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September/October 2023
Frailty and the Microbiome What’s the Gut Got to Do With It? Frailty involves aging-related physiological decline, including loss of muscle and strength, poor endurance, slow gait, and low physical activity level. Frail older adults are at increased risk of falls, disability, infections, hospital admissions, the need for long term care, and death. Over the last several decades, research has demonstrated that frailty is a syndrome with several contributing factors, including poor nutrition, history of falls, cognitive impairment, certain chronic diseases (eg, diabetes, osteoporosis), decreased mobility, and loneliness/depression.1 As a result of technological advances in molecular and genomic analysis over the last decade, another contributing factor to the development of frailty has been identified—the microbiome. The human microbiome refers to the collection of microscopic organisms that live in and on the body and provide health benefits related to metabolic, physiologic, and protective functions. These organisms include protozoa, bacteria, archaea, fungi, and viruses. The term microbiome is most frequently associated with the gastrointestinal tract and digestive diseases and infections, such as inflammatory bowel diseases and Clostridioides difficile (C. diff) infection. But, the human microbiome also includes the skin, mouth, urinary tract, and respiratory tract. Recent research has indicated that the human microbiome may, in fact, be contributing to age-related diseases, including frailty.2-4 The Gut Microbiome Stress, medications, lifestyle, diet, and environment can disrupt the balance and diversity of the gut microbiome. When imbalances occur, referred to as gut dysbiosis, infections and inflammatory responses may result. Research has found that these microbiome-driven inflammatory responses are at the root of some disease processes. Studies have found altered microbiome diversity and function associated with many diseases, including obesity, diabetes, atherosclerosis, autoimmune diseases, autism, depression, and nonalcoholic fatty liver disease.2,4 Antibiotic medications are especially disruptive, causing decreased microbiome diversity within a few days; effects can last for weeks or months. Antibiotics are commonly prescribed for older adults, especially those in nursing homes. By decreasing gut microbiome diversity, antibiotics make the gut vulnerable to growth of antibiotic-resistant bacteria, such as C. diff and Enterococcus faecium. In addition to antibiotics, other types of medications can affect the mucosal lining of the gut or alter pH, thereby also decreasing organism diversity. In older adults, polypharmacy—the use of multiple drugs at the same time—can induce dysbiosis.2,4 Medications that are commonly prescribed for older adults—proton pump inhibitors, statins, antipsychotic drugs, and NSAIDs, for example—all have been shown to decrease the diversity of gut microbiota and make the gut more hospitable to pathogenic bacteria. Polypharmacy involving these medications is common in older adults and contributes to disruptions in the gut microbiome.2,4,6 Research into aging and age-related diseases has found significant associations of frailty with inflammation and dysregulated immunity. Because gut dysbiosis has been shown to adversely affect the immune system and induce inflammation, research has been investigating the potential association between the microbiome and frailty. Some animal and human studies have suggested that the gut microbiome may even influence muscle mass and function, further contributing to frailty.2,4,6 Short-chain fatty acids derived from microbiota activity promote mitochondrial fatty acid oxidation in muscle tissue. Research suggests that changes in the microbiome in older adults result in decreased short-chain fatty acid production, which subsequently results in physiological processes that reduce muscle strength and quality. Animal studies have shown that changes in the microbiome affect aging, including reduced muscle mass. Gut dysbiosis leading to inflammation has been linked to muscle atrophy in rodent studies. Population studies of frail older nursing home residents have shown that bacteria producing short-chain fatty acids were reduced compared with those in more active community dwelling adults.4,5 Other research has suggested that an age-altered gut microbiome might contribute to reduced appetite and protein consumption, decreased metabolism, and decreased ability to absorb nutrients, all of which contribute to the development of sarcopenia and frailty.6 However, studies directly linking the gut microbiome composition as a cause of sarcopenia, an aging-related decrease in muscle mass associated with frailty, are lacking.4,5 Studies in older adults do suggest that age-related changes in the gut microbiome include a decline in microbiota diversity and changes in dominant bacterial species. For example, Bacteroidetes were more abundant in older adults, compared with a greater