The intestinal microbiota: determinants of resiliency?
Authors: Robin M Voigt, Faraz Bishehsari
Journal: The Lancet Healthy Longevity (2021)

Advanced age (>65 years) is often characterised by the impaired ability to respond to biological stress, or, in other words, reduced biological resiliency. This loss of resiliency can manifest as an increased susceptibility to infection and the emergence of age-associated diseases. Addressing the underlying root cause of age-associated reduction in biological resiliency has the potential to promote healthy ageing, which has massive implications as the life expectancy of the world's population continues to increase (known as the silver tsunami). One factor that might influence biological resiliency is the intestinal microbiome. The intestinal microbiome (the collection of microorganisms in the gastrointestinal tract) is relatively stable during early adulthood, with changes emerging after approximately 65 years of age in so-called age-associated microbiota dysbiosis.1Claesson MJ Cusack S O'Sullivan O et al.Composition, variability, and temporal stability of the intestinal microbiota of the elderly.Proc Natl Acad Sci USA. 2011; 108: 4586-4591Crossref PubMed Scopus (1006) Google Scholar, 2O'Toole PW Jeffery IB Gut microbiota and aging.Science. 2015; 350: 1214-1215Crossref PubMed Scopus (432) Google Scholar, 3DeJong EN Surette MG Bowdish DME The gut microbiota and unhealthy aging: disentangling cause from consequence.Cell Host Microbe. 2020; 28: 180-189Summary Full Text Full Text PDF Scopus (33) Google Scholar Although the specific features of age-associated dysbiosis differ between studies, these changes tend to be characterised by an enrichment in pro-inflammatory bacteria and pathobionts and a concurrent decrease in putative beneficial, commensal bacteria, such as those that produce short-chain fatty acids (SCFAs). Whether these microbiome changes are the consequence of ageing host mechanisms (eg, cellular senescence) or are related to lifestyle changes associated with ageing (eg, medication use, reduced physical activity, dietary changes, or alterations in sleep or circadian rhythms) is unclear. Nevertheless, a growing body of literature shows that the intestinal microbiome can affect host immunity and metabolism and consequently influence susceptibility to age-associated pathologies, including infection, cancer, and neurodegenerative disease. The study by Susana Fuentes and colleagues4Fuentes S den Hartog G Nanlohy NM et al.Associations of faecal microbiota with influenza-like illness in the ageing population: an observational study.Lancet Healthy Longev. 2021; 2: e13-e23Summary Full Text Full Text PDF Scopus (3) Google Scholar provides new insight by showing that the intestinal microbiome could be used as a potential biomarker to indicate susceptibility to influenza-like illness (ILI) in adults 60 years and older. This observational study of older adults compared participants with ILI with asymptomatic participants and reports microbiome changes, some of which were specific to the acute ILI event and subsequently changed in the recovery phase (eg, a reduced abundance of Firmicutes and an increased abundance of Bacteroidetes). Dissimilarly, the abundance of Proteobacteria was higher in groups during infection and after recovery than in the control group, suggesting that elevated Proteobacteria abundance could be a feature that confers susceptibility to ILI. Indeed, the prevalence of baseline respiratory disease was significantly higher in the ILI group than in the control group, which suggests that participants in the ILI group were more susceptible to infection than were those in the control group (however, the control group did have a significantly higher uptake of influenza vaccine than did the ILI group). Of note, the ILI group had a higher baseline prevalence of antibiotic use than did the control group; whether such predisposing microbiome changes are due to frequent antibiotic use, an inherent immune dysfunction, or both needs to be studied in future longitudinal cohorts. The intestinal microbiome might be important in conferring susceptibility to viral infection and host response to infection. For example, virus–bacteria interactions are observed with influenza A virus and picornaviruses.5David SC Norton T Tyllis T et al.Direct interaction of whole-inactivated influenza A and pneumococcal vaccines enhances influenza-specific immunity.Nat Microbiol. 2019; 4: 1316-1327Crossref Scopus (10) Google Scholar, 6Rowe HM Meliopoulos VA Iverson A Bomme P Schultz-Cherry S Rosch JW Direct interactions with influenza promote bacterial adherence during respiratory infections.Nat Microbiol. 2019; 4: 1328-1336Crossref PubMed Scopus (39) Google Scholar, 7Aguilera ER Nguyen Y Sasaki J Pfeiffer JK Bacterial stabilization of a panel of picornaviruses.MSphere. 2019; 4: 4Crossref Scopus (18) Google Scholar These interactions influence virus stability and the infection of eukaryotic cells (thereby influencing viral infectivity potential). In addition to affecting the virus, the intestinal microbiome can also impact host immune function. Studies in humans have shown that bacteria can robustly influence the immune response, including antibody production, following vaccination with the influenza vaccine and clinical trials have shown that probiotic administration can beneficially modulate the immune response to influenza vaccination.8Oh JZ Ravindran R Chassaing B et al.TLR5-mediated sensing of gut microbiota is necessary for antibody responses to seasonal influenza vaccination.Immunity. 