Podcasts 科学播客 | 「肠道微生物组：影响后代命运的无形力量」

Benjamin Thompson

Our bodies are teeming with microorganisms. But these microbes aren’t just functionless passengers travelling in and on a human vessel. Many of them appear to play important roles in how our bodies operate. Especially those that live in the gut.

Disruption of the gut microbiota has been linked to issues with organs like the liver, kidney and the brain. But Jamie Hackett from the European Molecular Biology Laboratory and his colleagues wanted to know whether another set of organs should be added to the list: the reproductive organs. They also were interested in whether any disruptions could even have effects on future offspring. Here’s Jamie.

我们体内充满了微生物，但这些微生物不仅仅是“搭车旅行”的乘客，它们似乎在我们的身体运行中扮演了重要角色，尤其是生活在肠道内的微生物。

肠道微生物组的紊乱已被证明与肝脏、肾脏和大脑等器官的问题有关。然而，欧洲分子生物学实验室的Jamie Hackett及其同事想知道是否还有其他器官应当被列入受影响名单：生殖器官。他们还想知道这种紊乱是否会对未来后代产生影响。有请Jamie。

Jamie Hackett

The idea that the environment of a parent prior to conception may influence the phenotype or even a disease risk in offspring is something that's really kind of captured people's imagination over the last decade or so it's a really interesting idea. At the same time, I think there's been quite a lot of healthy scepticism about whether this is actually happening in a meaningful way in mammals.

过去十年中，人们越来越关注这样一个想法，即在受孕前父母的环境可能会影响后代的表型甚至疾病风险，这是一个非常有趣的概念。同时，我认为人们对这是否在哺乳动物中产生有意义的影响一直持有一定的的怀疑态度。

Benjamin Thompson

And this is something that Jamie and the team have tried to shed some light on, and they've published a paper about it in this week’s Nature. In particular they looked at how disrupting the gut microbes in male mice prior to conception could affect their progeny.

这是Jamie和他的团队试图解答的一个问题，他们的研究结果已发表在本周的《Nature》期刊上。他们特别研究了在受孕前通过干扰雄性小鼠肠道微生物组对其后代的影响。

Jamie Hackett

The initial way we chose to disrupt the microbiota was by using non-absorbable antibiotics administered at a fairly low dose. So we're not trying to ablate the microbiome here, we're just trying to perturb it.

我们最初选择通过使用不被身体吸收的抗生素来扰乱微生物组，并且剂量较低。我们的目的不是消灭微生物组，而只是进行扰动。

Benjamin Thompson

By using antibiotics that aren’t absorbed by the body and only stay in the guts, the team could be confident that any effects they saw were down to disruption of the microbes living there. Mice that had their gut microbes disrupted were otherwise healthy, but when these males were mated with untreated female mice this wasn’t the case for some of their offspring. On average these pups had a reduced birth weight, but some had more significant issues.

通过使用仅停留在肠道、不被身体吸收的抗生素，团队能够确定他们观察到的影响确实源于微生物的紊乱。肠道微生物受到扰动的小鼠本身健康状况良好，但当这些雄性小鼠与未经处理的雌性小鼠交配后，其后代的情况有所不同。平均来看，这些小鼠后代的出生体重降低，但部分个体有更严重的问题。

Jamie Hackett

What we began to see that a fraction of these mice, they were severely underweight, we saw quite a severe growth restriction. And ultimately, many of those mice were not able to survive. And we just didn't see that when the fathers had that to say, an unperturbed microbiome, and it was in the range of 10% of the offspring. This is not a deterministic thing whereby if you perturb a prospective father's microbiome, there's going to be an effect. It's more that you're changing the risk of an adverse pregnancy or disease risk in the offspring.

我们开始注意到，有一部分小鼠体重严重不足，生长严重受限。最终，其中许多小鼠未能存活。若其父亲的微生物组未受扰动，就不会出现这种情况，受影响的后代比例约为10%。这并不是一个确定性的影响，换句话说，扰乱准父亲的微生物组不一定会造成结果，但确实提高了后代不良妊娠或疾病风险的概率。

Benjamin Thompson

But this could be reversed. Stopping antibiotics allowed the gut microbes of the treated mice to recover. When they subsequently went on to have more offspring, this increased risk of health issues wasn't seen, strongly hinting that these microbes were central to the phenomenon.

