How Taking Probiotics May Affect Brain Decline and Aging by Changing Gut Bacteria

Microbiota refers to the community of living organisms residing in a given environment. The microbiota is distributed in different cavities of the human body, from the mouth, in the acoustic meatus, the pharyngeal cavity, the surface of the dermal layer, and the digestive tract, among others, the IM being one of the densest as it includes all species of microorganisms residing in the gastrointestinal tract. This microbiota is indispensable for various metabolic functions, such as the development of immunity and nutrition [3,16].

Even though colonization of the IM begins in uterine life, the composition, diversity, and metabolism changes throughout the different stages of life [16,17]. The development of IM begins before birth, because of the exposure of the fetus to maternal microbial metabolites and bacterial communities from the skin, vaginal, oral cavity, and gastrointestinal tract. At birth, there is a significant transfer of the microbiota from mother to baby, which is determined by the type of delivery. Subsequently, the type of feeding determines the transfer of microorganisms, maintaining a stable colonization until the introduction of complementary feeding, at which point IM dynamically diversify until the first five years of age. From this moment and throughout adulthood, colonization remains relatively stable until the age of 60, at which point its diversity decreases again [17,18,19].

During aging, the IM changes to a less healthy one, with an increase in E. coli and other proteobacteria, along with a decrease in beneficial anaerobes such as Bifidobacteria and Bacteroides, and a decrease in the Firmicutes/Bacteroidetes ratio. On the other hand, an increase in Akkermansia has been found in centenarians, which has been related to longevity [20].

Studies focused on the analysis of intestinal bacterial communities in older adults have determined that the most predominant species are Bacteroides, Prevotella, and Ruminococcus, regardless of nationality, sex, age, or BMI. Likewise, a lower proportion of Firmicutes and Bacteroidetes has been reported compared to younger adults, in addition to a lower count of short-chain fatty acids (SCFA)-producing species. All of these modifications are even associated with the immunosenescence and fragility characteristics of aging [21].

Thus, metagenomic studies have identified bacterial species as potential biomarkers of aging, such as Bacteroides, Eubacterium, and Bifidobacterium. Likewise, the presence of Akkermansia muciniphila has been associated with improved health. Thus, alterations in the composition, diversity, and functionality of the immune system are closely related to conditions associated with aging, such as immunosynthesis and inflammaging, which in turn reduce longevity and contribute to increased morbidity and mortality [22].

The bacterial colonization of the human intestine begins at birth, and subsequently depends on intrinsic factors such as genetics and physiological state, while extrinsic factors considered are diet, bacterial exposure during childhood, stress levels, puberal development, antibiotic consumption, and aging, and these conditions can lead to a dysbiosis, a state related to a wide variety of health conditions [23].

In addition, nine characteristics of aging have been identified as follows: genomic instability, telomere wear, epigenetic alterations, loss of proteostasis, mitochondrial dysfunction, cellular senescence, deregulated nutrient detection, stem cell exhaustion, and altered intercellular communication, which have been related to changes in the microbiome [24].

Thus, aging has been associated with the progressive alteration of the physiological balance between the host and the commensal IM, a situation defined as dysbiosis. The above is due to a greater diversity in the IM being associated with a better health state, characteristic of youth, while a low microbial diversity has been associated with the disease state, typical of aging [24,25].

It is worth mentioning that changes in bacterial diversity during aging have been linked to changes in diet, immunosenescence, and exposure to various drugs. In addition, intestinal dysbiosis contributes to the development of a wide variety of diseases, which consequently decreases healthy aging [21]. Therefore, recent information suggests that maintaining a "young" or "healthy" IM may contribute to the maintenance or control of immunosenescence [22]. Although genera such as Akkermansia, Bifidobacterium, and Christensenellaceae have been identified as being related to longevity, there is a common tendency to accumulate mostly potentially proinflammatory metabolites [18].

Hence the importance of maintaining an eubiosis, because it conditions homeostatic systems such as the endocrine and immune systems but also the nervous system. To maintain this eubiosis, it is important to maintain a healthy lifestyle and maintain the consumption of probiotics, which will ensure a healthy longevity [26].

The gut–brain axis suggests that the gut and the brain have a bidirectional communication, maintaining communication through the modulation of the immune system, the vagus nerve, the enteric nervous system, the neuroendocrine system and the circulatory system, a process that is carried out through the synthesis of neuroactive substances, metabolites, and hormones. Due to the above, communication between the organs occurs and can influence the function of the other, so it is important to maintain proper intestinal health in order to strengthen the cognitive reserve and thus be able to delay the neurological changes characteristic of this age group [27,28].