2014; 41: 478-492Summary Full Text Full Text PDF PubMed Scopus (298) Google Scholar, 9Ichinohe T Pang IK Kumamoto Y et al.Microbiota regulates immune defense against respiratory tract influenza A virus infection.Proc Natl Acad Sci USA. 2011; 108: 5354-5359Crossref PubMed Scopus (831) Google Scholar, 10Samuelson DR Welsh DA Shellito JE Regulation of lung immunity and host defense by the intestinal microbiota.Front Microbiol. 2015; 61085Crossref PubMed Scopus (188) Google Scholar, 11Rizzardini G Eskesen D Calder PC Capetti A Jespersen L Clerici M Evaluation of the immune benefits of two probiotic strains Bifidobacterium animalis ssp. lactis, BB-12® and Lactobacillus paracasei ssp. paracasei, L. casei 431® in an influenza vaccination model: a randomised, double-blind, placebo-controlled study.Br J Nutr. 2012; 107: 876-884Crossref PubMed Scopus (126) Google Scholar, 12Davidson LE Fiorino AM Snydman DR Hibberd PL Lactobacillus GG as an immune adjuvant for live-attenuated influenza vaccine in healthy adults: a randomized double-blind placebo-controlled trial.Eur J Clin Nutr. 2011; 65: 501-507Crossref PubMed Scopus (107) Google Scholar Thus, there is compelling evidence that commensal bacteria in the intestine influence susceptibility to infection by altering the host immune response in the lung and systemically.8Oh JZ Ravindran R Chassaing B et al.TLR5-mediated sensing of gut microbiota is necessary for antibody responses to seasonal influenza vaccination.Immunity. 2014; 41: 478-492Summary Full Text Full Text PDF PubMed Scopus (298) Google Scholar, 9Ichinohe T Pang IK Kumamoto Y et al.Microbiota regulates immune defense against respiratory tract influenza A virus infection.Proc Natl Acad Sci USA. 2011; 108: 5354-5359Crossref PubMed Scopus (831) Google Scholar, 10Samuelson DR Welsh DA Shellito JE Regulation of lung immunity and host defense by the intestinal microbiota.Front Microbiol. 2015; 61085Crossref PubMed Scopus (188) Google Scholar, 11Rizzardini G Eskesen D Calder PC Capetti A Jespersen L Clerici M Evaluation of the immune benefits of two probiotic strains Bifidobacterium animalis ssp. lactis, BB-12® and Lactobacillus paracasei ssp. paracasei, L. casei 431® in an influenza vaccination model: a randomised, double-blind, placebo-controlled study.Br J Nutr. 2012; 107: 876-884Crossref PubMed Scopus (126) Google Scholar, 12Davidson LE Fiorino AM Snydman DR Hibberd PL Lactobacillus GG as an immune adjuvant for live-attenuated influenza vaccine in healthy adults: a randomized double-blind placebo-controlled trial.Eur J Clin Nutr. 2011; 65: 501-507Crossref PubMed Scopus (107) Google Scholar Fuentes and colleagues4Fuentes S den Hartog G Nanlohy NM et al.Associations of faecal microbiota with influenza-like illness in the ageing population: an observational study.Lancet Healthy Longev. 2021; 2: e13-e23Summary Full Text Full Text PDF Scopus (3) Google Scholar found that a bacterium that produces the SCFA butyrate (ie, Butyricimonas) negatively correlated with the systemic CC chemokine family. This finding agrees with the preponderance of literature suggesting that SCFAs are anti-inflammatory. Interestingly, decreased butyrate and SCFA-producing bacteria and increased pro-inflammatory cytokines are generally associated with ageing and these characteristics could confer susceptibility to reduced resiliency in people of advanced age.3DeJong EN Surette MG Bowdish DME The gut microbiota and unhealthy aging: disentangling cause from consequence.Cell Host Microbe. 2020; 28: 180-189Summary Full Text Full Text PDF Scopus (33) Google Scholar Given the substantial effect of the intestinal microbiota on the immune system, the implications of the study by Fuentes and colleagues4Fuentes S den Hartog G Nanlohy NM et al.Associations of faecal microbiota with influenza-like illness in the ageing population: an observational study.Lancet Healthy Longev. 2021; 2: e13-e23Summary Full Text Full Text PDF Scopus (3) Google Scholar are broader than just respiratory illnesses such as ILI. A wide variety of age-associated diseases are mediated by inflammation; thus, disease development and progression might be modifiable by the intestinal microbiota. Such examples include (but are not limited to) malignancies, such as colon cancer, and neurodegenerative diseases, such as Parkinson's disease and Alzheimer's disease. Age-associated changes in the microbiota could reduce biological resiliency by modulating the immune system, which is widely known to be dysregulated in people of advanced age. Microbiota-directed interventions (eg, prebiotics and probiotics), as relatively non-invasive modulators of the immune system, could therefore be viable approaches to enhance the efficacy of vaccines, reduce viral infections, decrease the burden of age-associated diseases mediated by inflammation, and promote healthy ageing. We declare no competing interests. Associations of faecal microbiota with influenza-like illness in participants aged 60 years or older: an observational studyThe abundances of specific bacteria could be used as potential biomarkers for susceptibility to respiratory infections and as targets for intervention in the ageing population. Full-Text PDF Open Access