But it was possible that this effect could have been caused by the mice passing on their dysfunctional gut microbiome to female mice or their offspring, through contact perhaps. To rule this out the team turned to in vitro fertilization.

不过，这种影响是可以逆转的。停止使用抗生素后，接受治疗的小鼠肠道微生物得到了恢复。当它们随后有了新的后代时，健康问题的风险不再增加，这强烈暗示这些微生物是这一现象的关键因素。

不过，这种影响也有可能是通过接触等方式，小鼠将其失调的肠道微生物传递给了雌性小鼠或后代。为了排除这一可能性，团队转而使用体外受精。

Jamie Hackett

In those circumstances, there's no parental contact whatsoever, we just use donor sperm and donor oocytes. And again, we saw that when the sperm is derived from a father with a microbiome perturbation, the offspring are born with an increased risk of severe growth restriction.

在体外受精的条件下，完全没有父母接触，我们只使用供体精子和供体卵母细胞。结果再次显示，当精子来自肠道微生物组受扰的父亲时，后代出生后有更高的严重生长受限风险。

Benjamin Thompson

But how was the microbiome affecting the male mice’s reproductive organs? Well, the team showed that there were physical changes in the mouse testes — they were smaller, for example — but there were changes in levels of metabolites, and hormones known to be important in sperm production.

The sperm themselves also were affected. The team didn’t find any changes in their genomes, but they did find other changes, like alterations in levels of molecules that potentially influence how genes are switched on and off. Exactly what these changes are doing is unknown, but they appear to be having an effect post-fertilization.

那么，微生物组是如何影响雄性小鼠的生殖器官的呢？研究团队发现，小鼠的睾丸发生了物理变化——例如，睾丸更小——同时，代谢物和在精子生成中重要的激素水平也发生了变化。

精子本身也受到了影响。研究团队未发现基因组的变化，但发现了一些分子水平的变化，这些分子可能会影响基因的开关状态。这些变化具体起到什么作用尚不明确，但似乎在受精后产生了影响。

Jamie Hackett

If you look during mid-gestation, there aren't a lot of changes in the embryo itself. But where there are clear changes in the placenta. What this was implying is that the status of microbiome perturbation in the father at the time of conception was influencing placental development, which means the placenta is unable to function appropriately. And we suspect this is what's actually causing the slightly lower birth weight and the increased risk for severe developmental events in offspring.

如果在妊娠中期观察，胚胎本身没有太多变化，但胎盘确实发生了明显的改变。这表明受孕时父亲肠道微生物组的状态影响了胎盘的发育，导致胎盘无法正常发挥作用。我们推测，这正是导致后代出生体重略低以及不良发育事件风险增加的原因。

Benjamin Thompson

So, whatever these changes to the sperm are specifically doing, they can have an impact on placental development, but it’s not clear why. And the team have shown evidence that all this can be traced back to disruptions to the population of microbes living in the guts of male mice. Liisa Veerus from Rutgers University researches the effects the microbiome can have on health. She’s co-written a News and Views article for Nature and says she’s convinced by the huge amount of data the team present.

因此，无论这些精子具体发生了什么变化，它们都可能影响胎盘的发育，但原因尚不清楚。研究团队的证据表明，这一切都可以追溯到雄性小鼠肠道微生物群的紊乱。来自罗格斯大学的Liisa Veerus研究微生物组对健康的影响。她与人合作为《Nature》杂志撰写了一篇《News and Views》文章，表示团队提供的大量数据令她信服。

Liisa Veerus

I was incredibly impressed how, almost beyond the scope of this paper, the author's went to try and pinpoint what is happening, how they looked at sperm quality, how they looked at placental health, how they measured the health of offspring, how many different microbiome experiments they carried out to show that this effect is not because of the transfer of the microbiome itself, but through the indirect effects. So, they really included so many state of the art experiments. I was incredibly impressed.

