The Gut Microbiome as a Therapeutic Target for Cognitive Impairment

Abstract

Declining cognitive functions in older individuals have enormous emotional, clinical, and public health consequences. Thus, therapeutics for preserving function and keeping older adults living independently are imperative. Aging is associated dysbiosis, defined as a loss of number and diversity in gut microbiota, which has been linked with various aspects of cognitive functions. Therefore, the gut microbiome has the potential to be an important therapeutic target for symptoms of cognitive impairment. In this review, we summarize the current literature regarding the potential for gut-targeted therapeutic strategies for prevention/treatment of the symptoms of cognitive impairment. Specifically, we discuss four primary therapeutic strategies: wild-type and genetically modified probiotics, fecal microbiota transplantation, physical exercise, and high-fiber diets and specifically link these therapies to reducing inflammation. These strategies may hold promise as treatment paradigm symptoms related to cognitive impairment.

As the older adult population continues to grow, so does the importance for innovative solutions to prevent, mitigate, or reverse prevalent common age-related health conditions, such as cognitive impairment. Clinically, older adults with cognitive impairment have an increased incidence of functional disability, poor quality of life, and mortality (1,2). Cognitive impairment status also predicts outcomes for malnutrition, hospital admission, length of hospital stays, and nursing home admission (3).

Epidemiologic data demonstrate that the prevalence of cognitive impairment ranges from approximately 11% to 40% in clinical settings and 1.0% to 12% in the community (2). Older adults with cognitive impairment have the highest risk of dementia and limitations during activities of daily living. Given the tremendous clinical, social, and economic costs and the potential for intervention, cognitive decline and its component impairments are important clinical targets for therapeutic intervention strategies. Cognitive impairment may be reversible, thus the prospect for ameliorating cognitive deficit whereas symptoms are still reversible provides an opportune time to intervene prior to onset of disability.

Common clinical conditions that are involved in the onset of cognitive impairment include depression, cardiac dysfunction, cardiovascular disease, sarcopenia, dyslipidemia, insulin resistance, chronic inflammation, and hormone dysregulation (1). Importantly, each of these conditions has also been associated with dysbiosis of the gut microbiome (4)—defined as loss of number and diversity of microbes (including bacteria, viruses, fungi, protozoa, and archaea) symbiotically living in the human gastrointestinal tract (2,3). The gastrointestinal track represents a large microbial system that establishes a interdependency relationship between host-microbe and environment, playing a critical role on host immune response (5), influencing host-cell proliferation and vascularization (6), and regulating intestinal endocrine functions and neurologic signaling (7). Furthermore, gut microbiota also provides a source of energy biogenesis (8), regulating biosynthesis of vitamins and neurotransmitters (9), metabolizing bile salts (10), reacting or modifying specific drugs, and eliminating exogenous toxins (11). Therefore, gut microbiota have an important role in modulating host immune function, metabolic homeostasis, resistance and resilience to infection and modulation of gene expression (12).

Aging is associated with gut dysbiosis (13,14) and recently more attention has been given to the interaction between gut microbiome and the brain, which has been termed gut–brain axis (Figure 1). This relationship has been reviewed in depth elsewhere (15,16). Briefly, the gut–brain axis is the communication between the central nervous system, autonomic nervous system, enteric nervous system, immune system, and endocrine system with cognitive centers of the brain and peripheral intestinal function (17,18). The primary role of this communication is to monitor and integrate gut function and cognitive centers. Bidirectional communication can occur through multiple channels such as the production or expression of neurotransmitters, intestinal barrier integrity, modulation of enteric sensory afferents, bacterial metabolites (eg, short-chain fatty acids or SCFAs), and immune regulation (19–21).

Figure 1.

Therapeutic interventions on gut–brain axis.

