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Leldo et Eberl Microbiote
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Depression and gut microbiota: “A medical revolution awaits!”

Gérard Eberl, Director of immunology department at Institut Pasteur, Pierre-Marie Lledo, CNRS Research director "Genes and cognition" at Institut Pasteur

Accord­ing to your research 1 2, depres­sion is not only a brain dis­ease, but also an intesti­nal dis­or­der. Can you explain this?

Pierre-Marie Lle­do. These stud­ies are based on what we call the “holo­bionte” – a con­cept increas­ing­ly defend­ed in biol­o­gy based on the notion of mutu­al­is­tic sym­bio­sis. The term con­sid­ers a liv­ing being as a “supra-organ­ism” whose parts are in per­ma­nent com­mu­ni­ca­tion, and which shares its body with numer­ous micro-organ­isms such as those found in the intes­tine. Accord­ing to this con­cept, “the whole is more than the sum of its parts,” to para­phrase Aris­to­tle. Gérard has writ­ten some won­der­ful arti­cles, such as the one in the jour­nal, PNAS, on this notion of sym­bio­sis in the liv­ing world 3

Gérard Eberl. Even though us immu­nol­o­gists have been work­ing for more than a cen­tu­ry on the immune sys­tem, it is only recent­ly that we have been able to effec­tive­ly col­lab­o­rate with col­leagues in oth­er dis­ci­plines – par­tic­u­lar­ly neu­ro­science. We now know that you can’t look at the immune sys­tem with­out look­ing at the brain or look at the brain with­out look­ing at the gut flo­ra (micro­bio­ta) or the immune system.

P‑ML. Dis­rup­tion of com­mu­ni­ca­tion between these three sys­tems caus­es dis­eases such as depres­sion, or oth­er men­tal patholo­gies relat­ed to prob­lems in brain devel­op­ment. This obser­va­tion will lead us to a great med­ical rev­o­lu­tion and a rede­f­i­n­i­tion of clin­i­cal def­i­n­i­tions in neu­rol­o­gy and psychiatry!

Do we know if stress caus­es a dis­tur­bance of the micro­bio­ta or if it is rather the dis­tur­bance of the micro­bio­ta that favours the appear­ance of depres­sive symptoms?

GE. This is real­ly close to the con­cept of the chick­en and the egg! It’s often like that in immunol­o­gy. The micro­bio­ta changes its struc­ture because of pres­sure from the host organ­ism, either through the ner­vous or the immune sys­tem. As a con­se­quence, the imbal­ance in micro­bio­ta induces changes in the immune and ner­vous sys­tems that per­pet­u­ate this phe­nom­e­non. It is a cir­cu­lar causal­i­ty. 

In fact, it’s eas­i­er to under­stand how the micro­bio­ta affects the host than it is to under­stand the oppo­site. That’s because there are many ways to change the struc­ture of the micro­bio­ta. It can be dis­rupt­ed because of a change in diet, stress affect­ing peri­staltic move­ment or the immune sys­tem. It must be also said that we main­ly study these effects in mice, and there are many ways to explain a change in micro­bio­ta of a chron­i­cal­ly depressed mouse. So, the ori­gin of how this hap­pens in our mod­els has not yet been inves­ti­gat­ed for the sim­ple rea­son that it would take years of investigation.

As such, you have not yet specif­i­cal­ly stud­ied the micro­bio­ta of mice and its com­po­si­tion in detail. You have, how­ev­er, trans­plant­ed the micro­bio­ta of one mouse into that of anoth­er. What did you observe? 

GE. We trans­ferred the micro­bio­ta of a stressed mouse to a healthy mouse, which also became stressed and depressed as a result. In the sam­ples, we observed a low pres­ence of lac­to­bacil­li – a fam­i­ly of intesti­nal bac­te­ria. By cor­rect­ing this decrease in lac­to­bacil­li by treat­ing the mice with a par­tic­u­lar strain of lac­to­bacil­li (reuteri), we were able to restore a non-depressed phenotype. 

P‑ML. The chron­ic stress that caus­es the ani­mal to become depressed is thus accom­pa­nied by an imbal­ance, albeit minor, in the com­po­si­tion of the micro­bio­ta. While we have not estab­lished the fac­tors that cause this dys­bio­sis [imbal­ance of the micro­bio­ta], we have at least demon­strat­ed that sup­ple­ment­ing the diet with lac­to­bacil­li is suf­fi­cient to restore the ini­tial bal­ance of the intesti­nal micro­bio­ta – result­ing in an anti-depres­sant effect. 

GE. The inter­ac­tion between the micro­bio­ta and the brain is medi­at­ed in this case by the so-called “endo­cannabi­noid” sys­tem. The lack of lac­to­bacil­li in “depressed” mice leads to a decrease in arachi­don­ic acid, the pre­cur­sor of endo­cannabi­noids, cir­cu­lat­ing in their bod­ies. This decrease in turn has effects on the hip­pocam­pus, an area of the brain involved in depres­sion. 

We have demon­strat­ed that sup­ple­ment­ing the diet with lac­to­bacil­li is suf­fi­cient to restore the ini­tial bal­ance of the intesti­nal micro­bio­ta – result­ing in an anti-depres­sant effect

Can we adapt your obser­va­tions to humans?

