Ignite Creation Date:
2024-10-25 @ 7:51 PM
Last Modification Date:
2024-10-26 @ 3:43 PM
Study NCT ID:
NCT06649981
Status:
NOT_YET_RECRUITING
Last Update Posted:
None
First Post:
2024-10-14
Brief Title:
Aging Resilience Through Microbiota Optimization and Regulation
Sponsor:
None
Organization:
None
Study Overview
Official Title:
Intestinal Microbiota Transplant As a Strategy to Enhance the Resilience Capacity of the Elderly Aiming to Retain Muscular Cognitive and Metabolic Functions in a Stressful Environment
Status:
NOT_YET_RECRUITING
Status Verified Date:
2024-10
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
No
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
ARMOR
Brief Summary:
Sarcopenia characterized by the progressive loss of muscle mass and strength in older adults is a key factor in health deterioration It affects 15 of people between 65 and 80 years old and over 50 of those over 80 compromising autonomy and increasing the risk of diseases Sarcopenia not only impacts muscle function but also bone health mobility and is associated with cardiometabolic diseases and cognitive decline
It has been proposed that changes in the gut microbiota in aging individuals known as gut dysbiosis contribute to sarcopenia Species diversity decreases and bacterial representation is altered which could impair muscle function through various pathways such as mitochondrial dysfunction chronic inflammation and disruption of protein synthesis Muscle function loss is strongly associated with cognitive and metabolic impairment in older adults
Recently it has been demonstrated that fecal microbiota transplantation FMT is an effective procedure for modulating gut microbiota and has proven highly effective in managing cases of Clostridium difficile-associated chronic diarrhea The main objective of this project is to carry out FMT from young physically active donors to a cohort of older adults to evaluate its effect on muscle cognitive and metabolic function
Why donors who exercise There is growing evidence that gut microbiota diversity is increased in young physically active individuals The FMT is planned to be administered through lyophilized microbiota capsules By restoring microbial diversity it is expected to improve the quality and function of skeletal muscles leading to greater cognitive and metabolic resilience
This project has great potential to develop an innovative approach for treating highly debilitating diseases that affect older adults based on the lyophilization and encapsulation of gut microbiota from young trained donors which can be easily stored in a conventional freezer Due to the high percentage of older adults worldwide and the high prevalence of sarcopenia within this age group the aim of the project is to address a significant public health issue with a large target population eager for options to promote muscle health functional autonomy as well as cognitive and metabolic well-being
It has been proposed that changes in the gut microbiota in aging individuals known as gut dysbiosis contribute to sarcopenia Species diversity decreases and bacterial representation is altered which could impair muscle function through various pathways such as mitochondrial dysfunction chronic inflammation and disruption of protein synthesis Muscle function loss is strongly associated with cognitive and metabolic impairment in older adults
Recently it has been demonstrated that fecal microbiota transplantation FMT is an effective procedure for modulating gut microbiota and has proven highly effective in managing cases of Clostridium difficile-associated chronic diarrhea The main objective of this project is to carry out FMT from young physically active donors to a cohort of older adults to evaluate its effect on muscle cognitive and metabolic function
Why donors who exercise There is growing evidence that gut microbiota diversity is increased in young physically active individuals The FMT is planned to be administered through lyophilized microbiota capsules By restoring microbial diversity it is expected to improve the quality and function of skeletal muscles leading to greater cognitive and metabolic resilience
This project has great potential to develop an innovative approach for treating highly debilitating diseases that affect older adults based on the lyophilization and encapsulation of gut microbiota from young trained donors which can be easily stored in a conventional freezer Due to the high percentage of older adults worldwide and the high prevalence of sarcopenia within this age group the aim of the project is to address a significant public health issue with a large target population eager for options to promote muscle health functional autonomy as well as cognitive and metabolic well-being
Detailed Description:
Skeletal muscle loss in old age is a critical point for the development of very serious health conditions affecting the quality of life of older adults such as loss of autonomy loss of healthy cognition and the development of complex metabolic diseases Additionally intestinal microbiota can be modulated through fecal microbiota transplantation FMT and possibly this modulation could have direct effects that promote muscle health Therefore this project aims to investigate whether modifying the intestinal microbiota in older adults through FMT using young and trained donors can enhance skeletal muscle health and function leading to greater resilience reducing cognitive decline and metabolic dysfunction associated with aging especially in stressful contexts
The donors would be young and trained individuals Why trained donors There is growing evidence that the composition of the intestinal microbiota is regulated by physical exercise In animal studies chronic exercise has been shown to increase the biodiversity of the intestinal microbiota and reduce systemic and intestinal inflammation The bacterial profile associated with exercise is specific for example it does not correspond to that associated with a healthy diet suggesting that physical activity allows for the development of a specific microbial profile in intestinal bacterial communities Several studies have observed that changes in the intestinal microbiota associated with exercise are beneficial for promoting intestinal mucosal integrity and overall metabolic function in the individual
