Perturbations in the gut microbiota have been shown to affect various immune components and impair the efficacy of treatments such as cancer immunotherapy. Now, work from the group of Bali Pulendran shows that antibiotic-mediated disruption of the gut microbiota can impair the effectiveness of seasonal influenza vaccination in individuals with low levels of pre-existing immunity.

Credit: S. Bradbrook/Springer Nature Limited

Most studies exploring how the microbiota shapes immune function have used animal models. To examine the effects of the microbiota on the human immune system, Hagan et al. vaccinated antibiotic-treated or control subjects with the seasonal trivalent inactivated influenza vaccine (TIV). They initially enrolled 22 healthy adults and subjected 11 individuals to a 5-day broad-spectrum antibiotic regimen (commencing 3 days before vaccination and ending 1 day after) and collected biological samples regularly until 1 year after vaccination. Antibiotic-treated subjects showed a marked reduction in bacterial loads and profound changes in microbial community composition, chiefly characterized by an overabundance of Enterobacteriaceae and reduced proportions of Lachnospiraceae, Ruminococcaceae, Bacteroidaceae and Veillonellaceae. This restriction in bacterial diversity was apparent for at least 6 months after cessation of antibiotics administration.

In this initial study, the authors did not see any differences between the TIV-induced antibody responses of antibiotic-treated and control individuals. However, many individuals showed high baseline antibody titres; therefore, in a subsequent study the authors enrolled additional subjects with low pre-existing titres of antibody against influenza. In this follow-up study using individuals with limited pre-existing immunity, antibiotic treatment markedly impaired binding and neutralization antibody responses against the H1N1 A/California strain of influenza (although not against the other two strains targeted by the vaccine) following TIV vaccination. Specifically, the antibiotic-treated subjects showed markedly impaired production of IgG1 and IgA1 specific for H1N1 A/California following vaccination.

The authors found that antibiotic treatment alone was associated with increased expression of gene modules linked with pro-inflammatory signalling and dendritic cell activation, similarly to what had previously been observed in elderly subjects. These changes normalized following cessation of antibiotics, suggesting they were linked with perturbations in the gut microbiota. As the gut microbiota plays an important role in dietary metabolism, the authors examined changes in the blood metabolomes of the different groups. They found that antibiotic treatment was associated with metabolite changes, including changes in bile acid and tryptophan metabolism. The gut microbiota is responsible for converting liver-derived primary bile acids into secondary bile acids; notably, treatment with antibiotics led to a dramatic reduction in levels of secondary bile acids. Accordingly, the authors found prominent differences in the metabolic response to TIV between the antibiotic-treated and control subjects.

Analyses by the authors suggested an inverse correlation between the levels of individual secondary bile acids and expression of various inflammatory modules. In particular, the secondary bile acid lithocholic acid (LCA) showed a 1,000-fold reduction in the plasma of antibiotic-treated subjects and downregulation of LCA was associated with increased expression of inflammasome signalling genes. Further gene network analyses by the authors suggested that the increased inflammatory signalling associated with secondary bile acid disturbances and the impaired IgG1 response to TIV vaccination arise as independent effects of antibiotic-mediated disturbance of the microbiota.

antibiotic-mediated disruption of the gut microbiota can impair the effectiveness of seasonal influenza vaccination in individuals with low levels of pre-existing immunity

Virtually all humans have been previously exposed to influenza virus and this study indicates that, where pre-existing immunity exists, the immune system can maintain appropriate responses to pathogens despite significant metabolic disturbances arising from transient dysbiosis. However, in situations where immunity may be less mature (such as in adults with low pre-existing immune memory or in infants), dysbiosis may have a greater impact on the development of an appropriate immune response.