Depression and gut microbiota: “A medical revolution awaits!”

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