Another important potential link between cognitive impairment and the gut microbiome may be inflammation. Chronic low levels of inflammation are a hallmark of human aging and increased inflammation is associated with multiple diseases/disorders prevalent in older adults, including frailty. Furthermore, chronic inflammation is also a risk factor for several prominent health concerns related to: the nervous system (ie, Parkinson’s disease, Alzheimer’s disease (AD)), cardiometabolic issues (ie, cardiovascular disease, stroke, diabetes), cancer, digestive problems, the pulmonary system (ie, COPD, bronchitis), and musculoskeletal issues (ie, osteoarthritis, rheumatoid arthritis). Gut dysbiosis has also been linked to the same health concerns derived from chronic inflammation (14). Given the interaction of the gut microbiome with the systemic circulation, we recently demonstrated the richness and composition of the circulating microbiome are linked to indices of age-related inflammation in older individuals (22). In addition, Claesson and colleagues identified that older adults in long-stay care facilities had less diversity of their microbiome and the decrease in diversity was associated with an increase in frailty. The same population of older adults also had increased levels of inflammation and lower scores on health indices (ie, comorbidity indices, geriatric depression, and functional independence measures) (23).

Therefore, the gut microbiome has the potential to be an important therapeutic target for cognitive impairment. In this review, our aim was to summarize the current literature regarding the potential for gut-targeted therapeutic strategies for prevention/treatment of the symptoms of cognitive impairment and other dementias. For the purposes of this review, we identified four primary therapeutic strategies to discuss: (i) wild-type and genetically modified probiotics (GMP), (ii) fecal microbiota transplantation (FMT), (iii) physical exercise, and (iv) high-fiber diets (eg, SCFAs). Our discussion specifically links these therapies to reducing inflammation.

Strategy 1: Wild-type and Genetically Modified Probiotics

One potential gut-targeted therapy to ameliorate symptoms of cognitive impairment is the administration of probiotics. Probiotics are defined as live microorganisms conferring a health benefit on the host when administered in adequate amounts (24). There are multiple ways in which probiotics may modulate gut dysbiosis (25); however, in the context of cognitive impairment, the anti-inflammatory effects may be the key. One potential mechanism by which probiotics affect cognitive impairment maybe through reducing inflammation associated with the tryptophan–kynurenine signaling. Tryptophan is an essential amino acid and a substrate for the generation of several bioactive compounds. Most tryptophan is metabolized along the kynurenine pathway and metabolites in the tryptophan–kynurenine pathway are involved in inflammation, immune response, and neurotransmission and may act either in a neuroprotective or neurodegenerative way (26). For example, indole derivatives can be either beneficial or toxic, and the composition of the intestinal microbiota can modulate the derivative production (27).

Although less is known regarding probiotic effects on cognitive impairment, several clinical and preclinical intervention studies have reported beneficial effects of probiotics in several age-related diseases such as AD (28–30), neuroinflammation (31), diabetes (32), and vascular dementia (33). In the studies using animal models of AD, Kobayashi and colleagues demonstrated oral administration of Bifidobacterium breve strain A1 for 6 days to amyloid-β injection-induced AD mice reversed the impairment of alternation behavior in Y maze test and reduced latency time in passive avoidance test (34). The probiotics consumption also suppressed the proinflammatory and immune-reactive gene expression in hippocampus (34). Other studies in rodents with AD model reported probiotics ameliorated cognition deficits in spatial learning tasks and gross behavior activities (28–30), increased expression of neuronal proteolytic pathways (28), and reduced neurodegeneration (30). Despite promising findings in preclinical trials, there is limited human data supporting this concept. Two studies examined the effect of probiotic supplementation in patients with AD. Akbari and colleagues reported 12-week of probiotic treatment with a supplement containing Lactobacillus acidophilus, Lactobacillus casei, Bifidobacterium bifidum, and Lactobacillus fermentum positively affected cognitive function and metabolic homeostasis in AD patients (35). Leblhuber’s group showed supplementation with a multispecies probiotics increased Faecalibacterium prausnitzii in feces, and incremented circulating kynurenine in patients with AD (36).

