肥胖的另一元凶：你肠道内的细菌？

Another Cause of Obesity: The Bacteria in Your Gut?

肥胖的另一元凶：你肠道内的细菌？
By ALICE PARK Alice Park – Thu Nov 12, 10:50 am ET
5 ~# O$ _% n2 ]& C4 BIf you have ever fought the battle of the bulge, then you are all too familiar with its key players: diet, exercise and your genes. The less you move (calories out) and the more you eat (calories in), the more fat you gain - an equation that may be heavily influenced by your particular genes. But scientists have long known that these three factors do not adequately explain every case of obesity, and now researchers are discovering increasingly convincing evidence of another important contributor to body weight, one that until recently has been almost completely ignored: the bacteria that live in your gut.
5 ^( S- F$ B; A$ L& s$ j/ ]Technically, they're known as the gut microbiota, the universe of tens of trillions of microbes, most of which survive without oxygen, and which live and thrive in the human intestinal tract and colon. These microbes perform a vast range of vital functions, including helping to regulate the calories the body obtains from food and stores as fat - in other words, they may help regulate weight. And a new study published today in Science Translational Medicine suggests that the particular type and balance of bugs you harbor in your gut may help push your body toward either obesity or leanness, and that these microbe populations might even be manipulated to potentially change your weight. (Watch a video about obesity and social networks.)
/ Q4 w$ ?" g  s3 J5 z& M1 MThe new study builds on past research, in mice, that has suggested that heavy bodies may have a different make-up of gut bugs than thin ones: the gut microbiota of obese mice has been shown to have significantly more of one main type of bacteria called Firmicutes, and fewer of another kind called Bacteroidetes (both types populate human guts as well); in normal mice, the distribution is the opposite. Jeffrey Gordon at Washington University in St. Louis, who conducted the past research, experimented again with mice for the new paper. This time, however, he and his team used human microbiota to colonize mice guts and then fed the rodents the equivalents of typical human diets to see how their microbes - and their weight - might change.
Researchers started with mice that were specially bred to be germ-free - with no gut microbiota of their own - and to be able to nurture human gut microbiota instead. Researchers then injected the mice with samples of fresh and frozen human feces, the bacteria from which actually took hold and colonized in the gut of the mice. If that surprises you, it absolutely stunned the researchers. "We were surprised that so much of the diversity present in human microbial communities could be recaptured in mice," says Gordon, who has been studying gut microbiota for more than five years.
The fact that the human gut flora flourished in the rodents was indeed an experimental coup. Since the mice were genetically engineered to be germ-free, lacking a functioning immune system, the scientists could be certain that any bug colonies that took hold in the mice guts originated entirely from the human sample, not the mice. Being able to recreate the living human gut environment so faithfully in an animal was a welcome prize. (Read "The Year in Medicine 2008: From A to Z.")
The main advantage was that Gordon and his team now had the cutting-edge DNA sequencing capability to scan and analyze all the genes contained in those bacteria. That means researchers could determine not only which species of bacteria were present and in what proportions, but also which genes these bugs were actively using in different conditions. Before such genomic analysis technology became available, researchers could study only the gut microbes (animal or human) that could be cultured outside their intestinal home - something that not all of the oxygen-shunning bugs were amenable to - but never the complete microbiota of the gut. "We cannot recapitulate the entire microbial diversity that exists in these complex communities. We simply don't know how to culture them, so we could miss a lot of diversity," says Gordon.
That diversity and its impact came into plain view when the researchers started experimenting with the rodents' diet. When one group of mice was fed a typical Western diet, high in fat and sugars, they tended to gain weight and grow more Firmicutes gut bacteria and fewer Bacteroidetes. In mice given a low-fat, plant-based chow, the distribution of the two groups of bugs flipped and the animals remained lean. It's not clear whether the balance of gut bugs causes weight gain or is a result of it, but the findings suggest that a "gut profile" could potentially serve as a diagnostic tool for identifying who might have a propensity for obesity. If, for instance, your gut environment contains a preponderance of Firmicutes, then your body may be predisposed to digest calories in a way that leads to greater fat storage. In fact, in Gordon's earlier work with identical twins of different weights, he found that the obese twin tended to have more Firmicutes colonies than the leaner sibling.
- s+ T* e: B. u' S; V# N0 I" jGordon also found in his mouse populations that changing the animals' diet caused a dramatic and rapid shift in the population of bacteria in their gut. Switching a mouse from low-fat plant chow to a high-fat Western diet resulted in an explosion of Firmicutes in less than a day.
That suggests that factors like gut microbes, which scientists traditionally would not think of exerting influence on genes, may have a surprisingly powerful effect, changing how a body's genes would normally control the way it digest food and breaks it down into energy. It makes sense, when you consider that the vast majority of the cells and genes in the typical human body belong to the microbiota. "There is a vast reservoir of attributes associated with our human physiology that is derived from our gut microbial communities," he says. "Our genetic landscape is actually an amalgam so it's slightly different from the genetic determinism of human genes flowing from parent to offspring. It's also the microbial genes that are acquired from early environmental exposures and transmitted within families as well."
$ Y: [0 g& [$ b! k) YUltimately, says Gordon, with additional research, this work could lead to the identification of microbial markers that would make up a kind of obesity or leanness profile - a vital stats sheet of the gut world that would help people understand how their bodies are likely to respond to calories. Beyond that, the possibilities are even more exciting. With more research, Gordon even sees potential for applying the knowledge gained from these mice to agriculture - we could grow more foods that are specifically designed to provide the optimal balance of nutrients and energy at various stages of our lives. "This vast universe of microbes that live on and in us is terra incognita, but it is becoming more cognita every day," he says. "We are beginning to develop the tool box necessary to describe not only which microbes live within us, but to observe the consequences of our symbiosis with them on our health, our biology and our genetic landscape. There is a great deal of excitement but also a great deal of work that still needs to be done in this area."
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肥胖的另一元凶：你肠道内的细菌？

