When people think about malnutrition, they often think that not eating enough food leads to stunted growth, neurocognitive issues, weakened immune systems, and other health problems associated with malnutrition. While this is largely true, food scarcity and insecurity does lead to undernutrition, it is not the sole contributing factor to this pervasive global health problem. Jeffrey Gordon and his group at Washington University School of Medicine in St. Louis have shown once again that gut microbes play an important role in undernutrition in a paper in Science Translational Medicine.

To show the importance of the microbiome in undernutrition, Gordon’s team studied children in Malawi who were undernourished and others that were not. Specifically, they studied individuals with kwashiorkor, a form of severe undernutrition that occurs in children who often eat similar diets as other healthy children. They studied identical twins, one with the disease and one without the disease and sampled their gut microbes. They transplanted the bacteria from the sick child into germ-free mice to see what effects the bacteria would have. When transplanted into the mice, the bacteria were very harmful causing weight loss as well as severe damage to the lining of the intestines and colon.

The scientists looked for bacteria that were targeted by an important molecule of the immune system called immunoglobin A (IgA). IgA is prevalent throughout the body and specifically in the gut. It plays an important role in preventing the bacteria in the gut from interacting with the human cells that line our intestines. As we saw in the paper on the blog on Monday about emulsifiers in our food, when gut bacteria in the gut interacts with the epithelial cells of the gut lining, severe health problems can arise. The scientists found that IgA and the immune system largely targeted Enterobacteriaceae, a large family of bacteria found in the gut that includes E. coli, Salmonella, and many others. The scientists were able to prevent weight loss in the mice by transplanting two strains of IgA targeted bacteria from the guts of healthy children into the mice, before they were exposed to the bacteria from the undernourished child.

This is an important study as it not only shows the significant role that gut bacteria have on malnutrition, but it shows that it may be possible to use the microbiome as a diagnostic tool to identify which children are at risk for undernutrition, and it may also be a therapeutic target for intervention. The scientists also studied 19 other groups of twins and found that higher levels of Enterobacteriaceae led to a greater risk of kwashiorkor. By sampling children at a very early age for gut bacteria, it could be possible to identify which children were at greater risk of becoming malnourished and intervening with probiotics or other therapeutic foods to alter the microbiome.

Immunoglobulin A (IgA) is an antibody that is produced in the mucosal linings and is thought to play a critical role in maintaining the homeostasis between the body and the microbiome. IgA deficiency has been related to celiac disease and people who suffer from this deficiency are prone to bacterial infections. While studying IgA in mice, folks from Washington University, St. Louis noticed that IgA was not found in the feces of some mice, but was found in high levels in others. They investigated this high/low fecal IgA phenotype and showed that it was directly related to the microbiome. Their results were published last week in Nature.

The researchers began by doing various experiments between the high and low IgA mice. They first noted that mothers would pass their IgA phenotype to all their offspring, showing the trait was vertically transmitted. They then put high and low IgA mice in the same cages and learned that the low IgA trait was dominant, and high IgA mice would rapidly become low IgA mice. In order to discover if a virus was responsible, the scientists filtered the feces of low IgA mice to remove any bacteria and then transferred it into high IgA mice. These mice remained high in IgA, meaning that a bacteria, fungi, or other larger organisms were likely responsible.

The scientists then began experimentation with antibiotics. When broad spectrum antibiotics were given to low IgA mice it eliminated most of the bacteria in their gut. When these mice were given fecal transplants from high IgA mice, they became high IgA mice. This trait was also transferred to their progeny, and their children became high IgA mice. In addition, when the antibiotic ampicillin was administered to low IgA mice, their feces became high in IgA. Overall, these experiments led the scientists to believe that bacteria were responsible for the secreted IgA levels, and that ampicillin had the ability to kill whichever bacteria caused the low IgA phenotype.

The scientists then performed genetic analysis on all of their mice's stools to see which bacteria were present in high and low IgA fecal samples. There was one bacterial genus, Suterella, which was common to only low IgA mice. When this bacteria was cultured and given to high IgA mice, it caused them to become low IgA mice. Suterella apparently has the ability to confer the low IgA phenotype. (Interestingly, we had previously written about Suterella and its link to Down Syndrome and autism.)

Finally, the scientists studied the mechanism that could prevent IgA from being secreted in the low IgA mice, and they learned that it is likely the microbiome is both degrading IgA itself, and that it is degrading the proteins in the mucous responsible for secreting IgA.

Taken together these results show a very robust link between a specific phenotype and the microbiome. Before this study, most relationships between phenotypes, such as obesity, and the microbiome were merely associations, rather than causative. This study though, is crucial in that it shows secreted IgA levels can be directly caused by the microbiome, and there is a mechanism that explains the phenomenon.

Can gut microbes be used to diagnose and treat malnutrition?

Research shows that the microbiome can control certain phenotypes