P‑ML. For us, it’s not a big leap. We hope to have put our fin­ger on a fun­da­men­tal nod­ule between the micro­bio­ta and its action on the hip­pocam­pus through endo­cannabi­noids. These three ele­ments are also present in humans. Although, we must wait for clin­i­cal stud­ies to study the anti­de­pres­sant role of lac­to­bacil­li and oth­er bac­te­r­i­al species found in the intestines.

Will we treat depres­sion with fae­cal transplants?

P‑ML. Fae­cal trans­plants are com­plex because the humans, as a species, car­ry a great diver­si­ty of micro­bio­ta. Bring­ing in large num­bers of oth­er species of bac­te­ria means tak­ing the risk of upset­ting the bal­ance. On the oth­er hand, we can assume that a new gen­er­a­tion of pro­bi­otics using syn­thet­ic bac­te­ria might not affect the balance.

GE. Rather than fae­cal trans­plants, it is prefer­able to add bac­te­ria to the exist­ing micro­bio­ta – either with clas­si­cal pro­bi­otics, some of which were dis­cov­ered 100 years ago at the Pas­teur Insti­tute in par­tic­u­lar, or with new gen­er­a­tion solu­tions. By iden­ti­fy­ing bac­te­ria and the genes that con­tribute to these bio­log­i­cal process­es, it is pos­si­ble to gen­er­ate genet­i­cal­ly mod­i­fied syn­thet­ic bacteria. 

To do so we could com­bine the genes of dif­fer­ent bac­te­ria to pro­duce exact­ly what is need­ed. This would be a solu­tion to go beyond clas­si­cal pro­bi­otics, which have a sig­nif­i­cant but lim­it­ed effect. Even if there is pub­lic or offi­cial resis­tance to syn­thet­ic or recom­bi­nant bac­te­ria, this approach would be much safer than fae­cal transfers.

How can these dis­cov­er­ies be applied in prac­tice to treat patients?

P‑ML. Our work should encour­age the clin­i­cal world to take a more holis­tic view of depres­sion. Under the gener­ic term “depres­sion”, there are prob­a­bly sev­er­al patho­log­i­cal forms of mood dis­or­ders, which have lit­tle to do with each oth­er on a bio­log­i­cal lev­el. For some, stan­dard anti­de­pres­sants will suf­fice, but not for oth­ers. Remem­ber that 30% of patients are resis­tant to all drug treatments!

Our approach may help tar­get a sub­cat­e­go­ry of depressed indi­vid­u­als whose “hip­pocannabi­noid” recep­tors are not suf­fi­cient­ly acti­vat­ed because of the lack of antag­o­nists nat­u­ral­ly pro­duced by gut bac­te­ria. Psy­chi­a­trists and biol­o­gists should start look­ing for indi­ca­tors of these defi­cient meta­bol­ic path­ways. Cur­rent­ly, expert cen­tres are per­form­ing these tests, at least for research pur­pos­es, by build­ing up cohorts of patients with blood tests, but this should be done more systematically.

GE. There is a lot of talk about psy­cho­so­mat­ic dis­eases, char­ac­terised by phys­i­cal symp­toms of men­tal states. But the reverse com­po­nent, the “somatopsy­chic”, has not yet entered the vocab­u­lary. Is it the mind that makes the body sick, or is it the body that harms the mind? This is part of the holo­bionte con­cept. The brain is immersed in the envi­ron­ment and the envi­ron­ment of the body is con­trolled, reg­u­lat­ed by the brain. It is a feed­back loop! It is there­fore nec­es­sary to also con­sid­er the soma in order to heal the mind. 

Inter­view by Agnès Vernet 

1E. Siopi et al. Changes in Gut Micro­bio­ta by Chron­ic Stress Impair the Effi­ca­cy of Flu­ox­e­tine. Cell Rep. 2020 Mar 17;30(11):3682–3690.e6. doi: 10.1016/j.celrep.2020.02.099.
2G. Cheva­lier et al. Effect of gut micro­bio­ta on depres­sive-like behav­iors in mice is medi­at­ed by the endo­cannabi­noid sys­tem. Nat Com­mun. 2020 Dec 11;11(1):6363.doi: 10.1038/s41467-020–19931‑2.
3Mar­garet McFall-Ngai et al. Ani­mals in a bac­te­r­i­al world. PNAS. 2013, 110 (9) doi:10.1073/pnas.1218525110

Contributors

Gérard Eberl
Gérard Eberl
Director of immunology department at Institut Pasteur

Gérard Eberl obtained his Ph.D. at the University of Lausanne before completing a first postdoc at the Ludwig Institute on Cancer Research. A second position in New York led him to characterise the role of the nuclear hormone receptor RORt in innate lymphoid cells (ILC). In 2005, Gérard was recruited by the Institut Pasteur in Paris to lead the Lymphoid Tissue Development Unit, which became the Microenvironment & Immunity Unit in 2015. From 2015 to 2019, Gérard served as Chairman of the Department of Immunology at the Institut Pasteur.

Pierre-Marie Lledo
Pierre-Marie Lledo
CNRS Research director "Genes and cognition" at Institut Pasteur

Pierre-Marie Lledo’s research focuses on the adaptation and regeneration of neurons in the brain, and their interactions with the immune system. He is Research director at the CNRS, head of the Genes and Cognition laboratory, and director of the Perception and Memory unit and of Plasticity and Development of the Nervous System at the Pasteur Institute.