Flu vaccination response weakened by antibiotic effects on gut microbiome
Cell - Antibiotics-Driven Gut Microbiome Perturbation Alters Immunity to Vaccines in Humans
Emerging science on the widespread influences of the gut microbiome and its modulation of immune system function is highlighted in a study published in the journal Cell presenting evidence that microbiome loss from antibiotics weakens the response to flu vaccination in individuals with low pre-existing immunity. And their data illustrate the importance of bile acid production for the gut microbiome and immune function. This indicates that in order to be effective, flu vaccination timing should take into consideration previous broad-spectrum antibiotic exposure, at least for individuals with low pre-existing immunity--those most in need of vaccination.
Previous evidence of immune impairment after antibiotics
The authors note that there has been earlier evidence that microbiome variations can impair immunity. Interestingly, the microbiome modifications associated with commensal microbes prominent according to geographic location has an effect.
In addition to promotion of autoimmunity and allergy, variations in microbiome composition have been linked to reduced efficacy in various immune interventions, including prevention of HIV infection (Klatt et al., 2017) and anti-PD1 cancer immunotherapy (Gopalakrishnan et al., 2018; Routy et al., 2018; Zitvogel et al., 2018). This is particularly relevant in the context of vaccination, since the efficacy of many vaccines is known to vary significantly by geographical region (Collins and Belkaid, 2018; Levine, 2010; Littman, 2018), and microbiome composition is also strongly geographically dependent (Yatsunenko et al., 2012). Understanding how the gut microbiota can impact responsiveness to vaccination therefore has significant implications for increasing vaccine efficacy and improving global public health.
But there was still a dearth of evidence for how deliberate changes in the microbiome affect human the immune response to vaccination.
Striking impact of antibiotics on the response to H1N1 flu vaccine
The authors conducted a thorough and elaborate study over two separate seasons, with extensive profiling of immune responses in human antibiotics-treated and control subjects vaccinated with trivalent inactivated influenza vaccine. They also documented the profound contraction in total bacterial load, which species were most affected, both according to geographic region; and additional physiological consequences. The results were striking. Regarding the gut microbiome overall...
Relative abundance of bacterial species
Interestingly, at day 180 the microbial composition of the two groups still showed substantial dissimilarity, suggesting only partial recovery of the original microbial composition in the antibiotic group. We also examined alpha (within-sample) diversity to compare microbial richness and evenness in the antibiotic group samples pre- and post-antibiotics. Both measures were heavily compromised after the use of antibiotics, with the smallest number of different operation taxonomic units (OTUs) recorded on day 3. Notably, species richness and biodiversity were not fully recovered at 6 months, indicating long-lasting loss of unique bacterial species, consistent with previous studies.
As for the impact on adaptive immune responses to flu immunization by measuring multiple biomarkers associated with seroconversion under a variety of conditions and found multiple effects.
Taken together these results demonstrate that disturbance of the gut microbial community can impair antibody responses to influenza vaccination in absence of significant pre-existing humoral immunity.
Depletion of the gut microbiome increases inflammatory signaling
They documented that age-associated changes in combination with depletion of the gut microbiome by antibiotics can drive inflammation.
We identified expression changes in a substantial number of modules following antibiotics use, including increases in inflammatory signaling and activation of dendritic cells, and decreases in B cell and cell-cycle-related expression...These results indicate that antibiotics-driven depletion of the gut microbiome may drive inflammatory signaling in innate immune cells in a manner consistent with age-associated changes in immune responses.
Along with that were significant metabolic changes reflected by alteration of the blood metabolome (total content of metabolites present in the blood) that included perturbation of bile acid metabolism and the metabolic response to vaccination.
Antibiotics-treated subjects did display a large perturbation in their metabolome relative to control subjects...antibiotics-induced changes in multiple pathways, including bile acid metabolism and metabolism of tryptophan...This is consistent with established functions of the gut microbiota in regulating the bile acid pool (Ridlon et al., 2014) as well as in the control of tryptophan metabolism toward indole, kynurenine, and serotonin pathways (Agus et al., 2018)...When we examined the enriched metabolic pathways following vaccination...Thus, antibiotics significantly altered the metabolic response to influenza vaccination in the blood.
The immunomodulatory role of bile acids
Given that the loss of intestinal microbiota strongly altered the plasma metabolome, we wanted to explore potential connections between this metabolic disturbance and the cellular and transcriptional changes we observed following antibiotics treatment (Figure 4). In particular, dysbiosis of bile acid metabolism, which was significantly altered in antibiotics-treated subjects, has been associated with inflammatory bowel diseases (IBDs)...
Change of primary and secondary bile acids in antibiotics-treated subjects
Indeed, they showed an inverse correlation between levels of secondary bile acids and many inflammatory bacteria metabolites. This highlightsthe importance of healthy gall bladder function and bile acid metabolism for immune system regulation in the gut.
Lithocholic acid (LCA), which showed a 1,000fold reduction in the plasma following antibiotics treatment, had the strongest association with inflammatory responses, including modules involved in AP-1 signaling such as M35.0, which was upregulated post-vaccination in antibiotics-treated subjects but downregulated in control subjects . LCA is the most potent agonist of the bile acid receptor TGR5 (Kawamata et al., 2003), and TGR5 signaling has been shown to inhibit activation of the NLRP3 inflammasome in mice (Guo et al., 2016). Furthermore, AP-1 is known to play a critical role in the IL-1B-mediated induction of pro-inflammatory cytokines such as IL-6...These findings highlight a potential mechanism by which the microbiome may regulate inflammatory responses in humans.
Conclusions
This remarkable and detailed study pulls together a number of important lines of inquiry, including the role of the microbiome in regulating immunity overall and in response to immunization, the pro-inflammatory effect of antibiotic administration, metabolism, bile acid metabolism, and age-associated changes in immune function. The authors include among their conclusions...
In subjects with high baseline titers, there was minimal impact on the antibody response, but in the second cohort of subjects with low baseline titers we observed a striking impact of antibiotics treatment on the amount of H1N1-specific IgG1 following vaccination...With regards to innate immune responses, we observed that antibiotics administration alone induced significant cellular and transcriptional changes within the immune system, promoting a pro-inflammatory state. Integrative analysis revealed a strong association of these inflammatory responses with decreases in bacterial-mediated production of secondary bile acids...secondary bile acids such as LCA have also been shown to suppress pro-inflammatory cytokine production and nuclear factor kB (NF-kB) target expression...these results suggest that the inflammatory responses detected in peripheral blood following antibiotics treatment are driven by increased inflammasome signaling as a consequence of impairments in bile acid metabolism by the gut flora.
And further in regard to age...
...there is evidence that the gut microbiota of elderly subjects is less capable of producing other immunomodulatory metabolites, such as short-chain fatty acids...and gut permeability has been shown to increase with age in mice.
Additional effects of the perturbation of bile acid metabolism...
The findings suggest that the microbiome modulates bile acid metabolism and its consequent effects on inflammation through a different mechanism from its impact on antibody responses...These results highlight the capability of the microbiome to exert diverse effects on immune function, not only through direct interaction with immune cells in the gut, but also through indirect mechanisms such as regulating the systemic availability of critical metabolites.
They conclude with the clinical implications:
Here, we have demonstrated the potential for antibiotic-driven perturbation of the microbiome to influence immune responses to vaccination in healthy adults. As antibiotics and vaccines represent two of the most widely used medical interventions, this has important implications for clinical practice and public health. These findings should inform further research seeking to better understand mechanisms that control the interplay between the gut microbiota and our immune system.