The type of bacteria that colonize the human gut does not just influence our digestion and well-being. Metagenome sequencing has provided an international consortium involving scientists from the European Molecular Biology Laboratory at the University Hospital of Heidelberg with evidence that certain individuals have different gut types with different types of bacteria. Such individuals not only differ in their predisposition to disease, but also in their behaviour.
It is estimated that the human body is home to around 100 trillion (1014) microbes, which is around ten times more microbial cells than our own cells. Of these microbes, bacteria are the most abundant, and the majority of them live in the human colon. They digest food, synthesize some vitamins and essential amino acids and help our immune system to distinguish between friendly and harmful intruders.
In popular vernacular, the world of microbes in the human colon is referred to as “gut flora”; this term, which is not correct, goes back to the days when bacteria and other microorganisms were investigated simultaneously by botanists, even though bacteria and plants have nothing in common. The microbes of an adult human colon have a total weight of two kilogrammes – which is more than the human brain weighs. In addition, the microbes have between two and three million different genes, which is around 100 times more genes than a human has.
An international team of researchers is aiming to investigate this enormous diversity in greater detail and elucidate the importance of gut bacteria for human beings. As part of the MetaHIT project (see yellow box at the end of the article), which is funded by the European Commission, the researchers have analyzed the metagenome of the commensals in the human colon. The metagenome is all the genetic material of all individual organisms of a biocoenosis, i.e. the microbial community of a specific environmental sample; it is therefore not necessary to have complete knowledge of all the individual species of the biocoenosis.
The researchers from the MetaHIT consortium collected stool samples from volunteers and sequenced the DNA contained therein. The volunteers consisted of healthy, obese and adipose individuals as well as patients with chronic inflammatory bowel disease (IBD; including Crohn’s disease and ulcerative colitis). In a study published in 2010, Dr. Peer Bork from the European Molecular Biology Laboratory (EMBL) in Heidelberg and head of the bioinformatics work package of the MetaHIT consortium reported that the researchers had sequenced DNA 577 billion base pairs long, which is around two hundred times the length of the human genome. This vast quantity of base pairs was used to prepare a catalogue of 3.3 million microbial genes (or rather “open reading frames”, ORFs) in the human colon. More than 99 per cent of these genes were of bacterial origin. A comparison with older studies showed that these sequences contained the genetic information of practically all bacteria known to inhabit the human colon as well as the genetic information of many unknown ones.
It came as no surprise that the colon microbiomes differed between healthy individuals and IBD patients; this had already been shown in earlier investigations. The researchers also found differences between the two IBD types – Crohn’s disease and ulcerative colitis. However, the researchers also came up with completely new results, which Bork and his MetaHIT consortium colleagues published in the journal Nature in 2011. They found that people could be divided into three different types, based on which species of bacteria occurred in higher quantities in their gut. Each individual could be said to have one of three gut types, or enterotypes, as Bork calls them. These gut types are independent of traits like age, gender, ethnic origin and body mass index (BMI, measure of obesity and adiposity). “Or let me put it this way, our gut flora can settle into three different ecosystems,” said Bork explaining that the researchers originally expected the combination of microbes in the human intestine to be random or to differ according to a person’s lifestyle or diet.
Although the enterotypes did not correspond to the individual traits of the volunteers, the data of the MetaHIT project nevertheless showed that the gut types contained certain genes or functional modules that significantly correlated with age and BMI. They found, for example, that the guts of older people appear to have more microbial genes that play an active role in breaking down carbohydrates than young people have, possibly because as we age we become less efficient at processing those nutrients. So in order to survive in the human gut bacteria have to take on the task. Peer Bork explained that these genes could one day be used to help diagnose and predict outcomes for disease as “the fact that there are bacterial genes that are related to traits like age, gender and body mass index also suggests that there are other microbial genetic markers for other traits such as adiposity and colorectal cancer”.
Bork and his international colleagues first used stool samples to analyze the gut bacteria of 39 individuals from Europe, Asia and America, and later extended the study to a further 85 people from Denmark and 154 from America, which served to substantiate the initial findings: each person was found to have one of three gut types, or enterotypes, which can somehow be compared to human blood types. The researchers speculate that the reason why people have different gut types could be related to differences in how their immune systems distinguish between friendly and harmful bacteria. However, they do not yet know for sure whether this is the case and which genetic components are involved. Recently published research results obtained with mice (Science 10.1126, 2012; Nature Medicine 18, 538-546, 2012) suggest that there is only one specific time slot in the early development of the animals during which immunotolerance is established, resulting from the interaction between the commensals and the host immune system. In adult mice, the immune system then fights all pathogens that invade the colon for the first time. There is comprehensive evidence that the situation is similar in humans. Many more analyses are required in order to clarify the relationship between colon commensals, gut type, nutrition and diseases. In order to do this, Bork has developed a non-profit Web 2.0 tool that acts as both social network and DNA database (see link in the top right-hand corner). The website offers a place for people to share gastrointestinal problems, diet tips and experiences. They can send in stool samples and pay a fee to have their bacterial genome sequenced and their enterotype determined. The participants obtain access to their own data; all public results remain anonymous. Despite the relatively high price tag – the sequencing of the bacteria costs around 1,000 euros – hundreds of people have already submitted their sample in the hope that the scientific findings gained from the analyses will help alleviate their suffering.