Gut microorganisms affect response to cancer treatment
24 November 2013
A healthy population of microorganisms that live off other
microorganisms in the intestine is required for optimal response to
cancer therapy, according to a study led by scientists at the US
National Cancer Institute (NCI).
The researchers found that mice completely lacking these
microorganisms (bred to be without), or mice treated with
antibiotics to deplete the gut of bacteria, were largely impaired in
their ability to respond to immunotherapy that slows cancer growth
and prolongs survival.
The mice were also impaired in their ability to respond to
mainstay chemotherapy drugs such as oxaliplatin and cisplatin. These
findings in mice may underscore the importance of microorganisms in
optimal cancer treatment outcomes in humans.
Image of an evolutionary tree of mouse gut
superimposed over an image of colon tissue with
larger circles indicating greater abundance of bacteria.
circles are bacteria that prime mice to respond
immunotherapy; green shows bacteria that suppress
response to the drug.
Gut commensal microbiota are microorganisms that live in the gut
and thrive but do not affect their host — in this study laboratory
mice. Humans also harbour gut commensal microbiota that can
influence local and body-wide inflammation as well as modify the
tumour microenvironment, which consists of cells, signalling
molecules and mechanisms that may support tumour growth and also
cause drug resistance.
To study the importance of commensal bacteria, the scientists
used mice raised in sterile conditions from birth so they did not
harbour any bacteria, or alternatively, conventionally raised mice
that received a potent antibiotic cocktail that is known to decrease
bacteria by more than 10,000–fold. The mice received these
antibiotics in their drinking water, starting three weeks prior to
tumour inoculation. They continued to receive doses of the
antibiotic cocktail throughout the experiment.
To analyze tumours at comparable stages of progression, lymphoma,
colon, and melanoma cancers that could be transplanted were
selected, based on their susceptibility to therapeutic drugs. Cancer
cells from these tumours were then injected under the skin of the
mice, where they formed tumours that grew to reach a diameter of
one-fifth of an inch or more. The tumours were then treated with an
immunotherapy that included CpG-oligonucleotides, which stimulated
the immune system, or with the chemotherapy drugs oxaliplatin and
cisplatin, which attacked the tumours.
Germ-free mice, or mice that received the antibiotic cocktail,
responded poorly to drug therapy for their tumours. This resulted in
a lower production of cytokines (proteins secreted by lymph cells
that affects cellular activity and controls inflammation) as well as
lower tumour death therefore demonstrating that optimal responses to
cancer therapy required an intact commensal microbiota.
In an independent co-submitted study that will appear in the same
issue of Science, Laurence Zitvogel MD PhD, Gustave Roussy
Institute, Paris, and colleagues showed that a different type of
chemotherapy drug, cyclophosphamide, altered the composition of the
intestinal microbiota and damaged the intestinal wall, thereby
affecting optimal anti-tumour immune response and the therapeutic
effectiveness of cyclophosphamide.
“The use of antibiotics should be considered as an important
element affecting microbiota composition. It has been demonstrated,
and our present study has confirmed, that after antibiotic treatment
the bacterial composition in the gut never returns to its initial
composition,” said Trinchieri. “Thus, our findings raise the
possibility that the frequent use of antibiotics during a patient’s
lifetime or to treat infections related to cancer and its
side-effects may affect the success of anti-cancer therapy.”
In next steps, Goldszmid and Trinchieri will work in mice to
fully characterize the molecular signalling by which the bacteria in
the gut can actually send messages to distant organs or tumours and
change the type and level of inflammation present in those organs.
They also plan to characterize, in humans, the role of gut bacteria
on the bodies’ inflammatory response and tumour response to therapy.
Additionally, the researchers plan to design clinical studies by
giving antibiotics to healthy volunteers to study their effect on
the molecular mechanisms regulating inflammation.