In humans intestinal bacterial biodiversity has been observed to be higher in athletes compared to sedentary subjects normalized by body weight age and gender In fact there is evidence that a chronic exercise routine can restore the intestinal microbiota to a healthy profile in individuals with intestinal dysbiosis In rats and mice chronic exercise increases the biodiversity of Firmicutes Bifidobacteria and Actinobacteria and reduces the proportion of Bacteroides Some data show how the presence of intestinal microbiota affects muscle performance for example it was found that germ-free mice had greater swimming endurance compared to germ-free mice and when the latter were colonized with bacteria in the gut the mice increased their physical endurance and swam for longer
The main objective of this project is to carry out fecal microbiota transplants FMT from physically active young donors to a cohort of older individuals to evaluate their effect on muscle cognitive and metabolic function FMT in older adults is planned to be performed by administering lyophilized microbiota capsules By restoring microbial diversity it is expected to improve the quality and function of skeletal muscles leading to greater cognitive and metabolic resilience It is important to mention that modifications of the intestinal microbiota have been associated with direct and specific effects on brain and metabolic functions so the FMT from young and trained donors proposed in this project could have This project has great potential to develop an innovative approach to treating highly debilitating diseases affecting older adults based on the lyophilization and encapsulation of intestinal microbiota from young and trained donors which can be easily preserved in a conventional freezer This approach has been previously implemented for the treatment of C difficile infection with outstanding results This idea will have a profound impact on the quality of life of adult and elderly patients as it can be an alternative or complementary option to physical exercise therapy that older adults must undergo to prevent or treat sarcopenia but often cannot be adequately achieved due to physical limitations associated with old age Due to the high percentage of older adults worldwide and the high prevalence of sarcopenia among older adults the researchers aim to address a significant public health issue with a large target population eager for options to promote muscle health functional autonomy as well as cognitive and metabolic well-being
RESEARCH QUESTION The hypothesis is as follows Intestinal microbiota transplantation from young trained donors promotes resilience through the enhancement of muscle function thereby preserving cognitive and metabolic performance in older individuals exposed to stressful situations
GENERAL AND SPECIFIC OBJECTIVES General Objective To demonstrate that fecal microbiota transplantation from young and physically trained donors promotes muscle performance preventing cognitive and metabolic decline in older individuals in a stressful context
Specific Objectives To evaluate the effect of fecal microbiota transplantation FMT from trained young donors on the muscular health of aged individuals correlating the results with the degree of stress exposure of the elderly recipients of FMT
To assess the effect of fecal microbiota transplantation FMT from trained young donors on cognitive parameters of elderly recipients correlating the results with individuals stress levels and modifications of muscle function after FMT
To evaluate the effect of fecal microbiota transplantation FMT from trained young donors on metabolic parameters of elderly recipients correlating the results with individiduals stress levels and modifications of muscle function after FMT
In these objectives researchers aim to investigate whether FMT from trained young donors can improve muscle function in older individuals with beneficial consequences on cognitive and metabolic functions correlating the results with the degree of stress exposure of the participants
EXPERIMENTAL DESIGN The research is structured as a randomized placebo-controlled double-blind clinical trial Researchers will work with a group of 92 elderly individuals aged 65-84 years both women and men All the characteristics mentioned in the experimental design in addition to the fact that through its implementation researchers aim to answer the question Does the treatment FMT in this case generate a benefit in this project a muscular cognitive or metabolic benefit in the context of a condition or disease aging and stressful environment and also to evaluate the safety of the intervention classify this research as a Phase II clinical study Participants will be recruited at Clínica Universidad de los Andes or the Institute of Nutrition and Food Technology INTA of the Universidad de Chile after signing an informed consent document FMT will be administered using capsules of lyophilized fecal microbiota manufactured at the Center for Biomedical Research and Innovation CIIB of the Universidad de los Andes
Fecal Microbiota Donors The donors will be young individuals aged 20 to 35 years 2 males and 2 females physically active who engage in at least 150 minutes of high-intensity aerobic physical activity per week as this type of training improves the diversity and production of short-chain fatty acids SCFAs of the human intestinal microbiota The Global Physical Activity Questionnaire GPAQ and actigraphs will be used to measure physical activity in donors 2 weeks before stool donation For donor selection individuals will be considered to have reached a metabolic equivalent MET of 600 minutes or more per week
Donors will meet all criteria for donating fecal microbiota criteria already established for FMT treatment in patients with CDAD
During the initial stage of the selection process the medical history and risk behavior of potential donors will be assessed using a specialized questionnaire The questionnaire will be administered by a medical professional Objective evaluation includes the consequences of a specific response for the selection process The topics and elements to be addressed in this questionnaire are listed in Table 1
TABLE 1 Elements to Evaluate During Donor Selection Prior to Approval for Fecal Microbiota Transplantation FMT
Infectious Diseases
History of or exposure to infectious diseases with chronic activity HIV hepatitis B virus HBV hepatitis C virus HCV unsuccessfully eradicated Helicobacter pylori syphilis malaria trypanosomiasis tuberculosis Chagas disease strongyloidiasis
Any currently active or relevant infection within the last 6 months
Live attenuated virus vaccination within the last 8 weeks Country of birth Risk Behaviors
Current or previous intravenous drug use
High-risk sexual behavior within the last 6 months