Recently, probiotics have been proposed as a safe and efficacious vehicle to deliver other therapeutic compounds. Indeed, GMP have been purported as a promising intervention strategy as they provide precision and a higher degree of site specificity than convention drug regimens (37). One textbook example is the use of GMP secreting IL-10 in treating gut-related diseases in rodent models. Steidler and colleagues demonstrated intragastric administration of Interleukin-10 (IL-10)—producing Lactococcus lactis (L lactis) resulted in a 50% reduction in colitis in mice induced by dextran sulfate sodium and prevented the onset of colitis in IL-10 knockout mice (38,39). Human IL-10 orally delivered by Bifidobacterium has been successfully shown to alleviate inflammatory damage of colonic tissue in a murine model of ulcerative colitis (40,41). These preclinical trials substantially support the effectiveness of GMP administration in treating diseases within the gut. In line with these promising findings in animals, studies have further tested the safety and feasibility of GMP therapies for human diseases. A phase I trial showed mucosal delivery of transgenic bacteria expressing IL-10 was safe and decreased disease activity in patients with Crohn’s disease (42). These data provide evidence that GMP usage in animal models of disease can be translated into human trials with safety and success. The translatable usage of GMP secreting IL-10 can serve as a template for taking the same approach for cognitive impairment, described as an inflammatory disease itself.

Other than gut-related diseases, GMP has been purported as a highly promising treatment strategy for a variety of age-related diseases—for example, by manipulating the renin–angiotensin system (RAS). The traditional RAS was thought primarily to modulate blood pressure via angiotensin II binding to angiotensin II receptor type 1 (AT1) receptor. However, recently more attention has been given to the alternate RAS axis, which converts angiotensin I to angiotensin (1–7) or Ang (1–7) by the enzyme angiotensin converting enzyme 2 (ACE2). Contrary to the traditional RAS axis, the ACE2/Ang (1–7)/MAS axis induces several beneficial physiological effects (43), including anti-inflammatory. For example, using a diabetic mouse model, Li and colleagues have shown that genetically modified Lactobacillus paracasei (LP) secreting Ang (1–7) improved glucose tolerance and reduced diabetes-induced damage in kidney and retina (44). In line with this finding, a few studies have explored GMP secreting angiotensin converting enzyme (ACE) inhibitory peptides. Oral administration of Lactobacillus plantarum expressing ACE inhibitory peptides significantly decreased systolic blood pressure, increased nitric oxide, and decreased endothelin and angiotensin II in spontaneously hypertensive rats (45). Huang and colleagues established Escherichia coli expressing ACE inhibitory peptides, which caused a significant reduction of systolic blood pressure in spontaneously hypertensive rats after a single oral administration (46). Rao and colleagues designed a recombinant antihypertensive peptide multimer expressed in E coli, which was subject to simulated gastrointestinal digestion and showed potent ACE inhibitory activity (47). Altogether, these results underscore GMP as a highly promising treatment strategy for age-related conditions; and thus may also be useful in treating cognitive-related symptoms.

In fact, to the best of our knowledge, our group was the first to propose GMP manipulating RAS in the model of aging and provided a proof of concept of GMP overexpressing Ang (1–7) in promoting a positive shift in circulating RAS metabolites in aged rats (48). Our data suggest that Ang (1–7)-secreting L paracasei or LP-A increased circulating levels of Ang (1–7). LP-A also significantly decreased proinflammatory cytokines (COX2, IL-1β, and TNF-α) expression in the prefrontal cortex (unpublished). Interestingly, the dose of LP-A was optimized at ×3/week, rather than daily, for these inflammatory outcomes. To date, there is no study to directly assess the relationship between GMP and cognitive impairment. However, based on the discussion above and our preliminary preclinical data, GMPs are a potential therapeutic strategy to mitigate cognitive impairment.