' e* d  K7 l& d, T4 A: T4 b如果您有过减肥的体验，那么您一定会十分熟悉减肥的3个关键因素： 饮食， 运动和基因。简单地说，运动会消耗卡路里，而食物会增加卡路里。如果您吃得多动得少，那么您积累的卡路里越多，因此就会变胖。具体到个人，这个过程还会受到个体基因的影响。但长久以来，科学家们发现许多肥胖患者并不是由饮食， 运动和基因这3个因素导致的。越来越多的证据表明，肠道中的菌类，这个长期被忽视的因素，事实上是导致肥胖的另一个主要原因。专业上来说，它们被称为肠道微生物。这些在人类肠道和直肠中繁衍的微生物数量众多，大部分不需要氧气就可以存活。它们在消化过程中扮演着重要的角色，比如帮助肠道从食物中摄取和储存卡路里。从另一种角度上来说，肠道微生物可以帮助调节体重。今日发表在《科学-转化医学》上的一篇研究发现，肠道中的某些菌类以及菌群的平衡可以导致寄主身体变胖或变瘦。对肠道菌类的种群平衡调节就可以改变寄主的体重。（原文在此处会播放一段录像）

在最近对小鼠的研究中发现，体型胖硕小鼠的肠道中的菌类与体型消瘦小鼠中的菌类在菌群构成上存在区别。肥胖小鼠肠道中的硬壁菌（Firmicutes）显著高于对照，而拟杆菌（Bacteroidetes）则低于对照。这两种菌同样存在于人类肠道中。基于以上的研究结果，华盛顿大学圣路易斯分校的Jeffrey Gordon在小鼠中开展了进一步的实验，并发表了新的论文。

. A0 [% `& @3 f- t. D在本研究中，Gordon团队用人类肠道中的主要菌群替换了小鼠肠道中菌群，并用人类饮食配方饲养小鼠。如果肠道菌群会对寄主体重产生影响，那么实验中应该能够观测到小鼠体重的变化。研究中使用了通过特殊饲养技术获得的无菌小鼠。这种小鼠可以接受人类的肠道菌类在其肠道中繁殖。之后研究者将冷藏的新鲜人类排泄物接种到小鼠中，并观测到这些来自于人类肠道的菌类能够小鼠肠道中繁殖。这个发现使得研究者感到十分惊讶。Gordon说“我们观测到了人类肠道菌落的复杂菌群结构可以在小鼠中重构。这使我们感到十分惊奇”。他已经对肠道菌类从事了5年以上的研究。

实际上，小鼠肠道能够重构人类肠道菌群这个现象发现于一次实验意外。
( M7 e! y/ k2 @. n( Z. B! h; [在饲养无菌小鼠的实验中，小鼠具有一定的免疫系统缺陷。这样在实验中小鼠肠道中的菌类可以肯定来自于人类而不是小鼠本身。
能够在动物中重构人类肠道菌群是一个了不起的发现。

