Studies of the bugs within: telling sickness from cure
Gut microbiota, the bacterial communities that live inside our bodies, more and more appear to be related to our well-being. A major challenge for modern medicine, especially in regard to the role of “our” bacterial communities, is telling apart what is a cause of a disease and what is an effect of how we treat it.
Each of us carries intestinal gardens, where microbes process food for our own consumption. We evolved to benefit from this, but as our guests are selfish single-cell creatures, tense diplomacy was always needed. Since these bacterial communities in our gut play surprisingly large roles in how our bodies grow and function, when their “social equilibrium” is unbalanced, their carefully-adapted human hosts suffer consequences.
It was long suspected that unbalanced bacterial communities might increase the risk of type 2 diabetes, where the body cannot adjust properly to blood sugar spikes. That, in turn, increases the risks of many other diseases, like heart failure and stroke - therefore, understanding how gut microbiota influence these risk factors represents an important asset. Nowadays, using modern machinery, it is possible to sequence and discriminate the DNA of bacterial communities made up of billions of cells. Our team, in the MetaHIT consortium, set out to do so, and likewise did two other teams, in Sweden and in China. Each reported how the intestinal bacterial communities of diabetics differed from those of healthy volunteers. But these two studies disagreed on which exactly those differences were, and in our own cohort of participants (from Denmark), we saw yet another incompatible but strong signature. What to do?
The breakthrough came through testing systematically if there was any other factor (aside from simply considering whether the donor was healthy or diabetic) that could predict what their gut microbiome looked like. Numerous factors were recorded, most showing no effect. However, one stood out – diabetics receiving metformin, a drug commonly used against diabetes, had very different gut communities from either differently-treated diabetics or healthy volunteers. This led us to suspect that much of the previously reported patterns in the bacterial landscape reflected anti-diabetic treatment, rather than a property of diabetes itself.
It was very interesting to note that, between the Chinese and Swedish studies, there were large differences in how likely the diabetics were to have been treated with metformin, and with a similar pattern, the differences, concerned those bacteria affected by such treatment. Considering this factor directly, and also analyzing other relevant aspects (differences in patient recruitment, analysis methods and approach), we merged the three databases of information coming from the three studies and analyzed them computationally. We were able to see a core signature supported by all the available data. There were two main aspects of the results that we collected.
First, unrelated to any kind of treatment, diabetics seem to have fewer bacteria in their gut that can produce short-chain fatty acids (SCFAs) like butyrate from dietary fibre. It is increasingly recognized that such compounds improve health in several ways, including: (i) reducing insulin resistance, (ii) dampening inflammation, and (iii) protecting the intestinal lining. This finding, therefore, seems robust, and many teams now go forward to try to use it to develop better treatments for both diabetes and other diseases.
Second, when someone is given metformin, the changes in their gut microbiota (overgrowth of some specific strains of the bacterial community) are associated with some of the metformin’s more common side effects as abdominal pain and bloating. Based on the shifts of the bacterial community, these side effects might then possibly be prevented through a combined treatment with probiotics. More interestingly, the bacterial community shifts seem to increase the potential for short-chain fatty acid production. This suggests that some of the beneficial effects of the drug might take place exactly through changing the composition of the gut microbiota!
After we reported this, the Swedish team carried out a follow-up study where they were able to prove that such mediation actually takes place. They tracked volunteers taking metformin over time, and showed that if their gut microbiota from before and/or after such treatment was transferred into germ-free mice, that is, having no microbiota of their own, the mice seeded with post-metformin gut microbiota showed improved glucose tolerance, demonstrating the ability to counter the glucose tolerance impairment which is central to diabetes.
Thus the results of our study confirmed that the shifts in the gut microbiota of diabetic patients were mainly driven by metformin rather than by the disease. More than that, we also provided clues about the fact that some of the beneficial effects of the drug take place indirectly through its impact on the gut microbiota.
Going forward, these discoveries prove that, in clinical studies, we cannot ignore anymore the effects of treatments on the gut microbiota. Moreover, given that gut microbiota are complex communities, slightly different for each of us, such findings represent opportunities for innovative and more efficient applications in the field of personalized medicine.
Original Article:Forslund K, Hildebrand F, Nielsen T, Falony G, Le Chatelier E, Sunagawa S, Prifti E, Vieira-Silva S, Gudmundsdottir V, Krogh Pedersen H, Arumugam M, Kristiansen K, Yvonne Voigt A, Vestergaard H, Hercog R, Igor Costea P, Roat Kultima J, Li J, Jørgensen T, Levenez F, Dore J, Bjørn Nielsen H, Brunak S, Raes J, Hansen T, Wang J, Dusko Ehrlich S, Bork P, Pedersen O. Disentangling type 2 diabetes and metformin treatment signatures in the human gut microbiota. Nature. 2015;528(7581):262-266. doi:10.1038/nature15766.