The neural pathways of bidirectional gut–brain communications are intuitive. The vagus nerve is the tenth cranial nerve, from which the hepatic and celiac branches innervate the intestine which in turn transmits neurohormones, among which cholecystokinin (CCK), glucagon-like peptide-1 (GLP-1), peptide YY (PYY), serotonin, etc., stand out. These hormones propagate to afferent terminals and bind to their receptors, fulfilling different functions among them, such as the regulation of food intake and digestion, either directly in the brain or indirectly through the vago-cerebral pathway [29].

For this reason, intestinal dysbiosis has currently been considered a factor that promotes neurodegeneration, since it has been observed that in adults with Alzheimer's diseases, there is a significant alteration in the structure and composition of the IM, a situation that can increase intestinal permeability and induce inflammation. In addition, in older adults with neurodegenerative diseases, a reduced intestinal bacterial biodiversity has been observed [30].

IM dysregulation and subsequent neuroinflammation may play a crucial role in the pathogenesis of neurodegenerative diseases. IM modulates intestinal permeability and various immune functions by secreting toxins and fatty acids; thus, its disruption leads to oxidative stress, inflammation, altered blood–brain barrier (BBB), immune system activity, neurodibrial tangles, and Aβ plaques followed by neurodegeneration [30].

It is such that dysbiosis promotes the decrease of the SCFA and increase of harmful microbial components, as the lipopolysaccharide and inflammatory cytokines (such as interleukin-6 and tumor necrosis factor alpha), which in turn increases the permeability of the BBB and promotes neuroinflammation [31].

The reason why the diversity and composition of intestinal bacteria determine the abundance of microbiota-derived metabolites, neurotransmitters, and SCFA such as butyrate, propionate, and acetate is because the imbalance of these intestinal bacteria alters the aforementioned processes and results in an inadequate intestinal environment. This profile generates an environment of signaling molecules that can ultimately communicate with the brain through neural communication via the vagus nerve, and endocrine signaling involving the hypothalamic–pituitary–adrenal (HPA) axis and the immune system, which as a means of preservation and defense, increases cytokine secretion, modulating brain function, behavior, and cognition [14,32]. It has been shown that IM bacteria can produce different neurotransmitters, such as gamma-aminobutyric acid (GABA), which is produced by bacteria of the genus Lactobacillus and Bifidobacterium. This inhibitory neurotransmitter is the most important neurotransmitter in the central nervous system since dysfunction of the GABAergic system is implicated in the pathophysiology of several mental health conditions such as depression, anxiety, autism, and schizophrenia [5].

This is based on the fact that the symbiotic relationship between the host and the IM occurs through bidirectional signaling between bacteria and the CNS, which includes endocrine and immune pathways, but also mood, emotional, cognitive, and even habitus, as well as environmental interaction, where the communication pathways of the microbiota-gut–brain axis are schematized [33].

It is worth mentioning that lifestyle, and modification in eating habits, as well as the environment, can cause changes in the IM composition, which subsequently affect the intestine–brain axis. The relationship between IM and the environment is observed with greater evidence in people with scarce resources and poor sanitary conditions, especially in those who are constantly exposed to contaminated water and food, who are also characterized by anemia and impaired brain development, as well as epithelial affection with loss of enzymes and decrease in the functional surface of the intestine that causes poor digestion and malabsorption, in addition to alterations in the balance of the IM [34].

Among the changes in dietary habits that alter the composition of the IM, diets rich in fat or carbohydrates can be observed. Changes in temperature significantly influence the composition of IM and contribute to alterations in neurotransmitter levels in the stool, blood, and central nervous system [35].

There is growing evidence about the role of IM in neurodegenerative diseases, primarily due to microglial activation and neuroinflammation, characteristics of neurodegeneration. Because current treatment for neurodegenerative disease is based on controlling symptoms and disease progression, research has sought to design approaches beyond these types of interventions [28,31].

As previously reviewed, neurodegeneration is strongly influenced by the relationship between the gut–brain axis, the IM, and its metabolites, such as SCFA, bile acids, and tryptophan metabolites; which is why the modulation of IM for the production of metabolites that mitigate neurodegenerative processes is an emerging area of interest [31,36].

