New findings in healthy adults unravel connections between gut microbiome, metabolome and response to influenza vaccination

One way by which the gut microbiome shapes host physiology is by modulating immune responses.

Although the effects of commensal microorganisms on the immune system have been studied under disease states, as have their effects on vaccine responses in healthy individuals, their causal contribution in human immunity is limited.

A new study, led by Dr. Bali Pulendran from Stanford University (USA), has found that disruptions in the gut microbiome secondary to antibiotic treatment may adversely affect immunity to influenza vaccination in healthy adults.

A group of 22 healthy adults were recruited and vaccinated for influenza at day 0. Half of the participants were pretreated with antibiotics prior and subsequent to seasonal influenza vaccination.

Antibiotics led to an altered gut microbiota composition characterized by depleted 16S ribosomal ribonucleic acid copy numbers—which recovered slowly between days 7 and 30—as well as flagellin and lipopolysaccharide in stool. However, antibiotics did not affect influenza vaccination response.

The proportion of individuals with increased trivalent influenza vaccine-specific antibodies between pre- and post-vaccination sera did not differ between the antibiotic-treated group and the control group.

As the analyzed cohort had high influenza titers at baseline, the authors wanted to explore the impact of antibiotics on influenza vaccination in subjects with low baseline influenza titers.

In 11 additional participants with low baseline influenza titers, antibiotics led to a decrease in gut microbiota composition and diversity. Furthermore, antibiotics led to a decrease in immunoglobulin G1 (IgG1) and IgA against the H1N1 A/California influenza strain and altered antibody affinity to the influenza strain, unlike the results observed in participants with high baseline influenza titers.

These changes in immune cells were also accompanied by increased serum primary and decreased secondary bile acids together with AP-1/NR4A inflammasome activation, which shares patterns previously shown in mice as a consequence of aging.

Nevertheless, antibiotics did not alter other subsets of immune cells, such as B cells and T follicular helper cells, or the differentiation of antigen-specific B cells into plasmablasts and activated B cells.

Systems analysis of data (through a multiscale, multifactorial response network or MMRN) showed further relationships between gut microbiome composition, levels of related metabolites, inflammatory pathways and influenza vaccine responses. Within them, the associations between gut bacteria and metabolite dominated over the others.

For instance, antibiotic-driven gut microbiome alterations affected both H1N1-specific IgG1 titers and secondary bile acids by involving different mechanisms.

Altogether, these findings show the role of antibiotic-induced gut microbiome alterations on immunity by analyzing the increase of antigen-specific antibody response to an immune challenge. In the absence of significant pre-existing humoral immunity (low baseline titers), changes in the gut microbiome secondary to antibiotic treatment can impair antibody response to influenza vaccination.

A variety of mechanisms by which the gut microbiome influences humoral responses to vaccines can operate and this study shows the close teamwork between commensal microorganisms and related blood metabolome changes in determining the response to influenza vaccination.

Reference:

 Hagan T, Cortese M, Rouphael N, et al. Antibiotics-driven gut microbiome perturbation alters immunity to vaccines in humans. Cell. 2019; 178(6):1313-28. doi: 10.1016/j.cell.2019.08.010.