Impact of Diet on the Gut-Muscle Axis in Older Adults

Study Overview
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Brief Summary
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Muscle health declines during aging. One factor that may impact muscle health is the community of bacteria that live in our intestines, but studies aimed at improving muscle health by targeting the gut in older adults are sparse. The primary goal of this study is to use a diet that is enriched in soluble fiber, which is exclusively utilized by gut bacteria to make substances that can impact muscle health, to improve muscle-related measures in older adults.

Detailed Description
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During aging, skeletal muscle mass and physical function decrease, whereas levels of lipids and adipocytes increase within and between muscle cells, thereby worsening muscle composition. As a result of these age-related changes, older adults are at a higher risk for frailty, falls and fracture, disability and hospitalization, and all-cause mortality. Accordingly, elucidation of mechanisms that underlie muscle mass, muscle composition, and physical function, and interventions that positively affect these variables will be important for addressing the public health priority of an improved quality of life and healthy aging in older adults. The gut microbiome and its metabolic products are involved in mechanisms that impact skeletal muscle mass, muscle composition, and physical function, which has been defined as the gut-muscle axis. For example, muscle mass and physical function are reduced in animals that do not have a microbiome (germ-free mice), and in antibiotic-treated mice, an intervention that reduces gut bacterial content. Investigating further, gut bacteria-derived metabolites affect muscle mass, muscle composition, and physical function in young and aged animals, including positive effects for the short-chain fatty acids (SCFAs) acetate, propionate, and butyrate, and negative effects for indoxyl sulfate (IS) and para-cresol sulfate (PCS). Similarly, phenol sulfate (PS) and phenylacetylglutamine (PAG) are gut microbiome-derived metabolites that were associated with poor muscle composition and worse physical function in studies of older adult humans that were published by our group. Interestingly, higher colonic levels of SCFAs are associated with a lower pH, an important finding because growth of Enterobacteriaceae, a bacterial family that contains genes involved in the production of IS, PCS, PS, and PAG, is limited in an acidic environment and following exposure to physiological levels of SCFAs. Taken together, these data suggest that interventions aimed at increasing bacterial SCFA production may be an important approach for improving muscle-related measures in older adults. Soluble fiber fermentation by gut bacteria results in the formation of acetate, propionate, and butyrate, and fecal SCFAs proportionally increase, whereas circulating levels of IS and PCS are reduced in response to high-soluble fiber diets. As a proof of concept, fecal and circulating levels of SCFAs, muscle mass, and aerobic exercise capacity were increased in young mice that were fed a relatively higher soluble fiber diet, but few studies have attempted this approach in older adult humans. When considering that fecal levels of SCFAs decrease during aging, whereas plasma levels of IS, PCS, PS, and PAG increase, these data collectively suggest that a high-soluble fiber diet may be an important approach for improving muscle-related measures in older adults humans. To test this hypothesis, older adults will be randomized to consume a high- or low-soluble fiber diet for 12-weeks.

Official Title
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Impact of a High-Soluble Fiber Diet on the Gut-Muscle Axis in Older Adults

Conditions
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Sarcopenia, Dietary Exposure, Microbial Colonization

Intervention / Treatment
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* Other: Low-soluble fiber diet
* Other: High-soluble fiber diet


