An NIAID study team has examined the relationship between helpful bacteria, immune cells, and epithelial cells—cells that line the gut and absorb and process nutrients from food. The researchers observed that epithelial cells transition from a metabolic role to a protective role when immune cells are absent, suggesting that a healthy intestinal tract may rely upon a three-way conversation between immune cells, helpful bacteria, and epithelial cells. The team's findings appear in the November 20 issue of Nature Medicine.
The human gastrointestinal (GI) tract is a unique cellular environment. The gut is naturally colonized with helpful bacteria, viruses, and fungi—collectively known as commensals—as well as protective immune system cells and epithelial cells. This interaction between commensals, immune cells, and epithelial cells occurs in a delicate balance. When the balance is interrupted, conditions such as malabsorption of nutrients and GI diseases such as Crohn's can occur. It has been unclear how the processes that govern metabolism and immunity intersect.
Results of Study
B cells are one of the most abundant immune cell types in the gut. They make antibodies needed to defend hosts against harmful microbes. To determine if gut B cells help maintain the balance between immunity and metabolism, the NIAID study team, led by senior investigator Polly Matzinger, Ph.D., compared mice that lacked B cells (B-cell knockout mice) to normal mice.
The team observed that, without B cells, epithelial cells of the knockout mouse gut begin to switch on genes that make immune system components such as microbe-fighting molecules. These same cells also reduced the expression of genes needed for metabolic processes, such as fat and cholesterol breakdown. The team found that B-cell knockout mice had difficulty absorbing fat from their diet, compared to normal mice.
An absence of gut B cells was not by itself enough to cause mouse epithelial cells to take on protective functions; the presence of gut commensals also played a role in this transition. The team observed that mice lacking both gut B cells and gut commensals did not turn on genes for immune system components, nor did they reduce the expression of genes for metabolism. The investigators concluded that the combination of functioning B cells and presence of gut commensals contributes to the balance between immunity and metabolism in the GI tract.
The team's findings could have implications for human diseases. In two human immunodeficiency diseases, common variable immunodeficiency (CVID) and HIV/AIDS, fatty stools and malabsorption of nutrients are unexplained symptoms.
Investigators examined intestinal biopsies from three patients with CVID, and gene expression data on patients infected with HIV. They observed that the gene expression differences between people with immunodeficiencies and healthy volunteers were similar to the differences between B-cell knockout mice and normal mice.
The results of this study indicate that there may be a molecular switch that is flipped in epithelial cells, telling the cells to launch immune processes at the expense of metabolic processes. Further study is needed to understand the relationship between immunity and metabolism in the gut and to determine if people with certain immunodeficiency diseases might benefit from treatment strategies that boost metabolic function of their epithelial cells.
Shulzhenko N, Morgun A, Hsiao W, Battle M, Yao M, Gavrilova O, Orandle M, Mayer L, Macpherson AJ, McCoy KD, Fraser-Liggett C, Matzinger P. Crosstalk between B lymphocytes, microbiota and the intestinal epithelium governs immunity versus metabolism in the gut. Nature Medicine. 20 November 2011 [Online ahead of print].