Travel to high-risk foreign countries within the last 6 months
Current occupation in an environment facilitating the acquisition of potential pathogens eg veterinarian animal caretaker ranger prison worker
Tattooing piercing or acupuncture within the last 6 months
Major surgery within the last 6 months
Contact with human blood eg accident needle stick injury within the last 6 months
History of incarceration
Prior tissueorgan transplant
Blood product transfusion eg packed red blood cells plasma platelets immunoglobulins within the last 6 months of medical history
Medical History
Chronic diseases
Risk of Creutzfeldt-Jakob disease
Allergies or atopy eg food or drug allergies asthma
Hospitalization within the last 4 months
Ongoing pregnancy
Antibiotic treatments scheduled or received within the last 3 months
Regular medications or nutritional supplements
BMI accepted if 20 and 25 kgm2
Age accepted if 18 and 30 years
Intestinal Health
Previous or scheduled gastrointestinal surgery except for appendectomy
Gastrointestinal symptoms in the last 3 months eg diarrhea constipation hematochezia vomiting abdominal pain or adenomatous polyps or sessile serrated lesions removed
Any other relevant clinical sign or symptom in the last 3 months eg fever or rash
In addition to all the infectious agents described in Table 2 SARS-CoV-2 will also be ruled out through RT-PCR in the stool The presence of E coli ST131 will be studied through classical culture and PCR typing as well as the presence of antibiotic resistance genes If positive results are obtained for these markers the individual cannot be a donor For each dose of FMT a minimum of 150 grams of stool will be used transported to the laboratory under the most anaerobic conditions possible GutAlive system httpswwwmicroviablecomengutalive-2 and in the shortest time possible from collection Stool is a complex sample due to its variable water content and the only way to standardize the dose is by the weight of the stool as the amount of final powder can vary greatly Therefore the number of resulting capsules may vary widely However the microbial load will be equivalent as long as same logarithmic order is maintained Stool will be lyophilized by mixing it with semi-skimmed lactose-free milk at a ratio of 12 as a cryoprotectant The mixture will be homogenized in a Stomacher 230 rpm solid residues will be removed by gentle centrifugation 500 rpm 5 min and then all microorganisms will be collected by centrifugation 10000 rpm 15 min The supernatant will be removed and the pellet will be frozen at -80C for at least 1 hour after which it will be lyophilized at -50C for 18-20 hours The obtained powder will be encapsulated in enteric-coated capsules in batches that will be stored in the absence of moisture at 4C with a shelf life of 6 months An aliquot of all processes will be stored at -80C and sample and donor traceability will be carried out with RedCap software
Elderly Participants Number of participants 92 Ethnicity Chilean population Chile has a population with homogeneous ethnicity with indigenous 40 and European 60 ancestries
Age 65-84 years Biological sex 46 males and 46 females
Studys recruitment randomization intervention and follow-up process organized in the following steps
Recruitment Participants are recruited and undergo an eligibility evaluation They are assessed to determine if they meet the inclusion criteria and do not meet the exclusion criteria
Informed Consent Eligible participants who meet the study criteria provide their informed consent to participate
Pre-intervention Evaluations Before the intervention participants are assessed to classify them based on their levels of stress and anxiety
Randomization A total of 92 participants are randomized into four groups
Low stress level - Placebo group n23 Low stress level - IMT group n23 Mediumhigh stress level - Placebo group n23 Mediumhigh stress level - IMT group n23
Intervention Participants in the four groups undergo the assigned intervention
The first group receives a placebo with low stress level classification The second group receives IMT Intervention of Interest with low stress level classification
The third group receives a placebo with mediumhigh stress level classification
The fourth group receives IMT with mediumhigh stress level classification
Follow-up Follow-up evaluations are conducted at weeks 1 4 8 and 20 post-intervention for all groups to assess the outcomes of the interventions
This research is structured as a randomized placebo-controlled double-blind clinical trial This structure allows the study to compare the effects of the intervention IMT versus a placebo across different stress level classifications
Pre-Intervention Assessments
The 14-item Perceived Stress Scale PSS-14 will be used to assess the level of stress in participants Depressive symptoms will be evaluated using the 15-item Geriatric Depression Scale GDS which assesses mood disorder symptoms commonly associated with depression experienced in older adults both documents attached Anxiety symptoms will be measured using the Beck Anxiety Inventory BAI which is designed to obtain a measure of anxiety that is relatively independent of depression attached These instruments have high reliability and validity in community samples allowing us to classify the volunteers into low stress-anxiety and mediumhigh stress-anxiety groups
To favor the establishment of the new ecosystem the intestinal microbiota density of the participants will be reduced before the FMT with rifaximin a suitable non-absorbable antibiotic for intestinal decontamination for 3 days 1200 mgday administered in 2 daily doses The antibiotic and its administration schedule will be provided to the participants
The FMT will be conducted in the Clinical Trials Unit of the Universidad de los Andes Clinic by administering 4 capsules containing a compact lyophilized preparation prepared from approximately 150 grams of feces Control subjects will receive placebo capsules with identical appearance to the capsules containing the intestinal microbiota lyophilized material Free transportation will be provided to the participants between their homes and the Universidad de los Andes Clinic
Researchers will conduct this study using only non-invasive tests and analyses All proposed assessments to measure muscle cognitive and metabolic functions will be carried out before and after the FMT from 1 to 20 weeks after the FMT These assessments will be conducted at the Ambulatory Care Health Center of the National Institute of Agricultural Technology CEDINTA Free transportation will be provided to the participants between their homes and the CEDINTA All participants will undergo medical history before and after the intervention to obtain information about overall health status medication use antibiotics and dietary supplements history of intestinal diseases and any other intestinal disorder that may alter the intestinal microbiota
