The gut barrier is designed to protect humans from potential pathogens while enabling absorption of nutrients. The immune system lurks just beneath the surface, poised in case of an attack by invaders. It’s a good thing we have these checkpoints, as the gut is the largest interface of the environment with the human organism.
However, things aren't always sunny. Our inner ecosystems can be thrown off balance in many ways. Low biodiversity, higher pathogen levels, inflammation, oxidative stress, an immune response, mucosal loss, low intestinal epithelial turnover, malabsorption, and low levels of antimicrobial peptides—all present vulnerabilities in the gut barrier. This can allow closer proximity of microbes to the gut lining, and eventually the contents of the gut can leak into the blood unabated. (Learn more about the gut layers and leaky gut).
Indeed, this process becomes a greater concern as we get older. As we age, the gut mucus layer thins, gaps between epithelial cells expand, and tight junction components attenuate [1]. This increases the risk of leaky gut, or impaired intestinal permeability. In turn, leaky gut provokes a strong immune response that exerts a lot of collateral damage. Chronically activated, the immune system can destroy mitochondria, age B cells, and kill neurons, leading to memory loss, heart problems, fatigue, frailty, and other complications.
Because of this, microbiome disturbance has been suggested as a hallmark of aging in a meeting held in Copenhagen on March 2022. Despite this designation, the gut microbiome remains a black box: an estimated 40% of the microbiota is yet to be identified or cultured [2]. So far, though, research progress has established symptoms, biomarkers, and key signatures of youth and aging in the microbiome and metabolome. Fascinating work by scientists have involved swapping the microbiomes of old and young animals, a procedure called fecal microbiota transplantation (FMT). This research has elucidated the role of certain microbes and metabolites in aging, and it points to potential strategies, nutraceuticals, and interventions to slow or reverse the cellular aging process.
Leaky Gut Symptoms and Biomarkers Outline
What are the symptoms of leaky gut?
Because leaky gut leads to a myriad of issues, the symptoms are not limited to the gastrointestinal tract. If you suffer from any of the following conditions, you may have leaky gut, and further testing can determine whether this is the case. Signs of possible leaky gut can include:
Digestive issues: gas, bloating, diarrhea, constipation, indigestion / reflux, abdominal pain, food allergies or sensitivities (such as lactose or gluten intolerance); Celiac; IBD such as ulcerative colitis or Crohn’s disease; burning sensation of ulceration in your gut; IBS (highly prevalent in first-degree relatives of IBD patients) [3]
Neuropsychiatric conditions: headaches, brain fog, difficulty concentrating or focusing, ADD or ADHD, memory problems, confusion, mood disorders such as depression or anxiety, tics, mood swings, agitation
Skin concerns: acne, rosacea, eczema, psoriasis, rashes, hives, perioral dermatitis
Endocrine disruption: irregular periods, PMS, PCOS, or thyroid issues like Hashimoto’s, hypothyroidism, or Grave’s disease
Metabolic dysregulation: obesity, weight gain, nutrient deficiencies, chemical sensitivities
Inflammatory conditions: seasonal allergies e.g. hay fever, asthma, autoimmune diseases – e.g. type 1 diabetes, rheumatoid arthritis, lupus, frequent or recurrent infections (e.g. colds, or respiratory, vaginal, or bladder infections), joint or muscle pain, recurring Candida / fungal infections
Energy levels: low energy, chronic fatigue syndrome / adrenal fatigue, fibromyalgia
It’s important to note—having these symptoms or conditions does not necessarily mean you have leaky gut. Conversely, some people have leaky gut and exhibit minimal or very mild symptoms. Research also suggests that some autoimmune conditions may develop due to leaky gut. As a result, leaky gut is associated with many chronic conditions. It can also increase the risk of food sensitivities, such as lactose or gluten intolerance. Measuring biomarkers can help healthcare professionals ascertain whether a patient has leaky gut. Healing the intestinal barrier may alleviate symptoms of autoimmunity and food intolerances in cases where intestinal permeability is the root of the problem.
Bench-to-Bedside Biomarkers of Leaky Gut
Validated biomarkers are needed to know if a treatment is working [4]. Scientists and clinicians use a variety of different methods to diagnose intestinal hyperpermeability and monitor treatment efficacy. We searched the peer-reviewed literature for the most validated, reliable leaky gut biomarkers to date and have summarized them here. For brevity, we excluded numerous well-known and routinely-used biomarkers and tests, such as sugar probes (e.g. lactulose:mannitol ratios), serum zonulin, lipopolysaccharide (or LPS, which is liable to contamination), sCD-14, and Ussing chambers—upon in-depth examination, these measures contained numerous methodological limitations and did not meet our quality standards.
