cancer Drugs Don’t Work Properly Without Gut Bacteria

Your gut is home to tens of trillions of bacteria. Collectively, they act as another organ, one with many different roles. They influence your body weight, your ability to digest your food, your risk of catching infectious diseases, your chances of resisting infections or autoimmune diseases, the development of your brain, and more.

Now, we can add an entry to this growing list. At least in mice, gut bacteria can influence whether cancer treatments work.

Working independently, two teams of scientists showed that three cancer treatments rely on gut bacteria to mobilise the immune system and kill tumour cells—not just in the gut, but also in the blood (lymphomas) and skin (melanomas). Remove the bacteria with antibiotics, and you also neuter the drugs.

“It was a surprise,” says Romina Goldszmid from the National Cancer Institute, who led one of the studies. “Nobody would ever have thought we should worry about gut bacteria when thinking about treating cancer.”

The first team, led by Goldszmid and Giorgio Trinchieri, treated tumour-ridden mice with immunotherapy—a cocktail of substances that stimulates the immune system to attack cancer cells. The cocktail shrank the tumours, and prolonged the rodents’ lives. Two months later, around 70 percent of them were still alive. But if the mice drank a cocktail of antibiotics a few weeks earlier, the immunotherapy no longer worked. It failed to keep the tumours in check, and at the two-month mark, only 20 percent of the mice were alive.

The team showed that the gut bacteria stimulate immune cells that live inside the tumour, priming them to respond to immunotherapy. Think of the bacteria as cocking the pistol, while the immunotherapy pulls the trigger. Without that first step, nothing dies.

Goldszmid and Trinchieri’s team also tested a different cancer drug called oxaliplatin, which is used to treat cancers of the bowel, stomach and gullet. It works by damaging DNA, which supposedly prompts cancer cells to release a powderkeg of oxygen molecules. These are so chemically reactive that they wreak fatal havoc inside the tumours.

But the team found that the cancer cells themselves only produce a fraction of these killer molecules. The rest come from the immune cells that live among them. And once again, these cells only did their job if they primed for action beforehand by the gut bacteria. When the team killed the bacteria with antibiotics, oxaliplatin lost its sting.

Meanwhile, the second group led by Laurence Zitvogel from the Gustave Roussy Institute in France tested a drug called cyclophosphamide or CTX, which is used to treat breast cancer, lung cancer, and more. It seems to recruit two types of immune cells called TH1 and TH17 cells which cooperate to attack the tumours. Scientists have known about this immune response for decades, but Zitvogel’s team found that it happens for unexpected reasons.

Cyclophosphamide damages the layer of mucus that coats the intestines, allowing bacteria that live in the mucus to move deeper into the gut. Some of them travel into the spleen and the lymph nodes, where they nudge the resident immune cells into becoming TH1 and TH17 cells. So, cyclophosphamide does its thing by making the gut leaky, and allowing bacteria to migrate out of it! And once again, when the team killed the bacteria with antibiotics, the cancer-killing immune cells weren’t recruited, and the drug became drastically less effective.

What does this mean for cancer patients? “We have to be extremely cautious,” says Goldszmid. “These were mouse studies. It is now absolutely important that these be corroborated in careful human studies.”

Even if they are successful, putting this knowledge to practical use will be very hard. For example, doctors often treat cancer patients with a wide range of other antibiotics. This helps to deal with existing infections and to prevent new ones, especially after treatments like radiotherapy that can suppress the immune system. Based on the new studies, you could argue that these antibiotic assaults make matters worse, but what’s the alternative? “You don’t want to stop giving antibiotics to people who are immune-suppressed,” says Goldszmid.

Instead, doctors might give their patients probiotics to supplement their impoverished guts with the right bacteria. But, which bacteria? In Goldszmid and Trinchieri’s experiments, mice with lots of Lactobacillus in their guts responded poorly to immunotherapy. But Zitvogel’s team found that two species—Lactobacillus johnsonii and Lactobacillus murinus—were among those responsible for the effects of CTX.

This could mean that the same microbes could strengthen some cancer treatments while weakening others. Alternatively, it could mean that different species within the same groups have opposite effects—there are 25 species in the Lactobacillus group and they could do very different things. “It’s possible that we were not looking at the exact same bacteria,” says Zitvogel.

“Other work shows that the microbiome affects the development of colorectal cancer, and can be associated with more tumours. But here, if you disrupt the microbiome, you change the efficacy of an intervention,” says Christian Jobin from the University of Florida. “The microbiome affects the whole range of the disease from initiation to treatment. Harnessing the power of this knowledge will be very difficult for medicine.”

“For me, the take-home message is that we cannot ignore the gut microbiome and the possibility that it has an impact on the response to cancer treatments,” says Goldszmid.

Reference: Viaud, Saccheri, Mignot, Yamazaki, Daillere, Hannani, Enot, Pfirschke, Engblom, Pittet, Schlitzer, Ginhoux, Apetoh, Chachaty, Woerther, Eberl, Berard, Ecobichon, Clermont, Bizet, Gaboriau-Routhiau, Cerf-Bensussan, Opolon, Yessaad, Vivier, Ryffel, Elson, Dore, Kroemer, Lepage, Boneca, Ghiringhelli & Zitvogel. 2013. The Intestinal Microbiota Modulates the Anticancer Immune Effects of Cyclophosphamide. Science

Iida, Dzutsev, Stewart, Smith, Bouladoux, Weingarten, Molina, Salcedo, Back, Cramer, Dai, Kiu, Cardone, Naik, Patri, Wang, Marincola, Frank, Belkaid, Trinchieri & Goldszmid. 2013. Commensal Bacteria Control Cancer Response to Therapy by Modulating the Tumor Microenvironment. Science