abundance of Firmicutes in younger adults. At the bacterial species level, anaerobic bacteria have been found to decrease with age, as have bacteria associated with certain metabolic functions, such as digestion of starches.2,4 A 2016 genomic analysis found that a less diverse gut microbiome was strongly associated with frailty, and certain bacterial species increased in abundance while others decreased.7 Other research in older adults has also found frailty to be linked to a reduction in microbiome diversity.4,6 In older adults in long term care facilities, research has shown that butyrate-producing microbiota decreased and dysbiotic bacterial species associated with inflammation increased.2,5 These age-related microbiome changes may, in turn, reduce the ability of the older adult to mount an immune response to pathogens and inflammation.2,4 The Skin Microbiome Overall, Oh and her colleagues collected a total of 1,385 samples (1,072 skin, 159 oral, 154 stool) from 47 older adults. Data from these samples were then compared with matched samples from 95 healthy younger adults aged 18 to 55 years.3 The results were unexpected. “Surprisingly, we found that the greatest microbiome differences between the groups were associated with increased frailty, not chronological age,” Oh says. For example, frail older adults in the study had a significantly higher proportion of Clostridium species as well as changes in the proportions of these major bacterial phyla that have been associated with obesity and dietary differences. A second surprising finding, she adds, was that microbiome differences between the older and younger adults were most pronounced in the skin rather than the gut or mouth. In the oily areas of the skin, the younger adult group had substantial and consistent prevalence of Cutibacterium acnes, an important skin microbe that regulates a healthy skin environment. In contrast, C. acnes was depleted in both older adult study groups. And coagulase-negative Staphylococcus species and antibiotic-resistant bacterial strains, which are associated with greater infection risks, were increased in proportion in adults in the skilled nursing facility. The bacterial species diversity identified in the skin microbiome of frail older adults suggest aging-related changes in skin physiology that may be indicators of overall health.3 “The skin harbored the greatest number of potential risk factors for infectious disease. Thus, the skin [microbiome] could be a potential beacon for general declines in the health status of older adults,” Oh says. The presence of drug-resistant skin pathogens, such as those identified in this study, is associated with poor clinical outcomes as well as increased health care costs, adds study coauthor George A. Kuchel, MD, director of the UConn Center on Aging and UConn Pepper Center and chief of geriatric medicine at UConn Health. These study results led to the proposal of a new concept related to the skin microbiome and frailty in older adults. “We coined a new term—frailty-associated dysbiosis of the skin (FADS)—based on microbiome instability and divergence of microbial proportions between different areas on the body,” Oh explains. “The concept could inform future studies that seek to better understand how FADS and other factors can increase disease risk for older adults,” she adds. These findings need to be replicated by other studies, Kuchel says. “But they do highlight the importance of the biological underpinnings of frailty that may help guide future efforts to treat frailty,” he adds. Skin microbiome analysis is still in the research stages, though. “Whole genomic sequencing, as performed in our study, was able to diagnose important pathogens that would normally be missed as part of routine clinical care. Although costs remain high and this approach is not yet approved for clinical care, sequencing costs continue to decline, and if confirmed in other studies, it is possible that these diagnostic tools may be adapted clinically,” he says. Microbiome-Based Treatments It’s premature to make a link with treatments, Oh says. “We ultimately hope that the microbiome can either be used as a biomarker for overall health as well as a signal for problem host-microbiome interactions that could be pinpointed with a probiotic/prebiotic approach for remediation,” she says. Given the research focus on the microbiome and aging, treatments being considered for age-related conditions, including frailty, are targeting the gut microbiome. A 2022 review of more than 90 published studies8 by Mexican researchers evaluated the association of frailty with gut microbiota characteristics and scientific literature on the potential of probiotics and prebiotics to improve gut function in frail older adults. The review notes that probiotics include live microorganisms that provide health benefits when consumed as food or supplements. A prebiotic is a natural compound primarily derived from fruits or vegetables or a similar synthetic compound that’s an insoluble carbohydrate serving as an energy source for gut