Serum biomarkers
LPS-binding protein (LBP)
In leaky gut, LPS leaks into the blood, and intestinal epithelial cells and liver hepatocytes respond by secreting LPS-binding protein (LBP), a soluble protein that binds LPS and promotes immune responses. This, in turn, accelerates inflammaging [5]. As such, LBP can act as a proxy for LPS and can be detected via ELISA [6].
I-FABP
Another human protein to check for is intestinal fatty acid-binding protein (I-FABP). I-FABP is a cytosolic protein present in differentiated small intestine enterocytes and to a lesser extent in the colon. It is a key serum indicator of microbiota-related epithelial cell damage and disruption and a surrogate biomarker of intestinal epithelial permeability. Low amounts circulate in normal conditions, but increased I-FABP levels seen in intestinal ischemia, Celiac disease, and necrotizing enterocolitis [6].
Immunoglobulins
IgA/IgM responses to sonicated samples of common Gram-negative gut commensal bacteria can be used to screen for increased gut permeability in combination with IgM levels to zonulin. Serum IgG/IgA/IgM responses to occludin and zonulin and IgA responses to actomyosin can be tested. You could use similar types of tests to determine if you are gluten intolerant—just check for immunoglobulins to gluten.
Overall, our preferred serum leaky gut biomarkers are LBP and I-FABP.
Preclinical Biomarkers
In preclinical animal models, you can measure leaky gut by orally administering (PO dosing) fluorescein isothiocyanate (FITC)-labeled dextran (4 kDa) and quantifying the circulating FITC-dextran in blood [7, 8]. FITC-dextran is a fluorescent sugar probe.
Histology Biomarkers
One can quantify intestinal tight junctions, such as ZO-1, occludin, or claudin-1 via immunofluorescence staining. Low levels in intestinal tissue are a sign of leaky gut [9]. Tissue analysis of tight junction proteins is a useful strategy.
That said, although tissue zonulin is a useful marker, serum zonulin is not considered reliable at this time. Most ELISAs don’t detect zonulin but C3 and possibly properdin, a related molecule from same family with an unclear functional effect. Some zonulin ELISA kits are not specific to intestinal cells. As a result, serum zonulin must be interpreted with extreme caution [6].
How does the functional metabolome of the microbiome differ between youth and aging?
In the microbiome world, scientists often start by comparing differences between two or more groups. These correlational studies generate large multi-omic datasets. Multi-omics refer to complete collections of genetic or metabolic material in a sample. These datasets serve as a starting point for testing hypotheses, establishing mechanisms, and identifying therapeutic targets. For instance, serum can be analyzed via ultra-high performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) metabolomics, and the data can be analyzed via the integrated metabolomics analysis platform (iMAP) and principal component analysis (PCA) to reveal differences between two groups, such as young and older adults.
The functional metabolomics (that is, metabolism-related gene expression) of the microbiome change with age, both within species and as an ecosystem shifting. But what’s really interesting is to take a step further beyond identity of microbial species or their correlation with age and look at functional metabolic changes in centenarians or super-agers to reveal the key pathways involved in healthy aging. Microbes and nutraceutical postbiotics to introduce are present in healthy centenarians and lost in disease-related aging [10]. From comparative analytics, some patterns have emerged.
Protein Fermentation in the Elderly
With regards to macronutrients, our first clue comes from a metabolomic study of over 9,000 people. This study revealed that aging is strongly linked to microbial-derived amino acid derivatives in the bloodstream [2]. With age, there are higher concentrations of circulating branched-chain amino acids (BCAA) [11, 12]—that is, valine, leucine, and isoleucine. Levels of metabolites from protein fermentation, including ammonia and phenols, are also increased. At the same time, gut microbiota are hypothesized to contribute to sarcopenia, age-related muscle loss [2].
In the elderly, short-chain fatty acid (SCFA) synthesis and concentrations resulting from fiber fermentation are decreased. A role for insulin resistance in aging has also been purported [13]. Meanwhile, older age is also associated with lower secondary bile acids in circulation [11, 14, 15].