借助于目前最先进的DNA测序技术，Gordon团队能够对这些肠道菌群的全部基因进行扫描和分析。这意味着研究者不但可以定性定量地分析肠道菌种，也可以这些菌种是通过那些基因对不同的环境条件进行应答的。在这种遗传分析技术开发之前，研究者只能通过体外培养的方式对人类或者其他动物的肠道菌类进行研究。由于许多厌氧菌往往不能够在培养中难以存活，这就造成了以往的技术只能够检测到部分菌类，进而不能够反应肠道中完整的菌群构成。

- i6 q$ Z& f5 `7 H0 R2 Q7 [0 o& B! DGordon说“（如果没有我们开发的菌群重构技术）我们无法培养肠道细菌，因此也就无法重构菌群以及复杂的菌群结构，进而会使我们丢失许多的菌群，也就无法反映菌群与基因多样性的全貌”。

  W( D8 `4 U# L" Y3 Y随后的研究中，研究者通过使用不同种类的人类饮食配方喂养小鼠的方法研究肠道菌群以及基因多样性。其中一组小鼠按典型的西方饮食配方喂养，食谱中的脂肪和糖含量比较高。这些小鼠往往表现为体重增加。并且其肠道中的硬壁菌（Firmicutes）较多，而拟杆菌（Bacteroidetes）较少。而另一组则按低脂肪搞植物性植物的配方饲养。结果发现小鼠肠道中的硬壁菌（Firmicutes）较少，而拟杆菌（Bacteroidetes）较多。这些小鼠多表现为体重下降。

, Z: G; a% l7 t目前还不能肯定肠道中菌群的变化是体重变化的原因或是结果。但如上肠道菌群鉴定的研究为我们提供了一种判断肥胖倾向性的诊断工具。这也就是说，如果您的肠道中被检测出具有过多的硬壁菌，那么您会倾向于消化并获得更多的卡路里，这就会导致您肥胖。

在另外一个Gordon团队之前的双胞胎小鼠研究中发现，双胞胎中较胖的小鼠其肠道中具有较多的硬壁菌，而较瘦的小鼠则相反。
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. W6 a) c. w; E. ?4 f) TGordon团队还发现如果改变了饮食配方会导致肠道菌群构成快速而剧烈的变化。如果对长期食用低脂肪的植物性饮食配方的小鼠给予高脂肪的西方饮食配方的食物，那么只需要不足一天的时间，其肠道中的硬壁菌数量会大幅增加。这个结果说明肠道菌群可以对肠道基因起重要的调节作用。从而调控肠道基因消化食物获得能量。这种菌群对肠道基因的调节作用在以往的研究中是很少被注意到的。考虑到体内的细菌贡献了人体中大部分的细胞和基因，如上菌类与人体相互作用的观点具有重要意义。
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“目前在人类生理学的相关研究中，关于菌类与人体相互作用的相关研究尚存在广阔的空间。” ，Gordon谈到“人类基因能够在代间传递并具有较小的变异。同时我们的研究指出菌类可以从上一代的环境中获得基因并在人类家庭成员中将传播。”
Gordon表示，通过进一步的研究，这项研究最终将会发现并鉴定菌类标记。从而构建判断身体肥胖和瘦弱的肠道菌类构成谱。这样可以帮助人们检测自己的身体对获得卡路里的倾向性。
" ~+ T+ S  K/ X- b% n; t  另外，这项研究在农业和食品生产中具有十分乐观的应用前景。 Gordon将对肠道菌群进行进一步的研究，从而将从小鼠中获得的发现应用到农业生产中。这样可以通过设计和种植以及加工食品的方式调节肠道中的菌群平衡，进而调节我们的营养和能量代谢。
/ K/ A' c) \# u/ J- x  “目前我们对于我们身体中大部分菌类的了解并不多，不过我们对这些菌类的认识正日趋深入。”他说“我们正在开发技术手段，这将会使我们不仅仅只是鉴定身体中的微生物，而且还可以观测它们在我们健康、生物学过程以及遗传学特征方面上产生的影响。在这个领域中，将会有越来越多令人激动的发现，同时也意味着将会开展大量的相关研究。”
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