麻豆传媒

The moment we鈥檙e born, microbes start building our internal ecosystems. 麻豆传媒 explores why your body鈥檚 biodiversity matters

AT WASHINGTON University鈥檚 state-of-the-art Genome Institute they take an unusual interest in baby poo. They hope that studying fresh stool samples from the local neonatal unit will help them unlock the mystery of necrotising enterocolitis, a bowel disease that kills up to 5 per cent of premature babies. The disease obviously involves bacteria, yet it has proved impossible to pin the blame on just one microbe, suggesting that it may not be an infectious disease in the conventional sense. One possibility is that it is caused by a breakdown in the relationship between the gut bacteria and the body. If so, an abnormal combination of bacterial species in their stools may indicate which babies will get the disease. This is what they are looking for at Washington University in St Louis, Missouri.

The research is part of a bigger endeavour called the , which aims to identify and study all the microbes living in and on our bodies. It is transforming our understanding of the organisms that colonise our gut. It turns out that the 鈥済erms鈥� we do our best to exterminate with antibacterial sprays are not our enemies after all. In fact, we are locked in an intimate and vital relationship with them, and it shapes our physical development, helps train our immune systems and equips us with a set of metabolic abilities we would otherwise lack. Each of us is part of a vast and complex microbe-human ecosystem 鈥� less an individual than a 鈥渟uperorganism鈥�.

This realisation is forcing researchers to develop a more holistic approach to studying human biology. Instead of viewing necrotising enterocolitis as a regular infectious disease, for example, we may come to see it as nothing short of an ecological disaster 鈥� a catastrophic failure in interaction between species. Likewise, illnesses such as Crohn鈥檚 disease and even common conditions such as obesity and diabetes could all have roots in our relationship with our gut flora. In fact, the increasing prevalence of such conditions suggests that our internal ecosystems may be under threat from our modern lifestyles, with profound consequences for our health. We may soon be worrying as much about the biodiversity inside our bodies as we do about our external environment.

Microbiologists researching the human microbiome are fond of citing statistics and no wonder, for the numbers are jaw-dropping. The average person is home to about 100 trillion, 10¹⁴, microbes 鈥� mostly bacteria but also some viruses, fungi, protozoans and archaeans. You are in a minority in your own body: microbial cells outnumber your cells by 10 to 1. Your microbes contribute perhaps a couple of kilograms to your body weight and they are everywhere, colonising your gut, mouth, skin, mucous membranes and genitals. In fact, the only time anyone is free from microbes is in the womb. You are born 100 per cent human, but die 90 per cent microbial. Between these two events lies a vista of unexplored ecology that helps make us what we are.

Nowhere is the transformation from individual to superorganism more dramatic than in the gut, which is home to the vast majority of our microbiome. During a normal birth, a baby picks up vaginal and faecal microbes from its mother. Babies born by caesarean section acquire a different suite of microbes from the hands of people who deliver them. In the first few months of life, gut flora undergoes several dramatic shifts as different species take root and blossom, responding to a baby鈥檚 developing immune system and changes in its environment and diet. There are big differences between individuals depending on whether or not the infant is breastfed, for example. By age 3, the mature gut microbiome is in place, with the majority of microbes residing in the colon. Each of us carries hundreds of species from a total possible repertoire of more than 1000 different microbes (). The variation between individuals probably reflects factors such as genetic make-up, lifestyle, environment and diet. However, many microbial species are shared by us all, and the latest findings suggest that the overall ecological composition of microbes in any human gut falls into one of three basic groups, or 鈥渆nterotypes鈥� (Nature, ).

There is no doubt that we would be in serious trouble without this internal menagerie. A balanced and healthy gut flora helps keep disease-causing microbes at bay by occupying their preferred niches. Gut flora are also involved in the development of the immune system. The gut, being on the front line with the germ-infested outside world, contains a large amount of immune tissue, which learns to distinguish microbial friends from foe by sampling the gut flora. In mice lacking a microbiome, immune tissue fails to mature properly and carries fewer of the molecules that sense and react to pathogens. Microbes even help shape the gut. Microvilli 鈥� the tiny folds that form the gut lining and increase the surface area through which food can be absorbed 鈥� develop abnormally in microbe-free mice.

Findings like these support the idea that our gut microbes act collectively to create a greater whole, a sort of extra organ with its own functions. But exploring how exactly the gut microbes interact has been difficult because the vast majority of them cannot be cultured in the lab. That all changed with the advent of genome technology. The ability to extract DNA directly from samples and sequence it spawned a wealth of studies that build a picture of what is living inside us 鈥� or at least, at the far end of the gut, where the faecal samples originate. It turns out that our colons are dominated by two main bacterial phyla, the Firmicutes and the Bacteroidetes, with smaller numbers of Proteobacteria. A tiny minority of the flora are fungi and protozoa, about which little is known. The same goes for the viruses that lurk in the gut, preying on the bacteria there. These seem to comprise mostly unknown species and vary hugely from one individual to another ().

