The Emerging Scenario Of The Gut–Brain Axis: The Therapeutic Actions Of The New Actor Kefir Against Neurodegenerative Diseases Part 1

Abstract: 

The fact that millions of people worldwide suffer from Alzheimer's disease (AD) or Parkinson's disease (PD), the two most prevalent neurodegenerative diseases (NDs), has been a permanent challenge to science. 

Parkinson's disease is a common neurodegenerative disease, characterized by motor neuropathy as the main manifestation, and in terms of memory, it manifests as impaired executive function and cognitive impairment. Despite this, for patients with Parkinson's disease, memory maintenance and improvement are still an extremely important part, because it is related to the maintenance of life and social abilities.

There are many ways to help people with Parkinson's disease maintain and improve their memory. First of all, effective training is very necessary. Professional cognitive rehabilitation therapists can develop training programs for patients targeting different types of memory, such as spatial-based memory, language-based memory, visual-based memory, etc. These exercises can help patients with Parkinson's disease strengthen their thinking and attention and enhance the stability of their memory.

Secondly, moderate exercise is also an effective way to improve memory. Patients with Parkinson's disease can help improve the connections between brain neurons and promote information transmission and storage by performing appropriate exercises, such as walking around continuously and doing calisthenics. In addition, good sleep and eating habits are also important because they can help the patient's brain get enough rest and energy so that memory can be fully maintained.

Finally, an optimistic attitude also plays an important role in improving memory. When facing the obstacles and difficulties caused by Parkinson's disease, maintaining a positive attitude can help patients overcome low self-esteem and depression, improve self-confidence, and enhance memory.

In summary, although patients with Parkinson's disease face many challenges in memory, they can still maintain good memory by adopting appropriate methods, effective training, and maintaining a healthy lifestyle. The important thing is that everyone please maintain a positive attitude and believe that you can overcome everything caused by Parkinson's disease and your life will be better! It can be seen that we need to improve memory, and Cistanche deserticola can significantly improve memory because Cistanche deserticola is a traditional Chinese medicinal material that has many unique effects, one of which is to improve memory. The efficacy of Cistanche deserticola comes from the multiple active ingredients it contains, including tannic acid, polysaccharides, flavonoid glycosides, etc. These ingredients can promote brain health through a variety of pathways.

Click Know to improve short-term memory

New tools were developed over the past two decades. They were immediately incorporated into routines in many laboratories, but the most valuable scientific contribution was the "waking up" of the gut microbiota. 

Disturbances in the gut microbiota, such as an imbalance in the beneficial/pathogenic effects and a decrease in diversity, can result in the passage of undesired chemicals and cells to the systemic circulation. Recently, the potential effect of probiotics on restoring/preserving the microbiota was also evaluated regarding important metabolite and vitamin production, pathogen exclusion, immune system maturation, and intestinal mucosal barrier integrity. 

Therefore, the focus of the present review is to discuss the available data and conclude what has been accomplished over the past two decades. This perspective fosters program development of the next steps that are necessary to obtain confirmation through clinical trials on the magnitude of the effects of kefir in large samples.

Keywords: oxidative stress; inflammation; neurodegenerative diseases; kefir; chronic focal encephalitis; angiotensin II; autonomic nervous system; gut microbiota.

1. Introduction

Neurodegenerative diseases (ND) are characterized by the slow and gradual degeneration of axons and neurons of different areas of the central nervous system (CNS), resulting in movement and/or cognitive disorders. 

These complex disorders are closely associated with oxidative stress and inflammation, which are two main systemic conditions that aggravate neurodegeneration [1,2]. 

This review is focused on the discussion of the therapeutic benefits of the probiotic kefir on oxidative stress and inflammation, which are important contributors to chronic neural disturbances, including Parkinson's disease (PD), Alzheimer's disease (AD), dementia, and epilepsy. Despite the continuous search for effective multidisciplinary approaches and neuroprotective therapies [3,4], ND is yet incurable and the patients suffering from these diseases succumb to the high medical costs. 

Based on the current data, it is estimated that 50 million people worldwide are affected by these disorders, mainly in low and middle-income countries [5]. It is estimated that a new case appears every 4 s, and forecasts point out that in 2050, the number of people suffering from these diseases will reach 115.4 million due to population aging [6]. 

2. Gut Microbiota: An Extraordinary Army of Fighters to Defend the Host

Over the past 10 years, an extraordinary increase in the number of experimental and clinical studies aiming to understand the interactions among microbes inhabiting the host's gut was observed [6–8]. 