我真的非常钦佩，作者不仅完成了研究的核心内容，还试图深入探究这一现象的机理。他们研究了精子质量、胎盘健康、后代的健康状况，进行了许多不同的微生物组实验，证明这种效应并非因为微生物组本身的转移，而是通过间接效应实现的。他们真的包含了许多前沿实验手段。我对此印象深刻。

Benjamin Thompson

However, there’s still some big unresolved questions: why is this happening, and why doesn’t it happen every time? After all, it’s only a fraction of the mouse offspring that experienced the severe growth impairments. To understand it, Liisa thinks that researchers need to look at what happens in the gut when antibiotics are administered.

然而，仍有一些重大未解的问题：为什么会发生这种情况？为什么并不是每次都会发生？毕竟，只有一小部分小鼠后代存在严重的生长受限问题。因此，Liisa认为研究人员需要关注使用抗生素时肠道内发生了什么。

Liisa Veerus

Because we can think of microbiome as a jungle of its own, right. And when we give it antibiotics, it's almost like a forest fire. And some strains survive, some don't; some increase in abundance, their gene expression and the way they live in the gut changes. So, I think looking at the bacterial gene expression, really trying to delve more into the bacterial side, not the host side, can also give us indication of what could actually participate in signalling in the reproductive tissue.

我们可以把微生物组看作一个独立的“丛林”。当我们使用抗生素时，就好比一次森林大火。一些菌株存活下来，一些则消失；还有一些菌株的数量增加，基因表达和在肠道中的生存方式发生变化。因此，我认为研究细菌的基因表达，深入细菌方面而非宿主方面，可能会让我们更清楚什么在参与生殖组织中的信号传导。

Benjamin Thompson

There’s also the question of whether the results in this paper translate into humans. Jamie cautions that that is currently impossible to know, and that there are likely many interconnecting and overlapping pathways to uncover. Both he and Liisa also stress that antibiotics remain a vital medicine and that this work shouldn’t put people off using them.

But even if this work doesn’t show exactly how this intergenerational disease risk is transmitted, it adds more evidence to the idea that heritability is about more than just the genes encoded in DNA.

另一个问题是，这项研究的结果是否适用于人类。Jamie提醒道，目前还无法知道这一点，并且可能存在许多相互关联和重叠的途径需要探索。他和Liisa还强调，抗生素仍是至关重要的药物，这项研究不应让人们对使用抗生素产生顾虑。

即便这项研究未能完全展示跨代疾病风险是如何传递的，它也为遗传不只是DNA编码的基因这一观点增加了更多证据。

Jamie Hackett

At present, I think it's, it's interesting from a biological point of view, it tells you that in the case of these mice, lifelong disease risk or phenotype more generally, is not purely dependent on the genes you inherit, but there is some component of, of parental environment that is having, albeit a relatively small effect, an effect on phenotype, so that that conceptually is really interesting. It also tells us that we need to consider perhaps a little bit more how the environments that were exposed to is affecting mammalian physiology, all the way through from the kind of molecular responses within the organism to a much bigger scale, which is intergenerational effects.

目前来看，我认为从生物学的角度而言，这是很有趣的。它告诉我们，以这些小鼠为例，终生的疾病风险或表型不仅仅取决于所遗传的基因，还存在父母环境因素的影响，尽管影响相对较小，但确实有作用。所以这个概念是非常有趣的。这也提醒我们，或许需要更多地关注我们所处的环境如何影响哺乳动物的生理，从分子水平的响应到更广泛的层面，甚至是跨代影响。

Benjamin Thompson

That was Jamie Hackett from the European Molecular Biology Laboratory in Italy, and Liisa Veerus from Rutgers University in the US to read Jamie’s paper and Liisa’s News and Views article look for links in the show notes.

以上是来自意大利欧洲分子生物学实验室的Jamie Hackett和美国罗格斯大学的Liisa Veerus的观点。如需阅读Jamie的论文和Liisa的《News and Views》文章，请查看节目单中的链接。