More research is still needed regarding the capability to use probiotics as vehicles to deliver drugs and other therapeutic proteins as well as the optimal types of probiotics and dosing regimens for older individuals.

Strategy 2: Fecal Microbiota Transplantation

Another promising intervention that initially emerged to manage recurrent gastrointestinal diseases and that may be a potential strategy to manage cognitive impairment is FMT (12,49,50). FMT is the transfer of fecal matter from a “healthy” donor into the intestinal track of a recipient believed to harbor an altered or dysbiotic colonic microbiome (49–51) in attempt to directly change the recipient microbial composition. The rationale for this therapy is to re-establish normal gut microbiota and restore its colonization resistance into the recipient gastrointestinal track (50). FMT has been successfully used to treat infection with Clostridium difficile for nearly 60 years with the advantage of increasing the diversity of fecal bacterial populations and long-term engraftment in recipients (52). For example, FMT has been shown as a potential therapeutic in treating inflammatory bowel disease, which cause chronic inflammation in the gastrointestinal tract. Inflammatory bowel disease affects over 1 million people in the United States alone and incidence of these diseases worldwide continues to grow (53). It is clear that inflammatory bowel disease is associated with gut dysbiosis, with under-representation of the anti-inflammatory phyla Bacteroides and Firmicutes and increase in proinflammatory Proteobacteria (12). In a randomized controlled trial, ulcerative colitis patients underwent FMT with feces from healthy donors or were given autologous fecal microbiota (control) for 3 weeks (54). In the intention-to-treat analysis, 30% patients who received FMT from healthy donors and 20% of the controls were in remission. Responders demonstrated an increase in diversity of fecal microbiota (54).

Recently, there has been a cumulative interest in extending FMT to some pathologies that were associated to gut dysbiosis (55–57), in particular some functional and neurodegenerative diseases such as Parkinson’s disease (20), obesity and metabolic syndrome (12,50), and hypertension and chronic kidney disease (58,59).

Individuals with PD have been reported with a proinflammatory dysbiosis, characterized by low counts of “anti-inflammatory” butyrate-producing bacteria and higher “pro-inflammatory” Proteobacteria (60). Remarkably, fecal microbiota from PD patients or controls were transplanted into individual groups of germ-free recipient mice with oral gavage. Animals receiving PD donor-derived microbiota displayed not only gut dysbiosis but also enhanced neuroinflammation and motor dysfunction (61). Vrieze and colleagues reported, in a human study, transferring stool from lean donors to recipients with metabolic syndrome led to improvements in insulin sensitivity and increase of butyrate-producing intestinal microbiota (62). Finally, several studies also demonstrate that individuals with prehypertension and hypertension had a dramatically decreased gut microbial richness and diversity. Furthermore, by FMT from hypertensive human donors to germ-free mice, elevated blood pressure was observed to be transferable through microbiota, and the direct impact of the gut microbiota on blood pressure of the host was demonstrated (63).

Although the evidence from both, animal but particularly human studies is very limited, the applicability of FMT as a therapeutic approach to manage cognitive impairment points toward a promising future. In a preclinical model of accelerate aging, cognitive function in senescence-accelerated mouse prone 8 (SAMP8) mice was significantly decreased, which was associated with abnormal composition of the gut microbiota, compared to senescence-accelerated mouse resistant 1 (SAMR1) mice. Germ-free mice that received fecal transplants from SAMR1 mice but not from SAMP8 mice showed improvements in behavior and in microbiota α- and β-diversity indices (49).

Thus, FMT may be a modulation strategy to target cognitive impairment. However, before making claims of the beneficial effects of FMT, there is an urgent need to develop well-designed experiments, to allow a rigorous FMT causality relationship. In addition, still many questions remain unanswered concerning the FMT therapy in human subjects including the route of administration, frequency of application, microbiota screening in the donor, administration of antibiotics to the recipients, and others (12).