Altogether, these changes indicate a marked shift from saccharolytic (carbohydrate) fermentation towards unfavorable proteolytic fermentation [10]. The body uses more proteins than sugars to generate energy, and this creates a different host landscape that may be involved in the aging process and functional decline.
Microbial-derived Metabolite Differences: Meat and TMAO
Bacteria in the GI tract produce metabolites that influence cell senescence rate and age-related disease risk. Curating the exposome, modifying the diet, and increasing physical activity could modulate these processes [16]. (For types of physical activity that improve outcomes in older adults, see Dr. Peter Attia’s book, Outlive: The Science & Art of Longevity.) Scientists have analyzed metabolomic differences in older and younger subjects in efforts to pinpoint targets for nutraceutical interventions that slow the body’s aging process.
Old age in humans is significantly associated with increased plasma LPS [11, 13], and LPS challenge also universally lowered SCFAs [17]. Additionally, Mossad et. al compared plasma and brain samples from young and aged humans and mice. Performing metabolomic pathway enrichment analysis, they found age-related increases N6-carboxymethyllysine (CML), an advanced glycation endproduct (AGE), trimethylamine N-oxide (TMAO), and delta-valerobetaine (delta-vb), a precursor to TMA, in human serum and mouse serum and brain tissue [7, 12].
In particular, TMAO is an unwanted byproduct of meat fermentation. It is produced exclusively by bacteria—researchers have found that animals on antibiotics do not produce TMAO [18]. This metabolite has been linked to cardiovascular disease, cognitive impairment, leaky gut, inflammation, aging, neurodegeneration, mitochondrial dysfunction, and oxidative stress.
A way to a person’s heart is through their gut microbiota. TMAO contributes to cardiovascular disease. In a dataset of around 4,000 people, higher TMAO was associated with more advanced heart disease. TMAO facilitates atherosclerotic plaque deposits by interacting with HDL, increasing risk of heart attack or stroke. Chen and colleagues found that a TMAO challenge significantly reduced expression of tight junction proteins ZO-2, VE-cadherin, and occludin in endothelial cell monolayers, suggesting its systemic circulation causes leaky vessels [17]. TMAO also affects vascular aging and endothelial cell senescence by decreasing cell proliferation. It is thought to stimulate the TXNIP-NLRP3 inflammasome, activating IL-1beta and IL-18 release, as well as inhibit endothelial nitric oxide synthase (eNOS) and NO production. If that wasn’t bad enough, TMAO may compromise the immune response and impair one’s ability to recover from pathogens.
TMAO is also associated with cognitive impairment. Li and colleagues report in Aging Cell that mice treated with TMAO exhibit worse performance in Y-maze and Morris water maze, indicating impaired spatial memory [19]. A clinical study at UC Boulder, published in the journal Geroscience, found that higher plasma TMAO levels were correlated with worse memory and fluid cognition in middle-aged and older adults [20]. The metabolite also increases expression of senescence and neurodegenerative markers like beta-galactosidase (B-gal), neurofilament light (NfL), amyloid beta (AB), and total tau (t-tau), and it potentially downregulates SIRT1. Additionally, TMA, a precursor to TMAO, destroys blood-brain barrier integrity [21]. Finally, TMAO-treated mice also exhibit damaged mitochondria, lower total hippocampal SOD, and accelerated microglial and astrocytic activation [17, 22].
In another study, vegans were asked to eat an 8-ounce steak or eggs. Afterwards, scientists measured their blood TMAO levels. Intriguingly, the researchers found there had been no changes in TMAO levels [18]. It's possible that because of these individuals’ long-term lifestyle and dietary choices, they had a different established microbial community. As a result, they were less susceptible to TMAO challenge. This points to the importance of cultivating a stable, beneficial gut microbiome to maximize healthspan.
TMAO also perpetuates leaky gut. TMAO challenge significantly lowered tight junction protein claudin-1 expression in the jejenum, ileum, and colon by 50-60% compared with controls, indicating destruction of intestinal wall integrity. TMAO may potentially cause leaky gut via glucose metabolism. TMAO also significantly increased serum expression of imidazolepropionic acid, a metabolite of histidine [17].