Researchers will calculate the Frailty Index FI in participants from all groups before and after the FMT The FI will be assessed using a combined method of clinical and laboratory parameters Firstly researchers will use a self-reported FI created with 30 variables to assess health status Variables comprise different types of health problems including diseases n9 symptoms n6 disabilities for living n6 psychological problems n2 Romberg test physical performance Geriatric Depression Scale GDS score and Mini-Mental State Examination MMSE score For binary variables the presence of an impairment will be coded as 1 and its absence as 0 For each three-level variable 05 will be used to represent an intermediate response level For the MMSE it will be coded as 0 if 23 05 if MMSE15-23 and 1 if MMSE14 while GDS will be recoded as 0 if GDS11 and 1 if GDS11 Secondly a laboratory-based FI FI-lab will identify 15 parameters based on 9 laboratory tests in addition to pulse systolic and diastolic blood pressure pulse pressure BMI and waist circumference A normal reference range will be used to compare each parameter where 0 indicates values within the normal range and 1 indicates values outside the reference range Finally researchers will combine the two FIs to construct a 45-item FI FI-combined Each FI-combined will be defined as the score of each parameter of an individual divided by the total number of parameters considered with the FI ranging from a theoretical minimum of 0 no impaired parameters present to a maximum possible of 10 all impaired parameters present
For the assessment of muscle sarcopenia researchers will measure lean and fat mass using dual-energy X-ray absorptiometry DEXA and creatinine excretion A standard dynamometer will be used to measure isometric strength Additionally the Short Physical Performance Battery and the 6-minute walk test will be applied to estimate maximum oxygen consumption Physical activity will be evaluated using an actigraph for 7 days Researchers will measure the thickness of the rectus femoris muscle and the muscle pennation angle in the participants thighs using ultrasound As biomarkers for sarcopenia creatine kinase CK skeletal muscle troponin T sTnT insulin-like growth factor-1 IGF-1 C-reactive protein vitamin D TNF-α IL-6 IL-1β will be measured in blood
For cognitive performance participants will be assessed on a set of higher cognitive abilities such as attention executive functions working memory language and processing speed among others before and after the FMT intervention The Montreal Cognitive Assessment MoCA Trail Making Test A and B Digit Span Forward and Backward Frontal Assessment Battery FAB and Verbal Fluency FAS will be administered attachments Participants quality of life will be assessed using the SF-36 questionnaire one of the most commonly used and evaluated instruments for Health-Related Quality of Life HRQoL
For metabolic function a comprehensive analysis of metabolic markers in blood such as insulin glucose total cholesterol LDL-cholesterol HDL-cholesterol triglycerides and transaminases ALT AST gGT will be performed in fasting conditions Researchers will study the presence of non-alcoholic fatty liver disease NAFLD using ultrasound imaging Additionally concentrations of metalloproteinases-9 and IL-6 in serum will be measured by ELISA as these markers have been proposed to be correlated with the severity of NAFLD in humans Non-invasive scores of hepatic fibrosis will also be applied
With the bacterial genomic DNA isolated from the fecal samples of the participants researchers will study the microbiota profile using shotgun metagenomics or 16S gene sequencing Samples will be collected from both young donors and older recipients before and after the FMT Using bioinformatics tools researchers will identify a bacterial signature in older adults who received FMT from trained young donors Researchers will determine if this microbiome signature correlates with muscular cognitive and metabolic resilience especially in the group experiencing higher stress Researchers propose that key elements in this modified intestinal microbiota in older adults will serve as appropriate biomarkers for muscular cognitive and metabolic resilience in the context of aging
SAFETY IMT performed by qualified personnel has not been associated with any serious adverse events but mild or common adverse reactions may occur Marcella et al 2021 analyzed the presence of adverse reactions to IMT in a systematic review evaluating 129 studies involving 4241 patients They found that the most common adverse effects were transient diarrhea 10 transient abdominal crampsdiscomfort 7 nausea and vomiting 5 within 24 hours post-IMT Transient fever abdominal distension fatigue and borborygmi have also been reported in less than 2 of cases Constipation 2 and excess flatulence 3 were reported during follow-up
Severe adverse reactions such as bacteremia and death as a direct consequence of IMT are extremely rare incidence 01 and occurred only in patients with diseases causing damage to the digestive mucosa These diseases inflammatory bowel disease Crohns disease Clostridium difficile infection CDI and ulcerative colitis are exclusion criteria for this study Another study in 2022 evaluated the safety associated with the use of IMT in 5344 patients affected by CDI The researchers found that overall the safety profile was favorable in a medically complex patient population that usually has poor clinical outcomes Among the cohort 194 patients 36 experienced one or more serious adverse reactions SARs SARs were more common among patients with severe or severe-complicated CDI n 94 485 Among the SARs six events 01 were possibly related to IMT all in patients who were severely immunocompromised This included two patients with fever as well as one with abdominal pain in a patient with severe-complicated CDI and breast cancer Additionally two patients developed systemic inflammatory response syndrome-one after a heart transplant and one after a kidney transplant There was one reported case of an inflammatory bowel disease IBD flare-up in a patient with a history of ulcerative colitis not controlled with biological therapy and immunomodulators None of the reported SARs were definitively related to IMT Notably no cases of sepsis or transmission of infectious diseases related to IMT including infections with multi-drug-resistant organisms were reported This study will not include patients with CDI or those who are severely immunocompromised
