Gut microbes influence defense against influenza

modelThe bacteria in our intestines outnumber by tenfold the 100 trillion cells that comprise the human body. This gut microbiota has many beneficial functions, including the production of vitamins and hormones, fermentation, regulation of gut development, and shaping intestinal immune responses. They also play a role in pathological conditions such as diabetes and obesity, and influence the immune functions of distal mucosal surfaces such as the lung. Examples include the amelioration of allergen-induced asthma by colonization of the stomach with Helicobacter pylori, and involvement of the gut microbiota in development of immune defenses against influenza virus infection.

When the gut microbiome of mice is altered by treatment with antibiotics, subsequent intranasal infection with influenza A virus leads to reduced antiviral antibody and T-cell responses. The antibiotic treatment does not cause a general immunodeficiency – the mice can respond normally to protein antigens.

The defective immune response to influenza virus in antibiotic treated mice can be rescued by treating the mice with compounds that stimulate the innate immune response – such as lipopolysaccharide, a bacterial product. These compounds rescue the immune defect when administered either intransally or rectally at the time of influenza virus infection. Apparently stimulating the innate immmune response in the gut is sufficient to correct an immune defect in the lung.

How might gut bacteria be important for immune responses to a lung infection? When influenza virus infects the lung, development of immune defenses depend upon a complex of several proteins called the inflammasome. This structure is needed for the production of cytokines that promote adaptive immune defenses: antibodies and T cells. These cytokines are also needed for the activity of dendritic cells, sentinels that sense a virus infection, and travel to the nearby lymph nodes to inform T cells that there is a problem.

Antibiotic treatment of mice impairs the influenza virus-induced production of inflammasome-dependent cytokines. These results are consistent with the finding that antibiotic-treated mice respond normally to infection with herpes simplex virus type 2 and Legionella pneumophila, two pathogens for which the inflammasome is not required for adaptive immune responses. Furthermore, microbe-mediated inflammasome activation is needed for migration of lung dendritic cells to lymph nodes. In antibiotic treated mice, lung dendritic cells fail to migrate to local lymph nodes. Hence T cells are not informed of the infection, leading to poor antibody and cellular responses.

These findings reveal a link between the gut microbial community and inflammasome-dependent activation of cytokines. How gut bacteria effect this process is not understood. One idea is that bacterial products stimulate white blood cells in the intestine to produce compounds that migrate to the lung and activate the inflammasome.

If you are wondering about the practical consequences of these findings, read the last paragraph of the paper:

Because antibiotic use is prevalent in the treatment of respiratory infections, our results imply a possible deleterious effect of such treatment in initiating proper immune responses to influenza virus. Conversely, it will be important to determine whether probiotic therapy can be explored for immune-stimulating effects during the flu season.

Ichinohe T, Pang IK, Kumamoto Y, Peaper DR, Ho JH, Murray TS, & Iwasaki A (2011). Microbiota regulates immune defense against respiratory tract influenza A virus infection. Proceedings of the National Academy of Sciences of the United States of America, 108 (13), 5354-9 PMID: 21402903