Firmicutes and Proteobacteria can metabolize carnitine, choline, and betaine found in food sources such as meat, eggs, fish, and mushrooms, into TMA [7]. TMA is then converted to TMAO by flavin-containing monooxygenases [17]. That said, carnitine and choline are essential nutrients found in food, and it is preferable to target the microbiome to lower TMAO production. Rather than eliminating nutrient-dense food sources like meat and eggs entirely, cutting back on their consumption could be another potential strategy, as research has shown that Americans generally eat twice as much meat and half as much fiber as their body nutritionally requires. Kalagi et al. review dietary and pharmacological approaches in greater detail [23]. For example, 3,3-dimethyl-1-butanol (DMB), a compound in some cold-pressed extra-virgin olive oils, balsamic vinegars, grape seed oils, and red wine, blocks TMAO production. Another study from Brazil, published in the European Journal of Nutrition, reviews more dietary interventions to modulate TMAO production [24]. In conclusion, diets that block TMAO production could slow aging. We could all use a reminder to eat more vegetables.
Microbiome Differences
As we get older, our microbiome’s diversity and stability declines, along with butyrate producers [11, 17, 25].
Many articles lack consensus on whether F/B ratio is increased or decreased with aging [2, 11, 26]. The findings on Bacteroides, Bifidobacteria, Prevotella, Eubacterium, and even Faecalibacterium prausnitzii were also contradictory, with some studies reporting higher and others reporting lower relative abundances with age [17, 25]. Phyla-level summaries are convenient but less informative in painting a picture of gut function. Ideally, we aim for the species-level analyses, though this comes with its own disadvantages, such as rapid microbial evolution and increasing data complexity.
Reviewing the literature, the results were as follows:
Decreased with aging
Investigators consistently found that Lachnospiraceae and Ruminococcaceae were significantly reduced with aging [7, 12, 27].
In frailty-associated aging, anti-inflammatory Lactobacilli are decreased. L. plantarum is important in expressing insulin-like growth factor 1 (IGF-1), which affects muscle development and growth. Deficiency in Lactobacillus spp. is involved in gut inflammation and bacterial infection, suggesting Lactobacillus could present a possible therapeutic approach [13].
Verrucomicrobia is decreased in aged rats [13]. 5 children with progeria, a disease that accelerates aging, also displayed decreased Verrucomicrobia. However, there was no correlation between changes in bacteria and disease severity [11]. Additionally, 17 centenarians had balanced microbiomes mainly derived from phylum Verrucomicrobia [11].
Akkermansia decreases with aging. However, centenarians maintain levels of Akkermansia similar to healthy adults [28].
Increased with aging
Higher abundances of Proteobacteria are seen in the senior population than in young adults [17]. Children with progeria also had increased Proteobacteria. On the other hand, centenarians had decreased Proteobacteria, suggesting this bacteria’s role in lifespan [11].
Opportunistic Enterobacteriaceae, and Escherichia and Shigella that cause infections were increased in the senior population and amyloid-positive patients [11, 25]. Indeed, with aging, more pathobionts, such as Eggerthella lenta, are observed [17, 25].
In summary, aging shows a decrease in Lachnospiraceae, Ruminococcus, Lactobacillus, Verrucomicrobia, and Akkermansia and an increase in Proteobacteria and infection-associated microbes.
Limitations
A discussion of microbiome differences in young and older adults, as well as centenarians versus frail elderly, would not be complete without acknowledging some important limitations to interpreting these findings.
Cohort Effects
Knowing which microbes are beneficial is difficult because of cohort effects. Most investigations cross-sectionally compare different humans of different ages as opposed to tracking the same people longitudinally. The reality is prospective longitudinal studies may take decades to complete and require archived biobanks of blood and fecal samples that have been consistently kept at -80 degrees Celsius over many years—an expensive endeavor. Additionally, data from elderly in Sardinia, Icaria, Nicoya, or Okinawa may not be generalizable to American elderly, so it is ideal to integrate data from many diverse populations before drawing conclusions.
Exposure Effects
Another glaring issue confounds the meaningfulness of these findings: exposure effects. Proximity to urban areas and time spent outdoors are important factors in longevity. While examining which genes may be associated with longevity, it is important to keep those genes in the context of their environment, a concept Dr. Robert M. Sapolsky emphasizes in his book, Behave: The Biology of Humans at Our Best and Worst. That is, specific genes may act differently in different environments. (For instance, the same gene that provides an advantage in a rural setting may become a disadvantage in a city).
Lack of Living Controls for Centenarians
As Dr. Nir Barzilai, professor at Albert Einstein School of Medicine, points out in his book Age Later, studying centenarians is complicated by the lack of controls. It’s impossible to compare super-agers with age-matched frail controls because frailty is associated with increased risk of mortality. A helpful strategy is to compare centenarians and their adult offspring with age-matched control adults.