Finally another systematic review and meta-analysis in 2022 searched for IMT studies in patients with CDI using the rate of SARs related to IMT as the primary outcome Secondary outcomes included SARs unrelated to IMT and minor adverse events associated with IMT The combined analysis of 5099 patients who received 5551 IMTs showed that SARs related to IMT developed in less than 1 of patients The combined rate of SARs unrelated to IMT was higher reaching 29 The combined rate of minor adverse events also showed infrequent self-limited gastrointestinal and systemic discomfort This meta-analysis supports IMT as a safe option for treating recurrent CDI
For IMT performed exclusively in the elderly population a study of 31 patients with an average age of 77 years with CDI reported that 87 of patients resolved their infection and the most common adverse event reported in 4 13 of 31 respondents was the subjective worsening of arthritis Another study that performed IMT on 35 elderly patients average age 77 years with CDI reported no serious adverse effects
In summary the international experience using IMT reported in the literature shows the high safety of this procedure However the following risks should be considered 1 Infection Although IMT has been screened for pathogenic bacteria viruses fungi and parasites there is a risk of transmitting known and unknown infectious organisms contained in the donors stool There is also a theoretical risk of bacterial overgrowth in the small intestine Rarely bacteremia eg E coli Klebsiella sepsis and fatal events can occur after IMT 2 Exacerbation of inflammatory bowel disease IBD in individuals with underlying IBD 3 Allergyanaphylaxis to antigens present in the donors stool 4 Transmission of non-infectious diseases There is a theoretical risk of developing diseases that may be related to the donors gut microbiota These include obesity metabolic syndrome cardiovascular diseases autoimmune conditions allergicatopic disorders neurological disorders psychiatric conditions and malignancies This risk is very limited in the study as individuals with these known conditions are excluded from stool donation according to the donor screening procedures explained in this protocol
The donors would be young and trained individuals Why trained donors There is growing evidence that the composition of the intestinal microbiota is regulated by physical exercise In animal studies chronic exercise has been shown to increase the biodiversity of the intestinal microbiota and reduce systemic and intestinal inflammation The bacterial profile associated with exercise is specific for example it does not correspond to that associated with a healthy diet suggesting that physical activity allows for the development of a specific microbial profile in intestinal bacterial communities Several studies have observed that changes in the intestinal microbiota associated with exercise are beneficial for promoting intestinal mucosal integrity and overall metabolic function in the individual
In humans intestinal bacterial biodiversity has been observed to be higher in athletes compared to sedentary subjects normalized by body weight age and gender In fact there is evidence that a chronic exercise routine can restore the intestinal microbiota to a healthy profile in individuals with intestinal dysbiosis In rats and mice chronic exercise increases the biodiversity of Firmicutes Bifidobacteria and Actinobacteria and reduces the proportion of Bacteroides Some data show how the presence of intestinal microbiota affects muscle performance for example it was found that germ-free mice had greater swimming endurance compared to germ-free mice and when the latter were colonized with bacteria in the gut the mice increased their physical endurance and swam for longer
The main objective of this project is to carry out fecal microbiota transplants FMT from physically active young donors to a cohort of older individuals to evaluate their effect on muscle cognitive and metabolic function FMT in older adults is planned to be performed by administering lyophilized microbiota capsules By restoring microbial diversity it is expected to improve the quality and function of skeletal muscles leading to greater cognitive and metabolic resilience It is important to mention that modifications of the intestinal microbiota have been associated with direct and specific effects on brain and metabolic functions so the FMT from young and trained donors proposed in this project could have This project has great potential to develop an innovative approach to treating highly debilitating diseases affecting older adults based on the lyophilization and encapsulation of intestinal microbiota from young and trained donors which can be easily preserved in a conventional freezer This approach has been previously implemented for the treatment of C difficile infection with outstanding results This idea will have a profound impact on the quality of life of adult and elderly patients as it can be an alternative or complementary option to physical exercise therapy that older adults must undergo to prevent or treat sarcopenia but often cannot be adequately achieved due to physical limitations associated with old age Due to the high percentage of older adults worldwide and the high prevalence of sarcopenia among older adults the researchers aim to address a significant public health issue with a large target population eager for options to promote muscle health functional autonomy as well as cognitive and metabolic well-being
RESEARCH QUESTION The hypothesis is as follows Intestinal microbiota transplantation from young trained donors promotes resilience through the enhancement of muscle function thereby preserving cognitive and metabolic performance in older individuals exposed to stressful situations
GENERAL AND SPECIFIC OBJECTIVES General Objective To demonstrate that fecal microbiota transplantation from young and physically trained donors promotes muscle performance preventing cognitive and metabolic decline in older individuals in a stressful context
Specific Objectives To evaluate the effect of fecal microbiota transplantation FMT from trained young donors on the muscular health of aged individuals correlating the results with the degree of stress exposure of the elderly recipients of FMT
