The vital role of the intestinal flora in successful immunotherapy has just been revealed in a study published in the journal Science. Intestinal bacteria have been identified that can improve the therapeutic response to this drug and reduce a side-effect, “inflammatory colitis,” regularly encountered with this treatment.

This research implies that the efficacy of immunotherapy in oncology might in future be dictated by the composition of the patient’s intestinal flora. The researchers hope to develop a test for predicting the response to these treatments by analysing the intestinal flora. They also hope to offer those patients who need it the opportunity to reconstitute a flora which will restore the anti-tumour effect of the immunotherapy.

flore intestinale

This research was conducted jointly by French researchers from Gustave Roussy, Inserm, Institut Pasteur Lille and Institut Pasteur Paris, the AP-HP (Paris Public Hospitals) and Paris-Sud University, in collaboration with a team from the French National Institute for Agricultural Research (INRA), and was mainly funded by ARC Foundation for Cancer Research.

Certain bacteria naturally present in the intestinal flora are becoming the pillars of success for an immunotherapy used in clinical oncology,” comments Prof. Laurence Zitvogel, Director of the Tumour Immunology and Immunotherapy Laboratory (Inserm / Gustave Roussy / Paris-Sud University), and last author of the publication.


The role of two types of bacteria from the intestinal flora in the alleviation of these side-effects and in increasing the efficacy of an immunotherapy based on a monoclonal antibody against CTLA4 (ipilimumab) has just been demonstrated by Prof. Laurence Zitvogel’s team, with assistance from teams led by Dr Mathias Chamaillard, Institut Pasteur Lille, Dr Ivo Gomperts Boneca, Institut Pasteur Paris, and Dr Patricia Lepage, INRA.

The researchers showed that when the intestinal flora lacked the two bacterial types identified, either in germ-free mice or after treatment with broad-spectrum antibiotics, the drug was no longer effective against the tumour. Colonisation of the intestinal flora by one or other of these bacterial types is necessary and sufficient to restore the effect of the monoclonal antibody and improve the symptomatology of inflammatory colitis in these mice.

The relevance of these findings was also successfully tested in humans. The teams led by Prof. Caroline Robert, Head of the Dermatology Department in Gustave Roussy, and by Prof. Franck Carbonnel, Head of the Gastroenterology Department at Bicêtre Hospital, AP-HP, began a clinical trial in order to demonstrate the relevance of these findings in patients with melanoma.


Analysis of the intestinal flora of patients with metastatic melanoma following treatment with ipilimumab thus showed the importance of these immunogenic bacteria in sensitivity to the treatment and in tumour reduction. These results suggest that it is of interest to consider immunogenic bacteria as an adjuvant treatment for cancer.

“Concurrently with our work, an American team came to the same conclusions regarding the role of other bacteria in the efficacy of the anti-PD1 antibody nivolumab,” adds Prof. Laurence Zitvogel, who points out that this work shows that the microbiota dictates the therapeutic response, opening up interesting possibilities for treatment. We could thus offer patients with a relatively unfavourable intestinal flora a compensatory bacterial composition, whether by prebiotic treatment, by immunogenic bacteria from the intestinal flora, or by faecal transplant. However, there is a current lack of regulatory certainty in France regarding the transformation of intestinal flora into drugs that might become agents for adjuvant therapy in oncology with the help of legislators and regulatory agencies.

// About immunotherapy

Immunotherapies have enabled a revolution in cancer treatment. Not only do they make it possible to reduce the size of tumours, they also, for the first time, make it possible to prolong the survival of patients, or even cure them of metastatic or locally advanced cancer. These new immunotherapies, using monoclonal antibodies (anti-CTA4 or anti-PD1), make it possible to awaken the patient’s immune system. However, 20% of patients undergoing anti-CTLA4 treatment experience auto-immune side-effects such as “inflammatory colitis.”

//  About the intestinal flora

The intestinal flora, or intestinal microbiota, is composed of 100,000 billion bacteria. These colonise the intestine from birth, and are involved in the maturation of the immune defences. Every individual has his/her own unique microbiota. The composition of this flora is dictated by genetic, nutritional and environmental factors. Certain bacteria can promote the occurrence of diseases; conversely, others have a protective effect.