Strategy 3: Physical Exercise

Physical exercise has been well established as a preventive health strategy and clinical intervention to improve physical function, reduce cardiovascular risks, all-cause mortality, cognitive decline, and dementia. Regular physical exercise has been shown to have anti-inflammatory effects and may reduce the risk of inflammatory-related diseases. Various mechanisms have been proposed to explain the means by which exercise attenuates inflammation including via reduced body fat (particularly in the visceral compartment), increased anti-inflammatory cytokines production from contracting muscles, downregulation of Toll-like receptors on monocytes and macrophages, and downregulation of intracellular generation of reactive oxygen species (64). Recently research has focused on exercise altering the composition and functional capacity of the gut microbiota (65). However, the mechanisms by which physical exercise modulates the microbiome still remain understudied.

Initial preclinical studies have shown that physical exercise improves the gut microbiome. Campbell and colleagues reported that 12-week voluntary wheel running improved epithelial membrane integrity, reduced intestinal inflammation in proximal and distal gut, and increased microbial diversity in mice (66). Allen and colleagues using a germ-free mouse model, showed fecal transplants from exercise-trained donor mice increased microbiota diversity and reduced colon inflammation in recipient mice (67). Recipient mice with the microbiota of exercised donors showed reduced colon shortening, attenuated mucus depletion, and augmented expression of cytokines involved in tissue regeneration to an acute colitis insult. Other studies using rodent models also showed wheel running exercise training provide a variety of beneficial effects on the gut microbiome including enhanced microbial diversity (68–70), decreased inflammation and increased antioxidant enzymes in intestinal lymphocytes (71,72).

However, few human studies to date have examined the effects of physical exercise on gut microbiome. Recently, Taniguchi and colleagues reported a 5 week endurance exercise training in 33 Japanese men over 60-years-old, decreased C difficile and increased Oscillospira rates significantly during the exercise period compared to the controls (73). This was associated with improvement in cardio metabolic variables including increased VO₂ peak, increased high-density lipoprotein cholesterol levels, and decreased intrahepatic fat content. Munukka and colleagues recently examined a 6 week endurance exercise on gut metagenome in overweight women (n = 19) (74). Exercise training induced an increase in Akkermansia, which is health-beneficial, and a decrease in Proteobacteria, which is health-detrimental. However, exercise did not greatly affect systemic metabolites or body composition. Both studies have small samples sizes and are limited to endurance exercise. Likewise, Clarke and colleagues reported professional rugby athletes had enhanced diversity of the microbiota compared to age-matched controls (75). Further studies in larger cohorts, various exercise types, and involving aging populations are needed in this area.

Evidence has shown exercise as an effective intervention to preserve cognitive function under normal or disease conditions, even protecting against cognitive decline and neurodegenerative diseases (76). In a randomized control trial, Erickson and colleagues reported that exercise training increased hippocampal volume, and serum brain-derived neurotrophic factor level, which is central in the growth and the survival of striatal neurons in the brain, along with learning and memory in older adults (77). Notably, decreased brain-derived neurotrophic factor in the hippocampus is associated with gut inflammatory diseases including inflammatory bowel disease (78). Oral supplementation with Bifidobacterium has been associated with elevated brain-derived neurotrophic factor expression (78), while treadmill exercise training also increased Bifidobacterium in the cecal content of mice (79). Interestingly, whereas the treatment of mice with antibiotics decreased hippocampal neurogenesis and memory retention, both probiotics and wheel running exercise individually reversed these deficits (80). However, it is still unclear whether the beneficial effects of exercise on brain neurogenesis and cognitive function are modulated by a specific gut bacteria (81). Though no direct evidence has been shown that physical exercise is favorable in relieving cognitive impairment, proposed hypotheses and preliminary research show exercise is a promising therapeutic strategy for cognitive impairment in late life.

