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