Effect of ultra-processed diet on gut microbiota and thus its role in neurodegenerative diseases

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Ultra-Processed Diet- Gut Microbiota- and Its Role in Neurodegenerative Diseases Edwin E. Mart´ınez Leo , Maira R. Segura Campos PII: DOI: Reference:

S0899-9007(19)30192-3 https://doi.org/10.1016/j.nut.2019.110609 NUT 110609

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Nutrition

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29 April 2019 6 August 2019 23 September 2019

Please cite this article as: Edwin E. Mart´ınez Leo , Maira R. Segura Campos , Ultra-Processed Diet- Gut Microbiota- and Its Role in Neurodegenerative Diseases, Nutrition (2019), doi: https://doi.org/10.1016/j.nut.2019.110609

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Highlights  Ultra-processed foods consumption increases the risk of presenting a chronic-metabolic disease.  Changes in the gut microbiota composition is related to neurodegenerative diseases development.  Diets high in fat and simple carbohydrates is associated with neuroinflammation and reduction in cognitive function.  The state of the intestinal microbiota is a possible clinical marker candidate in the association assessment between neuroinflammation, cognitive decline and ultra-processed foods consumption.

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Ultra-Processed Diet- Gut Microbiota- and Its Role in Neurodegenerative Diseases Edwin E. Martínez Leo & Maira R. Segura Campos Facultad de Ingeniería Química, Universidad Autónoma de Yucatán. Periférico Norte Km. 33.5, Tablaje Catastral 13615, Col. Chuburná de Hidalgo Inn, 97203 Mérida, Yucatán, México. Corresponding author: [email protected]

ABSTRACT The current dietary pattern it is characterized by a high consumption of ultra-processed foods and a lower consumption of fiber and vegetables, environmental factors associated directly in the current chronic-metabolic diseases incidence. Diet is an environmental factor that influences the diversity and functionality of the gut microbiota, where dietary changes have a direct action on their homeostasis. The environment created in the gut by ultra-processed foods, it is hallmark of the Western diet, recognized as a trigger factor for low-grade systemic inflammatory and oxidative changes, that favor the development of neurodegenerative diseases (ND). From a systematic search, the present review analyzes the relationship and impact of the current feeding pattern, with the dysregulation of the microbiota and its influence on the development of cognitive declive. Since ND are late diagnosis, this review is a reason for the search for stricter public health strategies regarding the access and ultra-processed foods development.

Keywords Western diet, dysbiosis, neuroinflammation, Alzheimer's disease, Parkinson's disease, dementia.

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Introduction The ultra-processed foods consumption increases the risk of presenting a chronic-metabolic disease by 32% (1), which in the last decades have presented a growing prevalence, according to statistical data of the World Health Organization (WHO) (2,3). On the other hand, from 1999 to 2013, the annual sales per capita of ultra-processed products has gone up, thus displacing a natural diet, abundant in vegetables and foods rich in fiber (4). Ultra-processed foods are formulations ready for consumption, made from refined substances, with a careful combination of simple sugars, salt, fat, and various additives; include sugary beverage, snacks and 'fast foods', so nutritionally, they are not recommended foods for an abundant consumption, in a prolonged and constant way (5). Increase in the simple sugar’s consumption and fats, is directly related to an increase in intracellular pro-oxidants and alterations in the composition and functions of the gut microbiota (6, 7). Microbiota has an important metabolic function in the compounds generation that participate in the energy and intermediary metabolism of organs such as liver, adipose tissue, skeletal muscle and in a way, brain, organ with which it keeps a close communication (8). The communication between the microbiota and the brain has generated a range of research, on the issue of gut microbiota dysregulation and its association with alterations in the nervous system (NS), as a trigger for neurodegenerative disease (ND) (9-11). ND integrates a heterogeneous group of diseases that mainly have their point of affection in the NS, they are characterized by the progressive loss of neurons (neurodegeneration) in regions that compromise the function of such a system. Progressive neurons degeneration leads to the presence of neurological and neuropsychological signs and symptoms they include balance impairment, movement (ataxia), speech, breathing, heart functions, and cognitive decline (dementia). According to National Institute of Neurological Disorders and Stroke (NINDS), the most prevalent ND are: Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Friedreich's ataxia (FA), Huntington disease (HD) and spinal muscular atrophy (12,13). In the last century, the ND prevalence has increased, currently estimated at more than 30 million people with dementia, a figure that by 2030 is estimated to reach 75 million people. The dementia impact worldwide and the public health importance has been described by the WHO as alarming (2). Diet plays an important role in the microbiota homeostasis, being that short-term modifications in the dietary pattern, leads to alterations in its diversity and composition with greater degree of affectation in people with low fiber diets (14). The current lifestyle and the dietary patterns are not only factors that increase the risk of developing metabolic disease, but also in the medium term the ND development. Relationship between diet- microbiota and ND they are a 3