Another workaround is to group the data by physiologic as opposed to chronological age with an epigenetic aging clock (such as DNAmAge, an age acceleration measure). Then, you could compare biomarker differences across groups, looking for critical differences that could reveal aging-associated metabolites and key functional metabolic differences between super-agers and physiologic age-matched controls. This clock can also help evaluate whether a prospective therapeutic slows aging.
Opaque Interpretability
An additional difficulty arises: some metabolites rise and fall through different stages of life, and not in a discrete pattern. Centenarians and their adult aged-matched offspring may have different metabolite levels, complicating analysis of the functions of certain metabolites at different biologic ages. These limitations make it harder to interpret the data.
Microbiome and Metabolomic Data Detachment
As long as metabolomic and microbiome sequencing remain separate, we will remain limited in how much functional information we can glean from big datasets. If a microbe becomes more abundant with age, it’s unclear if it is involved in the aging process or in protecting the elderly against aging. Knowing the functional activity of microbes would go a long way towards forming the picture of health factors contributing to healthspan.
Vague Semantics in Literature
There’s also a risk of misinterpreting microbiome literature. When saying “abundance” of a bacterial species changed, scientists are usually referring to relative abundance, not absolute abundance. Relative abundance could be increasing, but absolute numbers could be decreasing. We have to be careful to use precise language and not to flatten quantitative data into qualitative data, either, using vague terms like “increased levels” of species when we really mean more relative to the ecosystem. This language should be abundantly clear in peer-reviewed publications, but unfortunately this isn’t always the case.
Summary
Microbiota dysbiosis leads to leaky gut, in turn triggering inflammation, which drives aging. Leaky gut not only causes GI symptoms but also brain, skin, hormonal, metabolic, inflammatory, and energy-related symptoms. Symptoms can include acne, headaches, ADHD, depression, anxiety, weight gain, irregular periods, fatigue, allergies, asthma, autoimmune disease, or thyroid issues. Serum biomarkers LBP and I-FABP are used to detect and quantify leaky gut in human patients.
As we get older, metabolism shifts towards proteolytic fermentation. Increased levels of LPS, TMAO, CML, and delta-vb contribute to the cellular aging process. The elderly microbiome is significantly different from younger microbiomes. Aging shows a decrease in Lachnospiraceae, Ruminococcus, Lactobacillus, Verrucomicrobia, and Akkermansia and an increase in Proteobacteria and infection-associated microbes.
In the future, microbiome research will have to overcome cohort and exposure effects, design experiments thoughtfully in light of the dearth of age-matched controls to centenarians, and unite metabolomic and microbiome data to form a functional picture of human health for development of precision medicines that target the root causes of age-related diseases.
This article covered the symptoms and biomarkers of leaky gut. Now that we know there are important group differences in microbiomes and metabolomes between youth and old age, what happens when you give a young adult an old microbiome and an older adult a young microbiome? In our next article, we will discuss fascinating microbiome research that explores the possibilities of microbiome modulation.
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Audiobooks for Further Listening
Outlive: The Science & Art of Longevity – Dr. Peter Attia
Age Later – Dr. Nir Barzilai
Behave: The Biology of Humans at Our Best and Worst – Dr. Robert M. Sapolsky
References
Mou, Y., et al., Gut Microbiota Interact With the Brain Through Systemic Chronic Inflammation: Implications on Neuroinflammation, Neurodegeneration, and Aging. Front Immunol, 2022. 13: p. 796288.
Siddiqui, R., et al., The Use of Gut Microbial Modulation Strategies as Interventional Strategies for Ageing. Microorganisms, 2022. 10(9).
Camilleri, M., Leaky gut: mechanisms, measurement and clinical implications in humans. Gut, 2019. 68(8): p. 1516-1526.
Kavanagh, K., et al., Biomarkers of leaky gut are related to inflammation and reduced physical function in older adults with cardiometabolic disease and mobility limitations. Geroscience, 2019. 41(6): p. 923-933.
Parker, A., et al., Fecal microbiota transfer between young and aged mice reverses hallmarks of the aging gut, eye, and brain. Microbiome, 2022. 10(1): p. 68.
Vanuytsel, T., J. Tack, and R. Farre, The Role of Intestinal Permeability in Gastrointestinal Disorders and Current Methods of Evaluation. Front Nutr, 2021. 8: p. 717925.