Massimo Caine , Founder and Director
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Utafiti wa wadudu ndani ya mwili: Kuelezea ugonjwa kutoka kwa tiba ya gut microbiota, jamii za bakteria zinazoishi ndani ya miili yetu, zinaonekana zaidi na zaidi kuhusiana na ustawi wetu. Changamoto kubwa kwa dawa ya kisasa, hasa kuhusiana na jukumu la jamii zetu za bakteria, ni kutofautisha nini ni sababu ya ugonjwa na nini ni athari ya jinsi tunavyolipia. Kila mmoja wetu ana bustani za matumbo, ambako vimelea hutengeneza chakula kwa ajili ya matumizi yetu wenyewe. Tulijitokeza ili tufaidike kutokana na hili, lakini kwa kuwa wageni wetu ni viumbe wenye chembe moja wenye ubinafsi, diplomasia yenye mkazo ilihitajiwa sikuzote. Kwa kuwa jamii hizi za bakteria katika matumbo yetu hutimiza fungu kubwa kwa kushangaza katika jinsi miili yetu inavyoendelea kukua na kufanya kazi, wakati "usawaziko wao wa kijamii" unapokuwa na usawa, majeshi yao ya kibinadamu yaliyobadilishwa kwa uangalifu hupatwa na matokeo. Kwa muda mrefu watu walidhani kwamba bakteria zisizo sawa zinaweza kuongeza hatari ya ugonjwa wa kisukari wa aina ya 2, ambapo mwili hauwezi kurekebisha kwa usahihi kwa spikes za sukari ya damu. Hii, kwa upande wake, huongeza hatari ya magonjwa mengine mengi, kama vile kushindwa kwa moyo na kiharusi - kwa hivyo, kuelewa jinsi microbiota ya matumbo inavyoathiri sababu hizi za hatari inawakilisha mali muhimu. Kwa kutumia vifaa vya kisasa, sasa inawezekana kuorodhesha na kutofautisha DNA ya jamii za bakteria zilizo na mabilioni ya chembe. Timu yetu ya MetaHIT imeweka lengo la kufanya hivyo, na hivyo ndivyo timu nyingine mbili, nchini Sweden na China. Kila mmoja wao aliripoti jinsi jamii za bakteria za matumbo za wagonjwa wa kisukari zilivyo tofauti na zile za wajitoleaji wenye afya. Lakini utafiti huu haukuonyesha tofauti yoyote kati ya utafiti huo na utafiti wa Denmark, ambao ulionyesha tofauti kubwa. Tunapaswa kufanya nini? Uvumbuzi huo ulikuja kupitia kupima kwa utaratibu ikiwa kulikuwa na sababu nyingine yoyote (mbali na kuzingatia tu kama mtoaji alikuwa na afya au ugonjwa wa kisukari) ambayo inaweza kutabiri jinsi microbiome yao ya matumbo ilionekana. Mambo mengi yalirekodiwa, lakini mengi hayakuonyesha athari yoyote. Hata hivyo, moja ilionekana - wagonjwa wa kisukari waliopokea metformin, dawa inayotumiwa kwa kawaida dhidi ya kisukari, walikuwa na jamii tofauti sana za matumbo kutoka kwa wagonjwa wa kisukari waliotibiwa tofauti au wajitoleaji wenye afya. Hii ilituongoza kugundua kwamba mifumo mingi iliyoripotiwa hapo awali katika mazingira ya bakteria ilionyesha matibabu ya anti-diabetes, badala ya mali ya ugonjwa wa kisukari yenyewe. Kwa mfano, utafiti wa China na Sweden ulionyesha tofauti kubwa katika uwezekano wa wagonjwa wa kisukari kutibiwa na metformin, na tofauti hizo zilihusu bakteria zilizoathiriwa na matibabu hayo. Kwa kuzingatia jambo hili moja kwa moja, na pia kuchambua mambo mengine muhimu (tofauti katika kuajiri wagonjwa, mbinu za uchambuzi na mbinu), tulijumuisha hifadhidata tatu za habari zinazotoka kwa masomo matatu na kuzichambua kwa kompyuta. Tulikuwa na uwezo wa kuona saini ya msingi mkono na data zote zinazopatikana. Kulikuwa na mambo mawili makuu ya matokeo ambayo tulikusanya. Kwa sababu ya hali hii, wagonjwa wa kisukari