Strategy 4: High-Fiber Diet

Changes in dietary habits have been proven to be one of the most powerful stimulus to modify gut microbial communities and gut metabolites (82). One of the most extensively studied dietary factors to maintain gut homeostasis and host health is dietary fiber. Lately fermentable fibers have drawn more attention in influencing cognitive function via fermentation products SCFAs. Mailing and colleagues recently reported that the gut microbiota plays a role in the host response to high-fiber diet intervention in an animal model (83), which further supports the gut–brain axis hypothesis. Notably, high-fiber diets and SCFAs are associated to decreased risk of several inflammatory diseases such as obesity, colon cancer, and cardiovascular disease, highlighting their anti-inflammatory effects, the ability to preserve gut microbiome homeostasis and host health (84).

In a prospective study, diet with a fiber content of 24.3 mg/day decreased the risk of Crohn´s disease by 40%, with the higher gains coming from fiber originated from fruit sources (85). Additionally, in a case–control study in 130 patients with Crohn´s disease, high-dietary fiber was associated to a lower risk for Crohn´s disease (86). The gastrointestinal disease is associated to gut dysbiosis (87).

Notably, the protective effects of high-fiber diets, and therefore, the indirect effects of SCFAs have been also associated with age-related diseases. In a recent analysis of the Diabetes Prevention Program study, in 2,924 middle-aged participants, baseline weight was negatively associated to dietary fiber consumption, after adjustment to caloric intake (88). Interestingly, weight loss after 1 year was associated with increases in dietary fiber intake and decreases in total fat and saturated fat intake. Therefore, high-fiber diets prompt has a promising therapeutic strategy to prevent diabetes in high-risk population (88). Remarkably, in a preclinical study, Marques and colleagues reported high-fiber diet modified the gut microbiota populations and increased the abundance of acetate-producing bacteria (89). Both fiber and supplementation with acetate decreased gut dysbiosis and prevented development of hypertension and heart failure in hypertensive mice (89).

Interestingly, only a small number of studies demonstrated the beneficial neurological effects of high-fiber diets. In germ-free mice, colonization with butyrate-production bacteria restored blood–brain barrier permeability to healthy levels whereas simultaneously increased brain histone acetylation and expression of occluding and claudin 5, which are associated with increased levels of tight junction proteins and gut integrity (90). Similarly, mice fed with a high-soluble fiber diet recovered faster from endotoxin-induced sickness (91). This diet successfully increased the abundance in SCFA substrates in the colon and resulted in reduced neuroinflammation, with increases in IL-1 receptor antagonist, which is an inhibitor of the proinflammatory IL-1β and TNF-α (91). In another preclinical study, diet containing 5% inulin resulted in an increase of SCFA metabolites in both adult and aged mice (92). Compared to adult mice, aged animals exhibited more anti-inflammatory microglial gains and improvements in neuroinflammation in the high-fiber diet, with a decrease in proinflammatory gene expression and microglial sensory apparatus (92). Butyrate has also been associated with a neuroprotective activity by promoting the synthesis of several neurotransmitters (gamma-amino butyric acid and serotonin) and hormones (93). Collectively, this evidence highlights the anti-inflammatory effects of SCFAs in the brain.

However, despite several experimental and prospective studies associating high-fiber diets and gut microbiome metabolites in the management of several gastrointestinal pathologies, on metabolic disorders and neurodegenerative diseases, to date, there is no evidence directly associate high-fiber diet or SCFAs with cognitive impairment. Nevertheless, it has been hypothesized that cognitive impairment may at least partially, share the same pathophysiological background (ie, gut dysbiosis) as many as these gastrointestinal disorders and neurodegenerative diseases (94). Therefore, this evidence may indicate that high-fiber diet represents a promising therapeutic strategy to counteract cognitive impairment.

Conclusion and Future Directions

In the last two decades, there has been unprecedented growth in research directed to explore the role of the gut microbiota in human health span, longevity, and aging. The ascension of the gut–microbiota brain axis has generated tremendous excitement within and beyond the scientific community, as a key integrative physiological regulator through the bidirectional microbiota–gut–brain communication. In addition, the plasticity of the microbiome makes microbiota-target interventions emerge as attractive and promising therapeutic strategies to prevent and treat cognitive impairment. However, despite some reported evidence about the potential applicability of some novel therapeutic approaches, several methodological and experimental challenges still need to be overcome to pass from a correlation/association interrelationship to a causality and efficacy effect.