Another approach, called metagenomics, is exploring what these gut microbes are capable of. Unlike conventional genome studies, which focus on individual organisms, this entails collecting all the genes in an ecosystem to create a global 鈥渕etagenome鈥� 鈥� effectively a parts list for the biological functions of that ecosystem. The most detailed inventory to date was published in 2010 by Metagenomics of the (MetaHIT), a European Union-based consortium. The researchers studied faecal samples taken from 124 European adults and found a staggering 3.3 million different microbial genes, meaning that they outnumber our own human gene set about 150-fold (). Not everyone had every microbial gene, but by comparing the individuals in the study the team identified a set of genes we all share. Capable of more than 6000 biochemical functions, this 鈥渕inimal metagenome鈥� represents the core genes needed for the survival of the entire ecosystem.

So what do these genes do? Many seem to be plugging metabolic gaps in our own genome. It is common knowledge that we are unable to synthesise enough vitamin B or any vitamin K without our gut flora, but microbes assume many other useful functions. For example, they contain genes that convert complex carbohydrates into simpler molecules called short-chain fatty acids, an important energy source accounting for between 5 and 15 per cent of our requirements. Other core genes break down plant cellulose and complex sugars such as pectin, found in fruit and vegetables, which allows us to digest foods we could not handle without them.

Gone is the idea that gut flora had a passive role in regulating our biochemistry. 鈥淲e are now persuaded that they are very much more active,鈥� says Jeremy Nicholson at Imperial College London. He has found that your gut microbiome even affects your ability to metabolise and respond to the painkiller paracetamol (acetaminophen) (). The MetaHIT project also found microbial genes that seem to be involved in metabolising drugs and other non-dietary compounds, such as toxins and food additives. It looks as if drug companies will have to take our microbial metagenomes, as well as our own human genomes into account when designing new drugs. Personalised medicine just became vastly more complicated.

It is also becoming clear what can happen when our relationship with gut flora goes awry. Among the participants in the MetaHIT project was a group of people with inflammatory bowel diseases such as ulcerative colitis and Crohn鈥檚 disease. Previous research suggested that this group would have a lower diversity of bacterial species in their guts. Sure enough, those in the MetaHIT study had 25 per cent fewer microbial genes than healthy people. Meanwhile, research in mice indicates that the balance of microbes in the gut can play a part in the development of type 2 diabetes. People with the disease harbour a greater proportion of Bacteroidetes bacteria than Firmicutes, according to research published last year ().

Gut flora might also be associated with obesity. When a team led by Jeffrey Gordon from Washington University in St Louis took microbes from the guts of lean and obese mice and transplanted them into germ-free mice, they found that those with the microbiome of obese mice put on significantly more weight (). Subsequent studies indicate that the microbiomes of obese humans have a greater ability to harvest energy from food (Obesity, vol 18, p 190).

While these associations are suggestive, it is not yet clear whether our gut microflora actually cause health problems or whether they simply change as a consequence. The system is so complex it will be hard to prove causation. With luck more detailed studies of the structure of the microbial communities in healthy and sick individuals will be a starting point for developing therapies. These might include drugs, probiotics, foods that alter the behaviour of our gut ecosystems, and even faecal transplants (麻豆传媒, 22 January, p 8). And this is just the beginning. The US Human Microbiome Project alone is being funded to the tune of $115 million. It aims to study the microbiomes of 300 individuals, in the gut as well as numerous other sites in the body, analysing some 12,000 samples and investigating diseases including Crohn鈥檚 and necrotising enterocolitis.

Meanwhile, other researchers are wondering whether the link with gut microbes might help explain why obesity, diabetes, autoimmune diseases and certain cancers are on the rise in western cultures. Could our modern lifestyles be having detrimental effects on the ecology of our microbiome? 鈥淲e鈥檙e exposed to all kinds of weird and wonderful foods that we didn鈥檛 have before, and our environment is much cleaner,鈥� says Nicholson. That鈥檚 not all 鈥� our tendency to overuse antibiotics could be inflicting lasting damage on our microbiomes. A study published this year showed that gut flora composition alters dramatically in response to a course of antibiotics, before starting to rebuild itself after about a week (). 鈥淚t does mostly bounce back but certainly not quite all the way,鈥� says Les Dethlefsen from Stanford University in California, one of the research team. He speculates that repeated disturbances of the ecological balance of the gut microbiome could permanently shift the functioning of the ecosystem 鈥� an alteration that would then be passed down from parent to child. 鈥淓very time we perturb the community, there is a roll of the dice,鈥� he says.

Working out what all this means, not to mention unpicking the staggeringly complex relationship between us, our microbes and all our genomes is one of the most daunting tasks today鈥檚 biologists face. So it is perhaps fitting that tackling these hugely complex questions, will require cooperation across a diverse range of disciplines, forming a scientific superorganism if you like.

鈥淐ould modern lifestyles be having detrimental effects on the ecology of our microbiome?鈥�

When this article was first posted, the first paragraph of the body copy incorrectly said that necrotising enterocolitis kills up to 1 in 5 premature babies.