Getting Healthier Through Microbiome Makeover

In this issue of EBioMedicine, Liping Zhao and colleagues show that children with obesity have similar gut microbiota dysbiosis regardless of their geneticmakeup,whether it is simple obesity (no underlying pathology) or genetic obesity (Prader–Willi syndrome). Furthermore, their microbiome profile can be changed by a 1-month dietary intervention. Interestingly, the authors also show that transfer of preintervention fecal microbiota from these children to germ-free mice recapitulates key obesity-related traits, an effect that is not seen if postintervention fecal microbiota from the same children is transplanted, suggesting a possible causative contribution of gutmicrobiota to obesity development. Microbes inhabit various niches of the human body, from the skin to oronasal and urogenital cavities, but the vast majority is found in the human gastrointestinal tract. Microbes outnumber human cells at a ratio of 10 to 1, and microbial genes outnumber human genes by over 100 to 1. Commensal microbes have an important role in digesting food and providing nutrients, in educating our immune system and in protecting us from infection. More than 30% of small molecules found in human blood are derived from microbes. Using high-throughput molecular technologies, large collaborative projects such as the European Commission-funded MetaHIT and the US NIH-funded HumanMicrobiome Project are aiding the discovery of increasingly important insights into the role of the microbiome in human health. The field of microbiomics holds a lot of hope, but at the same time, microbiome research also has the potential to create much hype. We must be cautious in interpreting overly positive news headlines, because most studies to date are based on small numbers, their findings are often preliminary, descriptive, and sometimes even contradictory. The human microbiome has been linked to a plethora of diseases, ranging from gastrointestinal conditions (inflammatory bowel disease, colorectal cancer) and metabolic syndromes (diabetes, obesity), to seemingly unrelated diseases such as rheumatoid arthritis, cardiovascular diseases (atherosclerosis), neurological disorders (multiple sclerosis, Alzheimer's disease), and mental health (anxiety, depression, autism). But how many of these links are true causal relationships? In microbiome research, many confounding factors need to be controlled for— for example, diet is amajor confounder that can affect both gutmicrobiota and obesity. For therapeutic applications, evidence for causality is crucial along with the underlying mechanisms of action. Thus, even when a correlation between the microbiome and health is sufficiently robust and reproducible, the application of such findings beyond diagnostic or prognostic use is not immediately apparent. Researchers urgently need to transition away from purely descriptive work toward more mechanistic studies.