The human gut microbiome appears to play diverse roles in host physiology, metabolism, and immunity. Most conclusions about what the trillions of bacteria in our intestines actually do come from studies in mice, or correlative studies in humans. An exception is an investigation in humans which shows that antibiotic-mediated alteration of the fecal microbiome* interferes with the antibody response to influenza vaccine.
The results of previous studies have shown that mice lacking the gene encoding toll-like receptor 5, an innate immune sensor which recognizes bacterial flagellin, have impaired antibody responses to inactivated influenza virus vaccine. This observation suggested that intestinal bacteria might influence antibody responses to vaccines.
To determine if antibiotic-mediated depletion of intestinal bacteria influences responses to vaccination in humans, 11 individuals were given a 5-day course of a broad-spectrum antibiotic cocktail. As expected, this treatment regimen caused a profound contraction in total fecal bacterial load. On day 4 the volunteers were immunized with formalin inactivated, trivalent influenza vaccine (containing H1N1, H3N2, and B viruses). When samples from treated and control groups were compared, no differences were observed in the ability of serum antibodies to neutralize infectivity of the vaccine viruses.
A second trial was done with volunteers who had not received trivalent inactivated influenza vaccine for the prior three influenza seasons. In this case, antibiotic treatment led to lower serum neutralizing titers, but only against the H1N1 virus, and not the H3N2 or B viruses. The effect was specific for serum IgG1 antibodies; IgG2 and IgG3 antibody levels were not affected. Levels of H1N1-specific serum IgA antibodies were also reduced after antibiotic treatment.
These results show that alteration of the fecal microbiome impairs antibody responses to influenza immunization in individuals who do not have pre-existing immunity.
How does depletion of the fecal microbiome reduce response to influenza vaccine? A study of blood metabolites in antibiotic-treated volunteers revealed increased expression of genes encoding pro-inflammatory cytokines. Curiously, this pro-inflammatory state is also observed after influenza immunization of the elderly. The microbiome does change with age, perhaps influencing responses to vaccines.
But how does an altered microbiome influence antibody responses? Clues come from a study of the blood metabolome, the results of which indicate a correlation between reduced IgG1 responses and alterations in fatty acid metabolism. The latter are thought to be important regulators of immune responses. How these metabolic alterations, brought about by changes in fecal microbiome, affect antibody responses remains to be elucidated.
A final question of interest is why impairment of antibody responses was observed only for the H1N1 strain, and only in individuals who had not been recently immunized. Authors speculate that recall memory responses might not be influenced by the fecal microbiome. Many adults have memory to influenza H3N2 and B viruses, but not H1N1. The mechanism by which primary and memory responses are differentially sensitive to the fecal microbiome is not known.
The authors write that “antibiotics and vaccines are two of the most widely used medical interventions”. It would therefore seem important to determine if the observations reported here extend to other vaccines. If so, it would be important to avoid giving vaccines while antibiotics are being taken.
*I write ‘fecal microbiome’ because that is what was measured, not the intestinal microbiome. The latter can only be measured by biopsy as the bacteria are tightly associated with the gut wall.