Dysbiosis can lead to increased intestinal permeability, which allows the passage of proinflammatory cytokines and microbial products into the bloodstream, which in turn generates systemic inflammation that, when extended to the central nervous system, can lead to neuroinflammation, neuronal damage, and cognitive decline, accelerating neurodegeneration [36,37,38].

Another factor that may play a role in neuroinflammation is the involvement of IM in the metabolism of several neurotransmitters responsible of mood regulation, cognition, and behavior, such as serotonine, dopamine, and acetylcholine, which are involved in the development of neuropsychiatric disorders such as depression, anxiety, and Parkinson's disease. Likewise, altered levels of neurotransmitters can negatively affect not only the formation and plasticity of brain synapses, but also the enteric nervous system. For this reason, the relationship between dysbiosis and neurotransmitter metabolism would prove to be a crucial therapeutic approach for diseases such as depression, Parkinson's disease, and Alzheimer's [31,37].

Similarly, SCFA-producing bacteria are essential for maintaining the intestinal barrier and modulating immune homeostasis. Once butyrate, propionate, and acetate cross the BBB, they enhance the expression of tight junction proteins, which prevents the influx of neurotoxic substances into the brain. For this reason, these fatty acids play an important role in controlling neuroinflammation, promoting neurogenesis, and contributing to overall neurofunction and neurotrophic factors [38,39].

Among the IM modifications related to neurodegeneration, the modification in F/B ratio has been identified, particularly due to the decrease in Firmicutes and the increase in Bacteroidetes. On the other hand, the increase in the relative abundance of Ruminococcaceae, Enterococcaceae, and Lactobacillaceae, as well as the decrease in Lanchnospiraceae, Bacteroidaceae, and Veillonellaceae, have been observed in patients with Alzheimer's disease [22]. Likewise, the reduction in the concentration of Faecalibacterium sp., Bifidobacterium sp., and Akkermansia sp., can increase neuronal injury, inflammation, and oxidative stress, leading to neurocognitive dysfunction [31].

Similarly, the reduction of Bifidobacterium and Lactobacillus with the increase of intestinal concentrations of proteobacterias and bacteroids, are related to the increase of lipopolysaccharides, a bacterial endotoxin that is characterized by disrupting the function of the blood–brain barrier [31,37].

On the other hand, the Verrucomicrobia phylum was found to be increased in Parkinson's disease and Alzheimer's disease, so research has correlated it with increased levels of LPS and consequently of proinflammatory factors such as TNFα, IL6, and C-reactive protein (CRP). A similar situation is observed with Collinsella, which is positively associated with neurodegeneration because it induces the degeneration of dopaminergic b¿neurons, which disrupts physiological maintenance and cell death [38].

Due to the above, the importance of maintaining a balanced IM, in which Lactobacillus and Bifidobacteria predominate, is highlighted, since the metabolites produced by these are considered an important pillar in the prevention and control of neurodegeneration [36].

Due to the growing field of research on the impact of dysbiosis on neurodegeneration, human clinical trials have focused on therapeutic modulation of IM, by dietetical interventions and consumption of probiotics, herbal medicines, probiotics, and symbiotics. This is conducted with the aim of promoting the production of SCFAs that have a neuroprotective role, by reversing dysbiosis [25,39].

Probiotics are non-pathogenic and generally safe microorganisms that are marketed and consumed as dietary supplements or functional foods because they promote probiosis mechanisms that include modulation of microbial communities, pathogen suppression, immunomodulation, epithelial cell stimulation, or intestinal barrier integrity. Due to the above, the administration of probiotics reinforces the hypothesis of the bidirectional relationship of the gut–brain axis for the prevention of intestinal dysbiosis [40].

The mechanism of action of probiotics is mainly based on preventing colonization and invasion by pathogenic microorganisms, improving the barrier function of the gastrointestinal tract, modulating the immune system, and reducing the proinflammatory response [40]. According to Florencia-Martinez et al. 2022 [41], among the most common mechanisms of action of probiotics are resistance to colonization through competition with pathogens, synthesis of short-chain fatty acids, regulation of the microbiota and enterocyte regeneration. Among frequent mechanisms include vitamin and mineral synthesis, strengthening of intestinal barrier, metabolism of bile salts and avoid calcium-based collectors, while rare mechanisms include endocrinological, immunological and neurological effects [40].