Most of the current data linking the microbiome to chronic diseases are from preclinical studies. In addition, the few human studies still need to confirm their relevance before they can be transferred to practical advice. For instance, several evidences suggest that probiotics, especially the GMP, may contribute to modulate the gut–brain axis, emerging as a promising intervention to target cognitive impairment by delivering a precise drug with high degree of site specificity. However, despite promising evidence from our research group in a preclinical model, through the overexpression of Ang (1–7), an important anti-inflammatory metabolite in the renin–angiotensin pathway, there is no evidence of similar outcomes in human studies. Therefore, more research is still needed to fully understand the mechanisms underlying their impact on cognitive impairment. Nonetheless, molecules in RAS are present in several organs and tissues (eg, brain and gut) (95) and, therefore, may be a potential physiological pathway to target cognitive impairment. Remarkably, the action of Ang (1–7) was associated to arachidonic acid production (an eicosanoid bioactive lipid member) and nitric oxide synthase activation (96) through Mas receptor, indicating the potential utility of GMP and bioactive lipids to modulate inflammation and counteract cognitive impairment.

FMT emerged as a successful therapeutic strategy to manage recurrent C difficile infection, but the applicability and extensibility of this approach to other gastrointestinal and extragastrointestinal disorders is still questionable based on the inconsistent efficacy results. Furthermore, although, it has been hypothesized that cognitive impairment may share some of the pathways that are associated with gut dysbiosis (94), suggesting that FMT may be a strategy to restore intestinal homeostasis in this condition, the potential utility of this method is still based on theoretical assumptions. Indeed, to date, there is no evidence from both preclinical and clinical studies that confirms the effectiveness of this therapeutic strategy to manage this age-related condition. Hence, more solid evidence from both animal and human models is still needed.

Physical exercise, one of the most studied and effective interventions to prevent and manage several chronic inflammatory, metabolical and functional diseases (97), is also a potential strategy to manage cognitive impairment through the bidirectional modulation of gut–brain axis (94). However, the few controlled human trials provide limited evidence with small sample sizes and different geographical, nutritional, morphological, and physical characteristics—known factors to influence the gut microbiota (82)—limit the generalization of the results into the vast heterogenic elderly participant community with cognitive impairment. In addition, there is a knowledge gap on the impact of exercise modality, intensity, and frequency on their mediating roles in gut microbiome, to precisely define the optimal exercise dose–response for each chronical and immune-based disease, particularly on cognitive impairment. Therefore, although there is a growing body of evidence pointing to promising exercise-health effects on cognitive impairment through the modulation of gut microbiota, this therapeutic strategy is far to be clearly elucidated.

Gut health and its impacts beyond the gut are starting to be viewed at least, partially dependent on the composition and function of the gut microbiome and its respective metabolic products (98). Therefore, correctly identifying effective dietary components that modulate gut microbiota is crucial since diet has emerged as one of the most significant environmental factors defining and shaping the mammalian gut microbiome (98). In fact, recently, the long-term impacts on mice fed with a low-fiber diet over multiple generations was shown to cause a progressive loss of certain fiber-fermenting bacteria’s that could not be restored solely by high-fiber diet (99). Therefore, this concerning evidence demonstrates the potential deleterious effects that sustained imbalanced nutritional patterns may have on gut modulation, and consequently in host health. Remarkably, high-fiber diet, particularly their end-degradation products, the SCFAs present as a potential therapeutic strategy to counteract gut dysbiosis and several age-related conditions. However, to date, studies specifically assessing the role of high-fiber diets, SCFAs, gut microbiota composition, and cognitive impairment are still lacking. So far, most of the studies are based on experimental animal models that only allow to establish an association effect. Diet and environmental factors may explain a 10% larger variation of gut microbiome composition in humans, compared to animals because of the controlled laboratory settings. More research is needed to clarify the influence of confounding variables in humans. Other diets can also have beneficial or detrimental impacts on gut microbiome and cognitive, which has been reviewed in depth elsewhere (100).

