Historically, medical research has focused on pathogenic bacteria when trying to understand the relationship between human health and microorganisms. This makes intuitive sense – since pathogens make us sick – but our bodies host way more nonpathogenic bacteria than pathogens and they function in keeping us healthy. Our gastrointestinal tract has trillions of bacteria in it and much recent work has been trying to understand these complex communities. Mice are a common model for understanding human gut microbes and health. Enter Obie, the obese mouse (Figure 1, left) and Lenny, the lean mouse (right).
Obie and Lenny are genetically different at a locus in their genomes that codes for leptin – a hormone that inhibits appetite. Mice that can’t make this hormone become very hungry and morbidly obese. These two mice also differ in the composition of their gut microbiota – obese individuals (both mice and human) have different amounts of the main bacterial phyla in their gut and as a result, are able to more efficiently extract calories from food. In other words, if you give both of them the exact same amount of food, Obie is going to get more calories from it than Lenny, contributing to Obie’s weight problem. In humans, where the status of our “leptin locus” is not normally known and probably not as straightforward as the case of Obie and Lenny– it’s been hard to tell whether this shift in gut microbiota is the CAUSE of obesity or the EFFECT of obesity. That brings me to today’s paper: a short communication in The ISME Journal (that’s open access!) by Fei and Zhao that addresses this exact problem.
Fei and Zhao use a series of complicated molecular techniques (that I don’t fully understand) to show several cool things.
First, they followed obese individuals (and their gut microbiota) through highly controlled diet and weight reduction. The predominant bacteria in the obese state was Enterobacter, which became undetectable by the end of the 23 week trial. They hypothesized that Enterobacter might be causing obesity so they isolated a single strain from the genus (called B29), grew it up in pure culture and attempted to confirm Koch’s Postulates – basically the gold standard for showing that a bacterium is responsible for a disease. They’d already fulfilled the first one: that the bacterium must be isolated from a sick host and grown in culture. Next, they did a series of experiments to see if they could induce the disease (obesity) in healthy individuals inoculated with B29.
Turns out, the bacterium alone was not enough to cause obesity – the bacterium had to be coupled with a high-fat diet. Mice that were inoculated with B29 and fed a normal mouse diet did not become obese. Neither did control mice given a high-fat diet in the absence of B29 nor mice on low-fat diet without B29 (Figure 2). The B29 (plus diet) CAUSED the disease (obesity)! Another of Koch’s postulates.
Fei and Zhao have used the germ-free mouse model and (slightly modified) Koch’s Postulates to show that a single human-derived bacterium can CAUSE obesity. Seems kinda simple but I think that’s actually a pretty big deal: a single bacterial species can cause obesity. This opens up a lot of medicinal and therapeutic possibilities! They can also repeat their protocol to isolate further bacteria possibly causing this disease – and potentially others – in humans. So which came first: the obese chicken or its obese microbiota? Neither. The scientists came first then told us all that bacteria may indeed precede obesity.
Fei N. & Zhao L. (2012). An opportunistic pathogen isolated from the gut of an obese human causes obesity in germfree mice, The ISME Journal, 7 (4) 880-884. DOI: 10.1038/ismej.2012.153