Inserm at COP21

Because of its impacts—those already perceptible and those expected during this century—climate change is also an issue for researchers in the life and health sciences. Inserm is contributing to COP21 by holding scientific symposia and conferences for the general public. From 30 November to 11 December, while the 21st Session of the Conference of the Parties to the United Nations Framework Convention on Climate Change (COP21/CMP11) is being held in Paris, Inserm will be hosting the following events:


Le Bourget – “Climate Generation” Village / Wednesday 2 December, 2:55–3:50 pm
A conference as part of the programme for the Research Day, entitled “Qualité de l’air: quelle prévention du risque sanitaire?” (Air quality: how do we prevent the risk to health?), with Robert Barouki (Inserm) Augustin Collette (INERIS) and Robert Vautard (CNRS/CEA)

Grand Palais (Paris) from Friday 4 to Thursday 10 DecemberSolutions COP21 Exhibition
Space, “La Recherche se Mobilise pour le Climat” (Research Rallying for Climate Action), hosted by the Ministry of Higher Education and Research and 15 research organisations

Thematic Area on Health

A TV panel on Thursday 10 December at 2:00 pm on the subject of “Air quality: how do we prevent the risk to health?” with Isabella Annesi-Maesano (Inserm) Augustin Collette (INERIS) and Robert Vautard (CNRS/CEA)

Contributions from Inserm experts and facilitators: Rémy Slama, Chantal Raherison, Isabella Annesi-Maesano, Shamila Nair-Bedouelle, Robert Barouki, Grégoire Rey and Michèle Garlatti

Inserm Climate and Health Exhibition: Slide presentation
See the exhibition booklet, which can be consulted online (only in French)


Open to the public from 12:00 noon to 6:00 pm on weekdays, and from 10:00 am to 8:00 pm on Saturday and Sunday

Press accreditation

An anti-diabetic drug corrects dyspraxia associated with neonatal diabetes

Researchers from Inserm and physicians from the Department of Paediatric Endocrinology, Gynaecology and Diabetology at Necker Hospital for Sick Children (AP-HP, Inserm U1016, Paris Descartes University, Imagine Institute) have developed an improved treatment for a rare form of early childhood diabetes associated with cognitive disorders. Their work, conducted in collaboration with the Neurophysiology Department of Pitié-Salpêtrière Hospital, AP-HP, shows that a drug used for decades to treat type 2 diabetes in older subjects acts on the brain of these children. It reduces their hyperactivity and improves their ability to perform precise movements such as writing. The work has recently been the subject of a publication in the journal Diabetes Care.



Neonatal diabetes is a disease that develops in the first months of life. There are many causes, but several years ago, researchers discovered that a mutation in the potassium channels that maintain membrane polarisation is often responsible. In the pancreas, this genetic defect affects secretion of insulin, which becomes trapped in the insulin-producing cells. However, the consequences do not end there, since these defective receptors are also present in the muscle and brain cells. They cause hypotonia and dyspraxia in the children.

Although treatment with insulin injections controls the children’s blood sugar levels, it does not correct the other symptoms.

In 2006, this same team of researchers and physicians had shown that use of glibenclamide, a drug used for decades to treat type 2 diabetes in older patients, eliminated the need for insulin injections in its own patients. This drug allows insulin secretion in accordance with the quantity of sugar present in the child’s bloodstream. It therefore enables better control of blood sugar levels without causing hypoglycaemic episodes.


In the study which has just been published*, the team shows that this drug also reduces the hyperactivity observed in the children, problems with fine movement (writing, spatial orientation), and impairment of muscle tone and complex brain functions (task planning) in the children. This enables a clear improvement in their socialisation and family and school life.

The study was carried out in 19 children with this rare form of neonatal diabetes, in whom insulin injections were replaced with oral glibenclamide. Electrophysiological muscle tests, brain imaging and tests for fine and precise psychomotor skills were carried out before and 12 months after introducing the drug. Results made it possible to show that the neuropsychomotor improvement observed was not related to an action of the drug on muscle, but to an effect of the drug on the brain.

“This study is the first to show that an oral diabetes can also act directly on the brain of these children,” explains Dr Jacques Beltrand, coordinator of the study. “It also shows that the effect is better in young children. This drug should therefore be given to these patients as early as possible.”

This work repositions a drug which previously had no indication for paediatric use, and was not available in a suitable dosage form for infants. The team of researchers from Inserm and Necker Hospital for Sick Children, AP-HP, is now involved in the development of a syrup suitable for children, which will allow easy administration and the most accurate dose possible (NEOGLI Study, NCT02375828).