Therefore, more evidence from tightly controlled intervention trials is needed to establish a rigorous cause–effect relationship in cognitive impairment. Table 1 summarizes the current human studies on interventions and gut microbiome and cognitive outcomes. This will advance the field passing from simple associations that may lead to either sub- or overinterpretations of the results when translated into the human context. In this scenario, the translation of these potential therapeutic strategies into clinical practice will require to evaluate the clinical relevance of the gut–brain axis into cognitive impairment and the development of rigorous clinical trials. This will establish a rigorous link between aging, gut microbiota, and cognitive impairment and the potential applicability of these therapeutics strategies as a modulation factor, transitioning from the current knowledge based on the basic science to the applied clinical setting.

Table 1.

Summary of Human Studies on Interventions: Effects on the gut Microbiome and Major Clinical Outcomes

Study	n	Population	Age	Gender	Ethnicity	Gut-based intervention	Lengths of intervention	Major outcomes
Akbari and colleagues (35)	60	Alzheimer’s disease	60–95 years	Male and female	Iranian	Probiotic milk with Lactobacillus acidophilus, Lactobacillus casei, Bifidobacterium bifidum, and Lactobacillus fermentum (2 × 109 CFU/g for each)	12 weeks	↑Mini-mental state examination score
Leblhuber and colleagues (36)	20	Alzheimer’s disease	67–86 years	Male and female	Austrian	Probiotic supplementation with L casei, Lactococcus lactis, L acidophilus, Bifidobacterium lactis, Lactobacillus paracasei, Lactobacillus plantarum, B lactis, B bifidum, and Lactobacillus salivarius	4 weeks	↓Fecal Zonulin ↑Fecal Faecalibacterium prausnitzii ↑Serum kynurenine
Braat and colleagues (42)	10	Crohn’s disease	N/A	N/A	N/A	10 capsules with 1 × 1010 CFU of L lactis expressing IL-10 twice daily	1 week	↓Crohn’s disease activity index
Rossen and colleagues (54)	50	Ulcerative colitis	30–56 years	Male and female	Dutch	FMT with feces from healthy donors via nasoduodenal tube	N/A	↑Diversity (Shannon index) of fecal microbiota Remission associated with proportions of Clostridium clusters
Taniguchi and colleagues (73)	33	Older adults	62–76 years	Male	Japanese	Endurance exercise with three-cycle ergometer-sessions/week, intensity progressive increase from 60% VO2 peak to 75% VO2 peak, duration progressive increase from 30 min/session to 45 min/session	5 weeks	↓C difficile ↑Oscillospira
Munukka and colleagues (74)	19	Overweight adults	33–40 years	Female	Finnish	Endurance exercise with three-cycle ergometer-sessions/week, progressively increased from low to moderate intensity, duration progressive increase from 40 to 60 min/session	6 weeks	↑Akkermansia ↓Proteobacteria ↑Jaccard distance of genus level β-diversity
Clarke and colleagues (75)	40	Professional rugby players	23–35 years	Male	Irish (except 1 Indian)	Comparison between professional rugby athletes and physical size, age- and gender-matched controls	N/A	↑Both α and β diversity representing 22 distinct phyla

Note: FMT = fecal microbiota transplantation.

Funding

This work was supported by National Institute of Aging (R01AG054538 to T.W.B. and C.S.C.).

Authors’ Contributions

Y.S., L.B., and L.R. wrote the manuscript. P.J.-L., L.M., T.B., and C.C. edited the manuscript.

Conflict of Interest

None declared.