As noted in the line graphs of Figure 1, which were constructed based on the number of papers that were published, they are indexed on the PubMed platform. The bottom graph of Figure 1 shows that the gut microbiota is 20 years old, i.e., as demonstrated by the few papers published in 2000 and the number of papers that were published in 2020. 

The line that indicates the evolution of papers related to probiotics has a similar slope and magnitude. The reason for this growing number of papers in this area could be because many investigators working with "omics-based" approaches have joined or created new opportunities in the field of microbiota [6–9]. Therefore, biomedical sciences are facing new opportunities and perspectives for new attractive scenarios.

Based on genetic sequence analysis of samples of meconium and feces [10], the general opinion is that the gut microbiota starts in the newborn under the influence of the health conditions of the prenatal mother's health, gestational age, mode of delivery, type of feeding, quality of the environment and exposure to toxins (see Figure 2, the schematic time course of evolution of the gut microbiota from infants to elderly people) [10–14]. 

Therefore, once the appropriate composition was established, the symbiotic community could be considered an incredible legion of 109 to 1012 warriors composed of five main phyla.

The first role of the gut microbiota is to protect the host against pathogenic microorganisms and to neutralize the effects of toxins and/or drugs [12–14]. The second role is to provide essential metabolites/vitamins, facilitating the absorption of ions and molecules and thus generating an additional source of energy for colonocytes [15]. 

For example, dietary components absorbed through different segments of the small gut provide short-chain fatty acids (SCFAs) and contribute to reducing food intake, increasing energy expenditure, and improving insulin sensitivity (see elsewhere for details [16,17]). 

The third phase is related to the trophic process (growth and differentiation) of epithelial cell lineages, which are important for the development and maturation of the immunological system initiated in fetal life [18]. Considering that aging-related diseases can be a consequence of changes during the early years of life (Figure 2), the analysis of the microbiota in infants has become an interesting issue [14,19]. 

It is important to emphasize that inadequate microbial colonization during this period can lead to dysbiosis, impacting health in adulthood. 

As shown in Figure 2, maternal disturbances such as hypertension, preeclampsia, obesity, and preterm delivery will affect the seeding of the newborn's gut microbiota. A healthy pregnancy supports the development of the immune system of the fetus during the first years of life [13,20], which is important because the development of the immune system is a key condition for long-term survival. 

In this regard, there is a consensus that the aging process, associated with DNA damage, significantly influences the development and severity of ND. Although the meconium of newborns already shows an abundance of phyla and a great diversity of species, it is necessary to establish reference guides of normal values for generating medical reports [19]. 

As illustrated in Figure 2, the composition of the gut microbiota in the newborn can be influenced by sequential factors: mode of birth (vaginal vs. cesarean), type of nutrition (formula vs. breastfeeding), and environmental exposure to contaminants (e.g., bisphenol A) [14,20,21] and toxins [22,23]. In addition, it is known that during this stage of life, the maturation of gut-associated lymphoid tissue (GALT) occurs [24]. 

During infanthood, the gut microbiota is an interface mediator between internal and external factors since the genetic sequencing approach shows a diversified composition of mutualistic bacteria and yeasts [19]. These microorganisms protect the host and are associated with the achievement of immune homeostasis at maturity, which is known as "eubiosis". 

In contrast, the term "dysbiosis" is associated with an imbalance between protective and pathogenic microorganisms, which makes the host susceptible to diverse invaders, providing nonhealthy metabolites and diverse immune outcomes [25]. Therefore, the goals of the present review are to discuss possible mechanisms by which the aging process can lead to ND and, in other cases, protect the person for more than one century. 

Recently, epidemiological studies estimated that in 2050, the world population older than 60 years will increase by 100% [26], which means that the high number of aging-related neurodegenerative and cardiometabolic diseases could also grow in the same proportion [27]. In many countries, people of all ages have been influenced by globalization and, unfortunately, abandoned the millenary "healthy diet" (e.g., the Mediterranean, and Asian diet pyramids; see the Book of Genesis 25:8 in the Bible) for the unhealthy Western-type diet [28–30], which is considered to be a negative factor. 

It is well established that a balanced microbiota is dependent on good dietary intake (rich in fiber, vegetables, and fruits with the secretion of bile acids accompanied by reduced intake of L-carnitine, lipopolysaccharides (LPS), and animal fats). Some evidence demonstrates that the dietary habits of the host are determinants of oxidative stress and inflammation. 