To assess the effect of fecal microbiota transplantation FMT from trained young donors on cognitive parameters of elderly recipients correlating the results with individuals stress levels and modifications of muscle function after FMT
To evaluate the effect of fecal microbiota transplantation FMT from trained young donors on metabolic parameters of elderly recipients correlating the results with individiduals stress levels and modifications of muscle function after FMT
In these objectives researchers aim to investigate whether FMT from trained young donors can improve muscle function in older individuals with beneficial consequences on cognitive and metabolic functions correlating the results with the degree of stress exposure of the participants
EXPERIMENTAL DESIGN The research is structured as a randomized placebo-controlled double-blind clinical trial Researchers will work with a group of 92 elderly individuals aged 65-84 years both women and men All the characteristics mentioned in the experimental design in addition to the fact that through its implementation researchers aim to answer the question Does the treatment FMT in this case generate a benefit in this project a muscular cognitive or metabolic benefit in the context of a condition or disease aging and stressful environment and also to evaluate the safety of the intervention classify this research as a Phase II clinical study Participants will be recruited at Clínica Universidad de los Andes or the Institute of Nutrition and Food Technology INTA of the Universidad de Chile after signing an informed consent document FMT will be administered using capsules of lyophilized fecal microbiota manufactured at the Center for Biomedical Research and Innovation CIIB of the Universidad de los Andes
Fecal Microbiota Donors The donors will be young individuals aged 20 to 35 years 2 males and 2 females physically active who engage in at least 150 minutes of high-intensity aerobic physical activity per week as this type of training improves the diversity and production of short-chain fatty acids SCFAs of the human intestinal microbiota The Global Physical Activity Questionnaire GPAQ and actigraphs will be used to measure physical activity in donors 2 weeks before stool donation For donor selection individuals will be considered to have reached a metabolic equivalent MET of 600 minutes or more per week
Donors will meet all criteria for donating fecal microbiota criteria already established for FMT treatment in patients with CDAD
During the initial stage of the selection process the medical history and risk behavior of potential donors will be assessed using a specialized questionnaire The questionnaire will be administered by a medical professional Objective evaluation includes the consequences of a specific response for the selection process The topics and elements to be addressed in this questionnaire are listed in Table 1
TABLE 1 Elements to Evaluate During Donor Selection Prior to Approval for Fecal Microbiota Transplantation FMT
Infectious Diseases
History of or exposure to infectious diseases with chronic activity HIV hepatitis B virus HBV hepatitis C virus HCV unsuccessfully eradicated Helicobacter pylori syphilis malaria trypanosomiasis tuberculosis Chagas disease strongyloidiasis
Any currently active or relevant infection within the last 6 months
Live attenuated virus vaccination within the last 8 weeks Country of birth Risk Behaviors
Current or previous intravenous drug use
High-risk sexual behavior within the last 6 months
Travel to high-risk foreign countries within the last 6 months
Current occupation in an environment facilitating the acquisition of potential pathogens eg veterinarian animal caretaker ranger prison worker
Tattooing piercing or acupuncture within the last 6 months
Major surgery within the last 6 months
Contact with human blood eg accident needle stick injury within the last 6 months
History of incarceration
Prior tissueorgan transplant
Blood product transfusion eg packed red blood cells plasma platelets immunoglobulins within the last 6 months of medical history
Medical History
Chronic diseases
Risk of Creutzfeldt-Jakob disease
Allergies or atopy eg food or drug allergies asthma
Hospitalization within the last 4 months
Ongoing pregnancy
Antibiotic treatments scheduled or received within the last 3 months
Regular medications or nutritional supplements
BMI accepted if 20 and 25 kgm2
Age accepted if 18 and 30 years
Intestinal Health
Previous or scheduled gastrointestinal surgery except for appendectomy
Gastrointestinal symptoms in the last 3 months eg diarrhea constipation hematochezia vomiting abdominal pain or adenomatous polyps or sessile serrated lesions removed
Any other relevant clinical sign or symptom in the last 3 months eg fever or rash
In addition to all the infectious agents described in Table 2 SARS-CoV-2 will also be ruled out through RT-PCR in the stool The presence of E coli ST131 will be studied through classical culture and PCR typing as well as the presence of antibiotic resistance genes If positive results are obtained for these markers the individual cannot be a donor For each dose of FMT a minimum of 150 grams of stool will be used transported to the laboratory under the most anaerobic conditions possible GutAlive system httpswwwmicroviablecomengutalive-2 and in the shortest time possible from collection Stool is a complex sample due to its variable water content and the only way to standardize the dose is by the weight of the stool as the amount of final powder can vary greatly Therefore the number of resulting capsules may vary widely However the microbial load will be equivalent as long as same logarithmic order is maintained Stool will be lyophilized by mixing it with semi-skimmed lactose-free milk at a ratio of 12 as a cryoprotectant The mixture will be homogenized in a Stomacher 230 rpm solid residues will be removed by gentle centrifugation 500 rpm 5 min and then all microorganisms will be collected by centrifugation 10000 rpm 15 min The supernatant will be removed and the pellet will be frozen at -80C for at least 1 hour after which it will be lyophilized at -50C for 18-20 hours The obtained powder will be encapsulated in enteric-coated capsules in batches that will be stored in the absence of moisture at 4C with a shelf life of 6 months An aliquot of all processes will be stored at -80C and sample and donor traceability will be carried out with RedCap software
Elderly Participants Number of participants 92 Ethnicity Chilean population Chile has a population with homogeneous ethnicity with indigenous 40 and European 60 ancestries