microbiota. The review authors note that published studies suggest that prebiotics, such as inulin, and probiotics containing Lactobacillus and Bifidobacterium species, may increase the variety and quantity of gut microbiota, thereby potentially improving nutrient absorption and malnutrition in older adults. They concluded, however, that there’s limited direct evidence reporting on the therapeutic effect of probiotics and prebiotics for frailty specifically.8 A 2023 review summarized the finding of recent studies of probiotic and prebiotic supplementation for frailty, as well as ongoing studies, including the following:6 • Supplementation with galacto-oligosaccharides increased Bifidobacterium species in older adults considered at risk of frailty in a small randomized trial. • Lactiplantibacillus plantarum supplementation improved hand grip strength and overall functional performance in a small study of frail older adults. • Fructo-oligosaccharides and inulin, in conjunction with protein supplementation, is under investigation to modulate the gut microbiota with the goal of improving muscle strength in frail sarcopenic older adults. • Probiotics with Bifidobacterium longum are being studied in an ongoing randomized trial in frail older adults to delay aging-related decline. • Probiotics with Lacticaseibacillus paracasei and Lactiplantibacillus plantarum are being investigated in preclinical studies to slow age-related muscle loss. Also under investigation to address frailty is fecal microbiota transplantation (FMT), the introduction of fecal microbiota from a healthy individual, usually via colonoscopy. FMT is approved to treat recurrent C. diff infection. It’s also under investigation as a treatment for inflammatory bowel diseases, obesity, type 2 diabetes, and neurological diseases. FMT acts as a “reset” for the gut microbiome by introducing a variety of species via the stool of healthy individuals. Interest in FMT for frailty has arisen because the treatment is well-tolerated and successful in very old frail patients with C. diff infection.9,10 FMT for aging-related diseases has been evaluated in animal studies. In a 2022 study of mice,11 FMT using stool from younger mice implanted into the intestines of older mice delayed aging-related declines in locomotor and exploration abilities. The researchers found aging changes related to changes in the gut microbiome of the mice. Specifically, Akkermansia bacteria in the gut microbiome appeared to be a microbial marker of aging in mice. The recent commercial introduction of oral FMT capsules is expected to facilitate studies of FMT for aging due to its ease of administration in comparison with colonoscopic methods. An early-stage clinical trial evaluating the effects of oral FMT capsules on aging, including frailty, has been registered (www.clinicaltrials.gov/ct2/show/NCT05598112). Initial results are not expected until late 2026, however. Advances in microbiome analysis will continue to fuel research into the effects of the human microbiome on aging and frailty. The timeframe for transition from research to clinical practice in geriatric medicine, however, is not yet known. — J.E. Whilldin is a medical research analyst and writer from the Reading, Pennsylvania, area. References 2. Haran JP, McCormick BA. Aging, frailty, and the microbiome—how dysbiosis influences human aging and disease. Gastroenterology. 2021;160(2):507-523. 3. Larson PJ, Zhou W, Santiago A, et al. Associations of the skin, oral and gut microbiome with aging, frailty and infection risk reservoirs in older adults. Nat Aging. 2022;2(10):941-955. 4. Piggott DA, Tuddenham S. The gut microbiome and frailty. Transl Res. 2020;221:23-43. 5. Ticinesi A, Nouvenne A, Cerundolo N, et al. Gut microbiota, muscle mass and function in aging: a focus on physical frailty and sarcopenia. Nutrients. 2019;11(7):1633. 6. D'Amico F, Barone M, Brigidi P, Turroni S. Gut microbiota in relation to frailty and clinical outcomes. Curr Opin Clin Nutr Metab Care. 2023;26(3):219-225. 7. Jackson MA, Jeffery IB, Beaumont M, et al. Signatures of early frailty in the gut microbiota. Genome Med. 2016;8(1):8. 8. Sánchez Y Sánchez de la Barquera B, Martínez Carrillo BE, Aguirre Garrido JF, et al. Emerging evidence on the use of probiotics and prebiotics to improve the gut microbiota of older adults with frailty syndrome: a narrative review. J Nutr Health Aging. 2022;26(10):926-935. 9. Nivet C, Duhalde V, Beaurain M, Delobel P, Quelven I, Alric L. Fecal microbiota transplantation for refractory Clostridioides difficile infection is effective and well tolerated even in very old subjects: a real-life study. J Nutr Health Aging. 2022;26(3):290-296. 10. Meng Y, Sun J, Zhang G. Fecal microbiota transplantation holds the secret to youth. Mech Ageing Dev. 2023;212:111823. 11. Zhang N, Zhang Y, Wang Z, et al. Regular fecal microbiota transplantation to Senescence Accelerated Mouse-Prone 8 (SAMP8) mice delayed the aging of locomotor and exploration ability by rejuvenating the gut microbiota. Front Aging Neurosci. 2022;14:991157. |
