Researchers identified gut microbiome characteristics associated with severity of frailty in older women and found that microbial changes were associated with poorer physical function, fall injuries, and death.
Research: Gut microbiota is associated with frailty in older women. Image credit: In Green/Shutterstock.com
Recent articles published in journals nature communications We found that in older women, increased frailty severity was associated with distinct gut microbiota characteristics that differed from those previously seen in healthy aging.
Existing frailty tools lack important health aspects
Frailty is a multifaceted age-related syndrome characterized by decreased physiological resilience and depletion of reserves. Frail people are more likely to fall, be hospitalized, become disabled, and die. Multiple tools have been developed to measure frailty, such as the Fried frailty phenotype, the Lockwood frailty index, and the clinical frailty scale.
However, while each captures different aspects of frailty, they do not encompass all of its functional, psychological, and physiological aspects. The Charlson Comorbidity Index (CCI) is often used to stratify mortality risk, but again it only incorporates disease-related risks.
Recognizing this, the authors developed and internally validated the Frailty Mortality Index (FMI). It incorporates three types of measures related to frailty and mortality risk: functional, physiological, and psychological. Variables include:
- age and weight
- Physical functions related to walking speed and rising from a chair
- current smoking habits
- spiritual quality of life
- Hospitalization period
- CCI
Frailty exhibits distinct microbiome changes beyond healthy aging
Previous research suggests that the gut microbiome may contribute to systemic inflammation, altered immune and neuroendocrine transmission, metabolic changes, and impaired musculoskeletal function.
Aging is often accompanied by a reduction in gut microbial diversity, loss of beneficial commensals, and expansion of opportunistic or proinflammatory species. These changes are associated with loss of muscle mass, decline in cognitive function, and multiple chronic diseases.
Of note, healthy aging is also accompanied by changes in the gut microbiome, whereas frailty is associated with a distinct microbial profile distinct from healthy aging. This motivated the current study, whose aim was to identify FMI-related changes in the gut microbiome that are associated with increased frailty severity and poor frailty-related clinical outcomes.
The authors used clinical and metagenomic data from the Swedish SUPERB cohort to capture these changes. The FMI was developed in the complete SUPERB cohort and subsequently applied to 2,081 women aged 75 to 80 years with complete metagenomic data and followed for a median of 8 years. Stool samples and clinical assessments were collected at baseline, and mortality, fall injuries, and hip fractures were prospectively assessed during follow-up.
Higher frailty scores predict worse clinical outcomes
Results showed that FMI was more strongly associated with mortality risk in this cohort compared to the established Charlson Comorbidity Index (CCI). Compared to women in the lowest quartile of FMI (‘no frailty’), women in the highest quartile (‘severe frailty’) had an approximately 5 times higher risk of death, a 63% higher risk of fall injury, and a 2.4 times higher risk of femoral neck fracture.
Participants with higher FMI scores were older, more likely to be current smokers, had higher CCI, and were more likely to have poor physical function. They also had more markers of systemic inflammation (as indicated by the Systemic Inflammatory Response Index (SIRI)) and were more commonly taking drugs such as metformin and proton pump inhibitors.
Gut microbial diversity decreased with increasing frailty
Higher FMI scores were associated with lower microbial diversity, gene richness, and predicted functional capacity. Low microbial diversity and gene richness were also associated with increased risk of mortality and fall injury, but neither showed a significant association with hip fracture. Gene richness reflects the functional potential of gut microbes.
Adjusted analyzes showed that variation in FMI explained 0.6% of the overall variation in gut microbiome composition, which was higher than the proportion explained by other risk factors for frailty tested, such as BMI, smoking, and physical function.
The authors proposed that reduced diversity and gene richness of the gut microbiome may indicate a reduced ability to adapt to disruptions such as colonization by pathogens. Concomitantly, the host is more likely to suffer from frailty-related adverse outcomes.
Taxon-specific changes in the gut microbiome
Among all taxa investigated, 404 bacterial species were significantly associated with FMI. After adjusting for gene richness, 63 species remained significantly associated with FMI, including 34 species that were significant before and after adjustment. Conversely, 29 species were significantly associated with FMI only after adjusting for gene richness, indicating a unique association between them.
Further analysis suggested that although many microbial associations overlap with comorbidities, the microbial signatures associated with FMI remained significant even after adjusting for a wide range of baseline diseases, indicating that they cannot be explained solely by comorbidities and poor baseline health.
The major species most associated with FMI included opportunistic pathogens. Enterocloster seed, Streptococcus mutansorally facultative anaerobes, and Clostridium Q Symbiosum. Some of these were independently associated with frailty-related measures such as functional limitations, fall injury, and mortality risk. Conversely, several potential butyrate-producing species include Faecalibacterium prausnitziiwas negatively correlated with FMI and associated with improved physical and mental functioning.
In an independent Chinese cohort, 52.3% of FMI-associated species showed directionally consistent associations with at least one physical function indicator or mortality. Among the top 5% of FMI-associated species, 11 (55%) showed statistically significant associations in the same direction, supporting the consistency of results across geographically distinct populations.
Metabolic signs reflect transition to frailty
The researchers examined gut metabolic modules (GMMs), which represent selected metabolic pathways of the gut microbiota. This indicated that GMM, which had a strong positive association with FMI, was involved in amino acid degradation and anaerobic respiration. Additional positively associated pathways include lactate metabolism, propionate production, and trimethylamine/trimethylamine-N-oxide metabolism. In contrast, several metabolic pathways that were negatively associated with FMI were associated with lower mortality and fall injury risk.
Exploratory models identified the taxa most strongly associated with FMI. Some taxa contributed as much as the gene richness of the gut microbiota and clinical markers in the predictive model. However, the authors note that these machine learning analyzes are exploratory and aimed at qualitatively prioritizing features rather than establishing independent biological effects.
Further research is needed before clinical translation
This study had several limitations. Because the microbiome analysis was cross-sectional, the researchers were unable to determine whether the changes in the gut microbiome preceded or developed as a result of frailty, making it impossible to draw conclusions about causality. The SUPERB dataset also lacked some of the information needed to directly compare the Frailty Mortality Index (FMI) to other established frailty indices.
Microbiome analyzes have focused on bacterial species and predicted metabolic pathways rather than directly measuring metabolic byproducts, but the potential role of archaea, bacteriophages, and strain-level variation remains unclear. Additionally, dietary intake, an important factor influencing the gut microbiota, was not assessed.
Additionally, the generalizability of the findings may be limited because the discovery cohort consisted only of community-dwelling Swedish women aged 75 to 80 years. Although the Chinese independent replication cohort included both men and women, we could only assess species-level associations between physical function and mortality because we lacked the information needed to directly calculate FMI.
New frailty index reveals microbiome patterns associated with health
FMI integrates multiple measures of frailty (functional, physiological, and psychological) to estimate mortality risk. In this study, we used FMI to identify species-level variations in the gut microbiome that are associated with increased FMI scores and adverse outcomes related to frailty and mortality risk.
Although some findings were supported by concordant associations in an independent Chinese cohort, the results remain observational and do not establish that microbiome changes cause frailty. Future studies using more diverse populations, longitudinal sampling, external validation, and strain-specific analyzes are needed to validate these findings before they can be applied to preventive or therapeutic interventions for frailty.
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