The goal of IM modulation therapies is to rebuild a dysbiotic microbiota into a microbiota in eubiosis. Probiotics are usually composed of combinations of the genera Lactobacillus and Bifidobacteria, which suppress inflammation and modulate the immune system by preventing the induction of the cytokine IL-8 in the human colonic epithelium, as well as reducing intestinal permeability and inhibiting endotoxemia [41,42].

This, due to positive changes in intestinal metabolites, such as SCFA, plays a crucial role in neuroreactivity by reducing neuroinflammation. This also improves tryptophan production, which in turn increases serotonine production [38].

As part of the therapeutic promises, it has been identified that oral supplementation with Bifidobacterium increases the concentration of lymphocytes, improving the activity of natural killer cells, phagocytosis in peripheral cells, and the concentration of neutrophils, contributing to the decrease of cellular immunosenescence [22]. Other trials have identified that multi-strain probiotics (composed of Bifidobacterium lactis, Lactobacillus bulgaricus, Streptococcus thermophilus, and Lactobacillus lactis), increase the concentrations of fatty acids that maintain adequate brain function, learning memory, and neurogenesis [29].

Similarly, it has been shown that an imbalance in SCFA production is associated with the development of diseases that promote neurodegeneration, such as Alzheimer's and Parkinson's. The reason why is because of the recommended supplementation with SCFA-producing bacteria such as Lactobacillus, Bifidobacterium, and Clostridium, particularly Lactobacillus and Bifidobacterium, which are key strains in the homeostasis of the gut–brain axis, due to their influence on reducing systemic inflammation and strengthening tight junctions. On the other hand, Lactobacillus rhamnosus modulates proinflammatory cytokines (TNFα and IL-6), and it directly strengthens the function of the BBB, as well as Bifidobacterium longum and Bifidobacterium breve, by restoring SCFA levels, reducing oxidative stress and glial activation. Likewise, it has been shown that the joint administration of B. bifidum, L. acidophilus, and B. longum in doses of 2 × 10⁹ CFU/day and selenium supplements, significantly improved cognitive performance [37,43].

Tian et al. 2022 conducted a double-blind, randomized controlled trial, where they studied Major Depressive Disorder (MDD) in patients over 18 years old without restrictions in the use of antidepressants, where they investigated possible psychotropic effects of a combined probiotic intervention of three strains Bifidobacterium breve CCFM1025, Bifidobacterium longum CCFM687, and Pediococcus acidilactici CCFM6432, evidencing a significant reduction in the depression indexes and significantly improving the gastrointestinal functions of the patients. Referring to that, the mechanisms possibly correlated with the modulation of hormones related to the HPA axis, brain serotonergic systems, and neuronal plasticity [44].

On the other hand, Schaub et al. 2022 tested the potential of a short-term high-dose probiotic supplementation as a complementary treatment for depression, where the main finding was an evident improvement of depressive symptoms after probiotic supplementation. Functional magnetic resonance imaging (fMRI) showed the brain structure called putamen, which is affected by depression, after the consumption of probiotics for 4 weeks during its activation. This postulates that putamen hyperactivity evoked by negative emotional stimuli contributes to the negativity biases found in patients with MDD, who perceive emotionally neutral faces as emotionally negative faces. It is worth noting the importance of compliance during probiotic supplementation as it is equally important as general antidepressant therapy, so it is important to consider the choice of probiotic formulation and dosage [45].

Another study on probiotic supplementation was conducted by Aljumaah et al., who performed a randomized, placebo-controlled, double-blind trial, in which the impact of L. rhamnosus GG supplementation on cognitive functions was evaluated in healthy adults aged 52–75 years for 3 months. The neuropsychological assessment consisted of completing the computerized NIH Toolbox for the Assessment of Neurological and Behavioral Function Cognition, which evaluates different cognitive domains. Among the results, the improvement in neuropsychological tests was observed during the three months of follow-up with probiotic supplementation. Thus, it was possible to demonstrate the existence of an association between IM and cognitive performance aimed at achieving successful aging and maintaining functionality and independence [46].

Asaoka et al. conducted a double-blind, randomized, controlled trial to study the effect of Bifidobacterium breve MCC1274 (A1) on improving cognition and preventing brain atrophy in elderly patients aged 65–88 years with mild cognitive impairment for 24 weeks, for which cognitive functions were assessed using the Advanced Driving Assistance Systems (ADAS-Jcog) and Mini-Mental State Examination (MMSE) tests, in addition to an MRI to determine changes in brain atrophy using the Voxel-based Voxel-Specific Regional Analysis System for Alzheimer's Disease (VSRAD). In the results, test scores were obtained at baseline at week 8, 16, and 24, in which it was observed that scores were uniformly improving and as for VSRAD data, probiotic supplementation suppressed the progression of brain atrophy and therefore is a practical approach for the prevention of cognitive decline in subjects with mild cognitive impairment [47].