Age 65-84 years Biological sex 46 males and 46 females
Studys recruitment randomization intervention and follow-up process organized in the following steps
Recruitment Participants are recruited and undergo an eligibility evaluation They are assessed to determine if they meet the inclusion criteria and do not meet the exclusion criteria
Informed Consent Eligible participants who meet the study criteria provide their informed consent to participate
Pre-intervention Evaluations Before the intervention participants are assessed to classify them based on their levels of stress and anxiety
Randomization A total of 92 participants are randomized into four groups
Low stress level - Placebo group n23 Low stress level - IMT group n23 Mediumhigh stress level - Placebo group n23 Mediumhigh stress level - IMT group n23
Intervention Participants in the four groups undergo the assigned intervention
The first group receives a placebo with low stress level classification The second group receives IMT Intervention of Interest with low stress level classification
The third group receives a placebo with mediumhigh stress level classification
The fourth group receives IMT with mediumhigh stress level classification
Follow-up Follow-up evaluations are conducted at weeks 1 4 8 and 20 post-intervention for all groups to assess the outcomes of the interventions
This research is structured as a randomized placebo-controlled double-blind clinical trial This structure allows the study to compare the effects of the intervention IMT versus a placebo across different stress level classifications
Pre-Intervention Assessments
The 14-item Perceived Stress Scale PSS-14 will be used to assess the level of stress in participants Depressive symptoms will be evaluated using the 15-item Geriatric Depression Scale GDS which assesses mood disorder symptoms commonly associated with depression experienced in older adults both documents attached Anxiety symptoms will be measured using the Beck Anxiety Inventory BAI which is designed to obtain a measure of anxiety that is relatively independent of depression attached These instruments have high reliability and validity in community samples allowing us to classify the volunteers into low stress-anxiety and mediumhigh stress-anxiety groups
To favor the establishment of the new ecosystem the intestinal microbiota density of the participants will be reduced before the FMT with rifaximin a suitable non-absorbable antibiotic for intestinal decontamination for 3 days 1200 mgday administered in 2 daily doses The antibiotic and its administration schedule will be provided to the participants
The FMT will be conducted in the Clinical Trials Unit of the Universidad de los Andes Clinic by administering 4 capsules containing a compact lyophilized preparation prepared from approximately 150 grams of feces Control subjects will receive placebo capsules with identical appearance to the capsules containing the intestinal microbiota lyophilized material Free transportation will be provided to the participants between their homes and the Universidad de los Andes Clinic
Researchers will conduct this study using only non-invasive tests and analyses All proposed assessments to measure muscle cognitive and metabolic functions will be carried out before and after the FMT from 1 to 20 weeks after the FMT These assessments will be conducted at the Ambulatory Care Health Center of the National Institute of Agricultural Technology CEDINTA Free transportation will be provided to the participants between their homes and the CEDINTA All participants will undergo medical history before and after the intervention to obtain information about overall health status medication use antibiotics and dietary supplements history of intestinal diseases and any other intestinal disorder that may alter the intestinal microbiota
Researchers will calculate the Frailty Index FI in participants from all groups before and after the FMT The FI will be assessed using a combined method of clinical and laboratory parameters Firstly researchers will use a self-reported FI created with 30 variables to assess health status Variables comprise different types of health problems including diseases n9 symptoms n6 disabilities for living n6 psychological problems n2 Romberg test physical performance Geriatric Depression Scale GDS score and Mini-Mental State Examination MMSE score For binary variables the presence of an impairment will be coded as 1 and its absence as 0 For each three-level variable 05 will be used to represent an intermediate response level For the MMSE it will be coded as 0 if 23 05 if MMSE15-23 and 1 if MMSE14 while GDS will be recoded as 0 if GDS11 and 1 if GDS11 Secondly a laboratory-based FI FI-lab will identify 15 parameters based on 9 laboratory tests in addition to pulse systolic and diastolic blood pressure pulse pressure BMI and waist circumference A normal reference range will be used to compare each parameter where 0 indicates values within the normal range and 1 indicates values outside the reference range Finally researchers will combine the two FIs to construct a 45-item FI FI-combined Each FI-combined will be defined as the score of each parameter of an individual divided by the total number of parameters considered with the FI ranging from a theoretical minimum of 0 no impaired parameters present to a maximum possible of 10 all impaired parameters present
For the assessment of muscle sarcopenia researchers will measure lean and fat mass using dual-energy X-ray absorptiometry DEXA and creatinine excretion A standard dynamometer will be used to measure isometric strength Additionally the Short Physical Performance Battery and the 6-minute walk test will be applied to estimate maximum oxygen consumption Physical activity will be evaluated using an actigraph for 7 days Researchers will measure the thickness of the rectus femoris muscle and the muscle pennation angle in the participants thighs using ultrasound As biomarkers for sarcopenia creatine kinase CK skeletal muscle troponin T sTnT insulin-like growth factor-1 IGF-1 C-reactive protein vitamin D TNF-α IL-6 IL-1β will be measured in blood
For cognitive performance participants will be assessed on a set of higher cognitive abilities such as attention executive functions working memory language and processing speed among others before and after the FMT intervention The Montreal Cognitive Assessment MoCA Trail Making Test A and B Digit Span Forward and Backward Frontal Assessment Battery FAB and Verbal Fluency FAS will be administered attachments Participants quality of life will be assessed using the SF-36 questionnaire one of the most commonly used and evaluated instruments for Health-Related Quality of Life HRQoL