Mossad, O., et al., Gut microbiota drives age-related oxidative stress and mitochondrial damage in microglia via the metabolite N(6)-carboxymethyllysine. Nat Neurosci, 2022. 25(3): p. 295-305.
D'Amato, A., et al., Faecal microbiota transplant from aged donor mice affects spatial learning and memory via modulating hippocampal synaptic plasticity- and neurotransmission-related proteins in young recipients. Microbiome, 2020. 8(1): p. 140.
Ma, J., et al., Gut microbiota remodeling improves natural aging-related disorders through Akkermansia muciniphila and its derived acetic acid. Pharmacol Res, 2023. 189: p. 106687.
Ragonnaud, E. and A. Biragyn, Gut microbiota as the key controllers of "healthy" aging of elderly people. Immun Ageing, 2021. 18(1): p. 2.
Meng, Y., J. Sun, and G. Zhang, Fecal microbiota transplantation holds the secret to youth. Mech Ageing Dev, 2023. 212: p. 111823.
Mossad, O., et al., Microbiota-dependent increase in delta-valerobetaine alters neuronal function and is responsible for age-related cognitive decline. Nat Aging, 2021. 1(12): p. 1127-1136.
Zhang, Y., et al., Gut microbiota dysbiosis promotes age-related atrial fibrillation by lipopolysaccharide and glucose-induced activation of NLRP3-inflammasome. Cardiovasc Res, 2022. 118(3): p. 785-797.
Khoruts, A., C. Staley, and M.J. Sadowsky, Faecal microbiota transplantation for Clostridioides difficile: mechanisms and pharmacology. Nat Rev Gastroenterol Hepatol, 2021. 18(1): p. 67-80.
Martinez-Gili, L., et al., Understanding the mechanisms of efficacy of fecal microbiota transplant in treating recurrent Clostridioides difficile infection and beyond: the contribution of gut microbial-derived metabolites. Gut Microbes, 2020. 12(1): p. 1810531.
Gulati, A.S., et al., Fecal Microbiota Transplantation Across the Lifespan: Balancing Efficacy, Safety, and Innovation. Am J Gastroenterol, 2023. 118(3): p. 435-439.
Chen, S.Y., et al., A Novel Trimethylamine Oxide-Induced Model Implicates Gut Microbiota-Related Mechanisms in Frailty. Front Cell Infect Microbiol, 2022. 12: p. 803082.
Goldsmith, J.R. and R.B. Sartor, The role of diet on intestinal microbiota metabolism: downstream impacts on host immune function and health, and therapeutic implications. J Gastroenterol, 2014. 49(5): p. 785-98.
Li, D., et al., Trimethylamine-N-oxide promotes brain aging and cognitive impairment in mice. Aging Cell, 2018. 17(4): p. e12768.
Brunt, V.E., et al., The gut microbiome-derived metabolite trimethylamine N-oxide modulates neuroinflammation and cognitive function with aging. Geroscience, 2021. 43(1): p. 377-394.
Hoyles, L., et al., Regulation of blood-brain barrier integrity by microbiome-associated methylamines and cognition by trimethylamine N-oxide. Microbiome, 2021. 9(1): p. 235.
Zhang, L., F. Yu, and J. Xia, Trimethylamine N-oxide: role in cell senescence and age-related diseases. Eur J Nutr, 2023. 62(2): p. 525-541.
Kalagi, N.A., et al., Modulation of Circulating Trimethylamine N-Oxide Concentrations by Dietary Supplements and Pharmacological Agents: A Systematic Review. Adv Nutr, 2019. 10(5): p. 876-887.
Coutinho-Wolino, K.S., et al., Can diet modulate trimethylamine N-oxide (TMAO) production? What do we know so far? Eur J Nutr, 2021. 60(7): p. 3567-3584.
Wang, X. and M. Wu, Research progress of gut microbiota and frailty syndrome. Open Med (Wars), 2021. 16(1): p. 1525-1536.
Rei, D., et al., Age-associated gut microbiota impair hippocampus-dependent memory in a vagus-dependent manner. JCI Insight, 2022. 7(15).
Staley, C., et al., Predicting recurrence of Clostridium difficile infection following encapsulated fecal microbiota transplantation. Microbiome, 2018. 6(1): p. 166.
Biagi, E., et al., Gut Microbiota and Extreme Longevity. Curr Biol, 2016. 26(11): p. 1480-5.