wana bakteria chache katika matumbo yao ambayo yanaweza kutengeneza asidi za mafuta za mnyororo mfupi (SCFAs) kama vile butyrate kutoka kwa nyuzi za chakula. Inasemekana kwamba kemikali hizo huongeza afya kwa njia kadhaa, kutia ndani: (i) kupunguza upinzani wa insulini, (ii) kupunguza uvimbe, na (iii) kulinda utando wa matumbo. Kwa hivyo, matokeo haya yanaonekana kuwa thabiti, na timu nyingi sasa zinaendelea kujaribu kuitumia kuendeleza matibabu bora ya kisukari na magonjwa mengine. Kwa upande mwingine, wakati mtu anapata metformin, mabadiliko katika microbiota yao ya matumbo (kuongezeka kwa baadhi ya aina maalum za jamii ya bakteria) yanahusishwa na baadhi ya athari za kawaida za metformin kama maumivu ya tumbo na bloating. Kulingana na mabadiliko ya jamii ya bakteria, athari hizi za upande zinaweza kuzuiwa kupitia matibabu ya pamoja na probiotics. Jambo lenye kupendeza zaidi ni kwamba mabadiliko ya jamii ya bakteria yanaonekana kuongeza uwezekano wa kutokeza asidi ya mafuta yenye mnyororo mfupi. Hilo laonyesha kwamba baadhi ya athari zenye manufaa za dawa hiyo zaweza kutokea hasa kupitia kubadilisha muundo wa viini vya matumbo! Baada ya kueleza juu ya hili, timu ya Sweden ilifanya utafiti wa kufuatilia ambapo waliweza kuthibitisha kwamba upatanishi kama huo kwa kweli hufanyika. Watafiti walifuatilia watu waliotumia metformin kwa muda, na walionyesha kwamba ikiwa microbiota yao ya matumbo kutoka kabla na baada ya matibabu hayo ilihamishwa kwa panya wasio na bakteria, yaani, bila microbiota yao wenyewe, panya waliopandwa na microbiota ya matumbo baada ya metformin walionyesha uvumilivu wa glukosi ulioboreshwa, kuonyesha uwezo wa kukabiliana na udhaifu wa uvumilivu wa glukosi. Kwa hivyo matokeo ya utafiti wetu yalithibitisha kuwa mabadiliko katika microbiota ya matumbo ya wagonjwa wa kisukari yalisukumwa hasa na metformin badala ya ugonjwa. Zaidi ya hayo, tulitoa pia dalili kuhusu ukweli kwamba baadhi ya athari za manufaa za dawa hufanyika kwa njia isiyo ya moja kwa moja kupitia athari zake kwenye microbiota ya matumbo. Kwa kuendelea, uvumbuzi huu unathibitisha kwamba, katika masomo ya kliniki, hatuwezi kupuuza tena athari za matibabu kwenye microbiota ya matumbo. Kwa kuongezea, kwa kuzingatia kwamba microbiota ya matumbo ni jamii ngumu, tofauti kidogo kwa kila mmoja wetu, matokeo kama hayo yanawakilisha fursa za matumizi ya ubunifu na ufanisi zaidi katika uwanja wa dawa ya kibinafsi. "Mchoro wa kwanza wa ""From the Heart"" ni wa K.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S Asili. 2015;528(7581):262-266. doi:10.1038/nature1576 "Msomaji wa ""Makosa ya Ugonjwa wa Ugonjwa wa Ugonjwa wa Ugonjwa wa Ugonjwa wa Ugonjwa wa Ugonjwa wa Ugonjwa wa Ugonjwa wa Ugonjwa wa Ugonjwa wa Ugonjwa wa Ugonjwa wa Ugonjwa wa Ugonjwa wa Ugonjwa wa Ugonjwa wa Ugonjwa wa Ugonjwa wa Ugonjwa wa Ugonjwa wa Ugonjwa wa Ugonjwa wa Ugonjwa wa Ugonjwa wa Ugonjwa wa Ugonjwa wa Ugonjwa wa Ugonjwa wa Ugonjwa wa Ugonjwa wa Ugonjwa wa Ugonjwa wa Ugonjwa wa Ugonjwa wa Ugonjwa wa Ugonjwa wa Ugonjwa wa Ugonjwa wa Ugonjwa wa Ugonjwa wa Ugonjwa wa Ugonjwa wa Ugonjwa wa Ugonjwa wa Ugonjwa wa Ugonjwa wa Ugonjwa wa Ugonjwa wa Ugonjwa wa Ugonjwa wa Ugonjwa wa Ugonjwa wa Ugonjwa wa Ugonjwa wa Ugonjwa wa Ugonjwa wa Ugonjwa wa Ugonjwa wa Ugonjwa wa Ugonjwa wa Ugon