For metabolic function a comprehensive analysis of metabolic markers in blood such as insulin glucose total cholesterol LDL-cholesterol HDL-cholesterol triglycerides and transaminases ALT AST gGT will be performed in fasting conditions Researchers will study the presence of non-alcoholic fatty liver disease NAFLD using ultrasound imaging Additionally concentrations of metalloproteinases-9 and IL-6 in serum will be measured by ELISA as these markers have been proposed to be correlated with the severity of NAFLD in humans Non-invasive scores of hepatic fibrosis will also be applied
With the bacterial genomic DNA isolated from the fecal samples of the participants researchers will study the microbiota profile using shotgun metagenomics or 16S gene sequencing Samples will be collected from both young donors and older recipients before and after the FMT Using bioinformatics tools researchers will identify a bacterial signature in older adults who received FMT from trained young donors Researchers will determine if this microbiome signature correlates with muscular cognitive and metabolic resilience especially in the group experiencing higher stress Researchers propose that key elements in this modified intestinal microbiota in older adults will serve as appropriate biomarkers for muscular cognitive and metabolic resilience in the context of aging
SAFETY IMT performed by qualified personnel has not been associated with any serious adverse events but mild or common adverse reactions may occur Marcella et al 2021 analyzed the presence of adverse reactions to IMT in a systematic review evaluating 129 studies involving 4241 patients They found that the most common adverse effects were transient diarrhea 10 transient abdominal crampsdiscomfort 7 nausea and vomiting 5 within 24 hours post-IMT Transient fever abdominal distension fatigue and borborygmi have also been reported in less than 2 of cases Constipation 2 and excess flatulence 3 were reported during follow-up
Severe adverse reactions such as bacteremia and death as a direct consequence of IMT are extremely rare incidence 01 and occurred only in patients with diseases causing damage to the digestive mucosa These diseases inflammatory bowel disease Crohns disease Clostridium difficile infection CDI and ulcerative colitis are exclusion criteria for this study Another study in 2022 evaluated the safety associated with the use of IMT in 5344 patients affected by CDI The researchers found that overall the safety profile was favorable in a medically complex patient population that usually has poor clinical outcomes Among the cohort 194 patients 36 experienced one or more serious adverse reactions SARs SARs were more common among patients with severe or severe-complicated CDI n 94 485 Among the SARs six events 01 were possibly related to IMT all in patients who were severely immunocompromised This included two patients with fever as well as one with abdominal pain in a patient with severe-complicated CDI and breast cancer Additionally two patients developed systemic inflammatory response syndrome-one after a heart transplant and one after a kidney transplant There was one reported case of an inflammatory bowel disease IBD flare-up in a patient with a history of ulcerative colitis not controlled with biological therapy and immunomodulators None of the reported SARs were definitively related to IMT Notably no cases of sepsis or transmission of infectious diseases related to IMT including infections with multi-drug-resistant organisms were reported This study will not include patients with CDI or those who are severely immunocompromised
Finally another systematic review and meta-analysis in 2022 searched for IMT studies in patients with CDI using the rate of SARs related to IMT as the primary outcome Secondary outcomes included SARs unrelated to IMT and minor adverse events associated with IMT The combined analysis of 5099 patients who received 5551 IMTs showed that SARs related to IMT developed in less than 1 of patients The combined rate of SARs unrelated to IMT was higher reaching 29 The combined rate of minor adverse events also showed infrequent self-limited gastrointestinal and systemic discomfort This meta-analysis supports IMT as a safe option for treating recurrent CDI
For IMT performed exclusively in the elderly population a study of 31 patients with an average age of 77 years with CDI reported that 87 of patients resolved their infection and the most common adverse event reported in 4 13 of 31 respondents was the subjective worsening of arthritis Another study that performed IMT on 35 elderly patients average age 77 years with CDI reported no serious adverse effects
In summary the international experience using IMT reported in the literature shows the high safety of this procedure However the following risks should be considered 1 Infection Although IMT has been screened for pathogenic bacteria viruses fungi and parasites there is a risk of transmitting known and unknown infectious organisms contained in the donors stool There is also a theoretical risk of bacterial overgrowth in the small intestine Rarely bacteremia eg E coli Klebsiella sepsis and fatal events can occur after IMT 2 Exacerbation of inflammatory bowel disease IBD in individuals with underlying IBD 3 Allergyanaphylaxis to antigens present in the donors stool 4 Transmission of non-infectious diseases There is a theoretical risk of developing diseases that may be related to the donors gut microbiota These include obesity metabolic syndrome cardiovascular diseases autoimmune conditions allergicatopic disorders neurological disorders psychiatric conditions and malignancies This risk is very limited in the study as individuals with these known conditions are excluded from stool donation according to the donor screening procedures explained in this protocol
Study Oversight
Has Oversight DMC:
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Is a FDA Regulated Drug?:
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Is a FDA Regulated Device?:
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Is an Unapproved Device?:
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Is a PPSD?:
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Is a US Export?:
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Is an FDA AA801 Violation?:
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