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Independently living older adults (> 65y) Sedentary (Godin-Shepard Leisure Time Physical Activity Questionnaire score < 10) Non-smoking Not already consuming a high-fiber diet (> 22, 28 g/day for women, men) Free of gastrointestinal disease (gastrointestinal cancer, inflammatory bowel disease, bariatric surgery, irritable bowel syndrome) Fluent in English Willing to attend three study visits (enrollment, baseline, and week-13) Willing to consume an abundance of fruits, vegetables, nuts/seeds Willing to consume an abundance of soluble fiber-rich foods (broccoli, brussels sprouts, flaxseeds sweetened with dates, lima beans, butternut squash, carrots, collard greens) Willing to tolerate mild gastrointestinal discomfort (bloating, belly grumbling, flatulence). Note that all attempts will be made to replace foods that may trigger these issues. Willing to not consume antibiotics during the 13-week study Willing to not schedule a colonoscopy during the 13-week study Exclusion Criteria: Unwilling to visit the Tufts Human Nutrition Research Center on Aging (HNRCA) 3x/week to pick up the pre-prepared study diet Unwilling to only consume the provided food (unsweetened tea and/or black coffee are allowed) Food allergies related to foods that are included in the study Chewing problems Unwilling to wear a daily step counter (pedometer) Unwilling to complete a daily questionnaire that will assess gastrointestinal comfort Malnutrition (BMI < 18.5 kg/m2) Use of supplemental probiotics or antibiotics, participation in an investigational drug evaluation, or a recent change in habitual medication use within the 1 month-period prior to the screening visit > 5% weight loss or weight gain within the past 6-months A recent history of alcohol abuse (within the past 5 years) A history of any significant injury or surgery that currently affects physical functioning and ability to perform physical function testing Treatment with immunosuppressive drugs A prior diagnosis of organ failure (heart, liver, renal, respiratory) Diabetes mellitus (type 1, or type 2 with insulin therapy) Chronic kidney disease (eGFR ≤ 30 mL/min/1.73 m2) Overt disease (cancer, dementia, cardiovascular disease) Chronic use of anti-inflammatory medication (corticosteroids) Already enrolled in another research study Active infection, including Tuberculosis , HIV, malaria, hepatitis, shingles, Methicillin-Resistant Staphylococcus Aureus (MRSA), SARS-CoV-2 Any major illness or condition that may interfere with study outcomes at the discretion of the study physician Won't remain in Boston for the 13-week study duration Unwilling to complete a daily checklist aimed at quantifying the amount of food eaten on the study diet

Ages Eligible for Study
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Minimum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: 24 older adults (> 65y) will be randomized to consume a high- or low-soluble fiber diet
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Low-soluble fiber diet<br> | Other: Low-soluble fiber diet<br>* 12 older adults (>65y) will be randomized to consume the USDA Guidelines for fiber intake (10g of total fiber/1000 calories), as the low-soluble fiber diet<br>|
| Active Comparator: High-soluble fiber diet<br> | Other: High-soluble fiber diet<br>* 12 older adults (>65y) will be randomized to consume 34-35g of total fiber/1000 calories, as the high-soluble fiber diet<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Quantification of SCFAs in fecal samples | Fecal levels of bacterial metabolites, including acetate, propionate, and butyrate will be determined at the baseline and week-13 study visits | Change from baseline when compared with the Week-13 visit | 
| Quantification of whole-body lean mass with DXA | Measurement of whole-body lean mass will be determined at the baseline and week-13 study visits | Change from baseline when compared with the Week-13 visit | 
| Quantification of hand grip strength | Grip strength will be determined at the baseline and week-13 study visits | Change from baseline when compared with the Week-13 visit | 
| Chair stand test | The number of chair stands that can be performed in 30 seconds will be determined at the baseline and week-13 study visits | Change from baseline when compared with the Week-13 visit | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Quantification of thigh muscle composition with computed tomography | Determined at the baseline and week-13 study visits | Change from baseline when compared with the Week-13 visit | 
| 6-minute walk test | The distance walked in 6 minutes will be determined at the baseline and week-13 study visits | Change from baseline when compared with the Week-13 visit | 
| Quantification of gut bacterial metabolites in plasma | Bacterial metabolites, including SCFAs but also indoxyl sulfate, p-cresol sulfate, phenol sulfate, and phenylacetylglutamine will be determined at the baseline and week-13 study visits | Change from baseline when compared with the Week-13 visit | 
| Quantification of gut bacterial composition in fecal samples | Determined at the baseline and week-13 study visits | Change from baseline when compared with the Week-13 visit | 
| Quantification of pH in fecal samples | Determined at the baseline and week-13 study visits | Change from baseline when compared with the Week-13 visit | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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skeletal muscle, soluble fiber, gut-muscle axis, microbiome, SCFA, Uremic metabolites