While knowledge in the field of probiotic supplementation and its impact on neurodegeneration continues to be elucidated, it is known that metabolites such as SCFA are important in maintaining adequate brain function, since they actively participate in neurogenesis. In addition, SCFA influences the maintenance of intestinal permeability, a condition that is associated with the appearance of disorders such as stress or depression [29].

On the other hand, the microbiota also contributes to modulating the expression of brain-derived neurotrophic factor (BDNF), which in turn promotes the survival of existing neurons as well as the growth of new neurons. Likewise, IM also participate in the production and modulation of neurotransmitters and neuromodulatory compounds such as GABA, serotonin, dopamine, acetylcholine, and noradrenaline [29].

Furthermore, the intestinal microorganisms induce the synthesis of SCFS, B12 vitamin, and neurotransmitters such as, serotonin, catecholamines, glutamate, and GABA, and neuromodulatory metabolites that can affect a person's health [48].

As a result of bacterial translocation, a characteristic of the last stage of life, a series of systemic inflammatory responses are triggered and promote inflammation of the central nervous system and neurodegeneration. This is the reason why the microbiota–gut–brain axis represents a significant modulator in improving the development and progression of neurodegenerative diseases [28].

As part of clinical therapies for neurodegenerative diseases, those are considered based on bacterial modulation through the intake of prebiotics, probiotics, and/or dietary interventions for the control of symptoms and the development of pathological conditions. Particularly, the aim of probiotic consumption is to introduce specific microbial strains that promote the production of metabolites with antioxidant and anti-inflammatory properties [28,48,49].

Based on this fact, clinical trials in humans have shown that supplementation with probiotics such as Escherichia coli, Lactiplantibacillus plantarum, and Bifidobacterium pseudocatenulatum improve function and prevent cognitive decline after 12 weeks of follow-up [49]. On the other hand, research has shown that supplementation with Bifidobacterium breve promises to be an effective intervention to improve immediate, delayed, and special memory functions after 4 months of intervention. In addition, supplementation with Lactiplantibacillus plantarum, from fermented soy, improve the cognitive composite score of older people after 12 weeks of intervention, and other similar results were obtained with supplementation of Lactobacillus and Lactobacillus rhamnosus GG [50].

On the other hand, some studies do not show a direct improvement in cognitive function but they do influence the improvement of metabolic factors associated with cognition, such as insulin sensitivity. Such is the case with the supplementation of bacteria such as Akkermansia muciniphila, Lactobacillus acidophilus, Lactobacillus casei, Bifidobacterium bifidum, and Bifidobacterium fermentum, also after 12 weeks of supplementation [50].

The progress in research has been such that today, as a result of knowledge about IM and the development of new technologies, next generation probiotics (NGP) have been formulated, which go beyond traditional strains such as A. muciniphila, Feacalibacterium preausnitzii, Roseburia intestinalis, and Bacteroides fragilis, and these contribute to the maintenance of epithelial and endothelial integrity, enhance the function of the central nervous system barrier, maintain a considerable anti-inflammatory effect, and restore the balance of neurotransmitters, which makes them powerful neuroprotectors [28,37].

According to the review by Sheng et al., 2024, the supplementation of bacteria such as Bifidobacterium breve A1, Lactiplantibacillus plantarum, Lactobacillus acidophilus, Lactobacillus casei, Bifidobacterium bifidum, Lactobacillus fermentum, Lactobacillus rhamnosus, Bifidobacterium longum, Lactobacillus lactis, Bifidobacterium infantile, and Lactobacillus reuteri, in doses of 1–2 × 10¹⁰ UFC/day, improves cognitive function. In addition, a reduction in serum C-reactive protein levels (inflammation indicator) and plasma malondialdehyde (oxidative stress indicator) was observed. Furthermore, it improves insulin metabolism, triglyceride levels, and improves intestinal discharge and intestinal transit time [28].

In addition to the effects on cognitive function, supplementation with a mixture of five strains of Lactobacillus with five strains of Enterococcus, showed beneficial effects on the damage caused by high-fat diets, such as intestinal permeability, metabolism, immunity, and physical deterioration [50].