More specifically, a low-protein diet was associated with high levels of Bifidobacterium and Lactobacillus species [31]. In this regard, low levels of Bacteroidetes and Clostridium maintain SCFAs compatible with a well-shaped and selective gut barrier (increasing mucus secretion with tight junction integrity), avoiding the consequent overweight state [32]. Interestingly, conditions of malnutrition lead to an imbalance of Bifidobacterium and Lactobacillus [32], facilitating the growth of facultative anaerobes contributing to dysbiosis [16,33]. 

In addition to diet, the gut microbiota is also considered to be highly vulnerable to aging, pollutants, hygiene, and other environmental factors, such as smoking, high alcohol intake, and/or sedentary life (as illustrated in Figure 2). The microbiota varies along the gastrointestinal tract (small and large portions) [34]. 

However, the main metabolism of microbes occurs in the luminal portion of the large intestine, which validates the use of stool samples to analyze the composition/distribution of microbes through microbiological, biochemical, or genetic approaches. 

Although a "gold standard" signature of healthy gut microbiota does not exist, our group currently considers a richness of> 400 species and a general diversity of> 7 as important indicators of gut stability. Therefore, due to the great variation between subjects of different ethnicities, genders, ages, and physiological statuses, a more accurate index still needs to be established for a better analysis. 

Despite that challenge, we account for the presence of at least four protector species: Lactobacillus spp. (1 to 6%) [35], Akkermansia muciniphila (1 to 5%) [36], Faecalbacterium prausnitzi (5 to 12%) [37] and Bifidobacterium spp. (1 to 6%) [38]. 

Despite the finding of the great variability in the dominant phyla Firmicutes and Bacteroidetes in healthy individuals, the relative percentage could also be used as an index of abundance [10]. In clinical practice, the most relevant marker of gut eubiosis can be calculated by the abundance of Firmicutes and Bacteroidetes (F plus B), in the range of 85–95%, and their proportion (F/B) has an index of approximately >0.7 [5]. 

Another piece of evidence is that most elderly healthy individuals exhibit a proportion of Firmicutes/Bacteroidetes (~0.6) [39]. On the other hand, it is commonly observed that unhealthy aging can result in dysbiosis [40,41].

To close this issue, it is important to recognize the relevance of morphofunctional gut integrity of the epithelial wall border covered by mucus to prevent the entrance of pathogens and undesired diet-derived chemicals from crossing into the systemic circulation. 

Other factors, such as inadequate protective mucin production, dendritic cell dysfunction, abnormal tight junctions (compromising the immune system), and decreased production of food-derived bioactive compounds that are fermented by gut microorganisms, are also typical phenotypes of dysbiosis [42].

3. Gut-Brain Axis: Extraordinary Advances and Opportunities to Improve the Treatment of Dysbiosis

The gut microbiota–brain arch reflex intercommunicates in a bidirectional way (via the direct autonomic nervous system, immunological and neuroendocrine routes), which is an important structure in the pathophysiology of neurodegenerative disorders such as AD, epilepsy, and PD, with the pathophysiology occurring mainly when the gut microbiota is dysfunctional [43–45]. 

The dominant linking appears to be through the vagus nerve, which is composed of approximately 80% afferent (sensory) and 20% efferent (motor) fibers connecting the visceral organs to the brain [44–47]. Additionally, known as the "crossroad of neuroimmune interactions" (see [43]), this nerve is an important sensor of changes in microbiota metabolites, transferring gut information to the central nervous system [48]. 

Overall, this system can integrate cognitive and motor functions, enabling the triggering of an adapted or inadequate response. New evidence indicates that there is a cholinergic anti-inflammatory pathway through vagal nerve fibers (through a vagus–vagal reflex), promoting the tight junction functional integrity between enterocytes and, therefore, avoiding the vulnerability of leaking gut elicited by dysbiosis [43,45]. 

On the other hand, inputs from external situations of stress (e.g., "fight or flight" reactions) involving the periaqueductal gray matter [49,50], amygdala, and hypothalamus can inhibit vagal nerve activity. The dysfunction of these structures can be due to dysbiosis, which compromises the gastrointestinal tract, triggering gastrointestinal disorders (e.g., irritable bowel syndrome and inflammatory bowel disease) and/or ND, as described above [45,51]. 

The influence of the microbiota on enteric–associated neurons transcends vagal nerve participation. We also need to highlight the important role played by the combination of glucocorticoids and catecholamines in gut homeostasis. Regarding glucocorticoids, there is evidence that demonstrates that gut microbiota can modulate the stress-related hormone corticosterone (cortisol in humans). For example, Sudo et al. [52] showed that probiotic supplementation reduced corticosterone in germ-free mice. 

Corroborating these data, hypercortisolism was observed in germ-free rodents [53]. However, it is still necessary to clarify the possible pathways involved in this complex double-way relationship that links the brain, gut microbiota, and adrenal cortex function, which are closely related [54,55]. In parallel, several recent studies have demonstrated that some species of bacteria can produce catecholamines (e.g., norepinephrine), which also contributes to sympathetic responsiveness [56,57]. 

Interestingly, in 2020, another group demonstrated a possible "microbiota–dependent" regulator in the gut that can activate the sympathetic pathway through a gut-brain circuit [58]. By acting through a complementary mechanism, it is also known that gut dysbiosis can be involved in the renin-angiotensin system overactivation [59–61] and potentiating target cells that express alpha/beta receptors. 

Therefore, it appears to be reasonable that there is a "vicious cycle" between the gut and the autonomic nervous system [62]. In recent years, we focused on cardiovascular/kidney diseases and probiotic supplementation using kefir. 

Although more details about kefir and its benefits on ND will be discussed in another section, it is important to show several direct/indirect sympatholytic mechanisms observed in our experimental investigations in mice and rats after exposure to beneficial bacteria (Figure 3).

4. The Brain–Heart–Kidney Interconnection: The Role of Kefir

The relationship between the brain and cardiovascular system has been a continuous focus of basic and clinical investigation. At the end of that century, the discovery of renin opened new avenues for the integrative relationship between the brain and the circulatory system. 

Here we revisited previous studies demonstrating integrative dots connecting the nervous system with the kidneys, heart, and blood vessels [47,64,66] and discuss its bidirectional systemic interactions (see Figure 3). 

We hypothesize that the prevalence of concomitant autonomic nervous dysautonomia, vascular dysfunction, and high blood pressure, is a pathophysiological condition, which when combined with cerebrovascular disorders can contribute to or aggravate ongoing AD and other chronic or acute related ND. 

This review highlights the therapeutic actions of kefir on the overactivity of the renin-angiotensin system (RAS), the imbalance of the autonomic nervous system, and the attenuation of the endothelial dysfunction observed in different experimental models of hypertension [9,63,64]. 

After approximately 200 years of experimental and clinical research that led to the discovery of the RAS, angiotensin II is considered to be one of the most integrative endogenous substances in the human body [67–72]. RAS homeostatic actions are provided by kidney sensors for reduced sodium and volume, leading to the production of renin into the venous blood and then synthesizing angiotensin I [69–72]. 

This peptide is converted to the bioactive octapeptide angiotensin II by an angiotensin-converting enzyme (ACE) that promotes hypertensive effects [73–76]. Currently, a growing body of evidence demonstrates an integrated association between RAS and the autonomic nervous system, which are important contributors to the etiology of hypertension (see Figures 1 and 3) [50,77]. 

Approximately 30 years ago, our laboratory demonstrated in the angiotensin-dependent model of hypertension (2K1C) that the predominance of the vagal system controlling the heartbeat was overpassed by sympathetic activity, which also includes an increase in the cardiac rhythm and force [78]. Similar to other research groups, we were challenged to include, in our main research field, the integrative actions between the brain, renal, and cardiovascular systems, aiming to understand the etiology of primary and secondary hypertension [68,69,73,74]. 

Recently, we reported the relationship between the neural control of blood pressure and gut microbiota. Our group and others have dedicated recent years to the investigation of the relationship between gut dysbiosis and hypertension [14,41,63,64,79,80]. 

Animal models (mice and rats) of essential and renovascular hypertension were used to investigate the effectiveness of probiotic kefir. In the spontaneously hypertensive rat (SHR) model, it was shown that chronic kefir administration (for eight weeks) caused a significant reduction of hypertension and improved endothelial dysfunction through the restoration of ROS/NO imbalance [7]. 

Later, this same group demonstrated in the same experimental model that this probiotic also protects against the effects of an environmental contaminant [14]. In addition, kefir showed similar effects to pharmacological ACE inhibitors [7,14]. Interestingly, this anti-ACE activity [65] and antiatherogenic effect (Figure 4) [80] can be achieved even using a soluble nonmicrobial fraction of kefir. Monteiro and collaborators recently published a paper that demonstrates the antihypertensive actions of the probiotic kefir [63]. 

The authors clearly showed that kefir prevents high blood pressure, through renal and systemic RAS inhibition, in 2K1C hypertensive rats (see Figure 3). Other remarkable effects of kefir in this experimental model include the improvement of the nephron structure and endothelial dysfunction, attenuation of the high levels of ROS (plasma and kidney tissues), and the damaged architecture of the aortic endothelial surface [63].

For more information:1950477648nn@gmail.com