possible therapeutic and preventive target since, the gut microbiota dysregulation is an important factor that is closely related to the ND. From a systematic search using keywords such as: ultraprocessed foods, diet, gut microbiota, neurodegeneration, neuroinflammation, present review analyzes the relationship and impact of the current dietary pattern with the development ND, through clinical studies that show whether a diet high in ultra-processed foods and the consequent dysregulation of the gut microbiota, could influence an early ND development.

A central matter: Gut microbiota and host health Human microbiome refers to the total microorganism’s population with their genes and metabolites that colonize the human body including gastrointestinal tract, genitourinary tract, oral cavity, nasopharynx, respiratory tract and the skin (15). Microbiome has evolved with humans over the millennia developing communities of specific microorganisms in anatomical niches of the body and whose balance and microbial diversity varies from person to person, based on factors such as hygiene, nutrition, social behavior and genetics (16). The human microbiota is made up of cells trillions, including bacteria, viruses, fungi and protozoa that coexist in symbiosis and colonize the skin and the surface of the mucous membranes of the human organism, mainly the gastrointestinal tract. The human being has 1014 microorganisms in the intestine and its diversity increases exponentially from the proximal end of the gastrointestinal tract to the distal end, being the colon, which houses most of the microbiota, varying according to factors such as hygiene, genetics and nutrition. Currently, 10 bacteria phylum have been identified in the gut microbiota of which Firmicutes and Bacteroidetes represent approximately 90%. The other 10% is made up of proteobacteria, actinobacteria, fusobacteria and verrucomicrobia, among others (17). Gut microbiota development begins at birth, based on the mother's microbial constitution (18). Newborns get, vaginally, microorganisms such as bifidobacteria and lactobacillus from the birth canal, while those born by caesarean section are initially colonized by bacteria from the hospital environment (19). Also, the gut microbiota composition of the infant that receive breastfeeding, has predominantly bifidobacteria and bacteria producing lactic acid, with few bacteroides, coliforms and clostridium. On the contrary, those children who are fed by infant formula have a greater number of bacteroides, clostridium and other enteric bacteria. Such differences may disappear with the introduction feeding complementary, moment in which the most complex microbiota begins to appear and that will maintain certain constancy in his adult stage, dependent on exposure to factors that could alter it (20).

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Gut microbiota has become recognized as a metabolic organ (even like the liver), by playing an important role in the homeostasis maintenance of the individual with functions on the nutrition, immunity regulation and systemic inflammation (21). Among the main known gut microbiota functions is the competition for nutrients and receptors, the pathogens displacement, antimicrobial factors production, regulation of the exchange enterocytes rate, epithelial cells differentiation, strengthening of the intestinal barrier and maintaining the functioning of the intestinal mucosa immunity by inducing IgA secretion (22,23). A widely studied microbiota function and of metabolic importance, is the short chain fatty acids (SCFA) production, by fermenting non-digestible carbohydrates from the diet. The SCFA (acetate, propionate and butyrate) are signaling molecules with function in organs such as liver, white adipose tissue, skeletal muscle, intestine and interest, on the components of the central nervous system (CNS) (21,22). Acetate acts as a substrate for the synthesis of fatty acids and cholesterol in the liver and other tissues, being cataloged as predominantly an obesogenic SCFA. In counterpart, propionate increases the expression of the gene that encodes leptin synthesis, protects against obesity induced by diet without causing hypophagia, decreases cholesterol synthesis by inhibiting the activity of the enzyme hydroxymethylglutaryl-CoA reductase and acts as a hepatic gluconeogenesis precursor, while butyrate has an important role in regulating colonic mucosa homeostasis, participates in cellular apoptosis, proliferation and differentiation, improves insulin sensitivity, increases energy expenditure and protects against disruption of the colonocyte membrane by reduces oxidative stress increasing glutathione concentrations (24). The correct metabolic functioning of the SCFA it depends on your production rate, which in turn depends on the gut microbiota homeostasis. Alterations in the diversity and composition of the microbiota, known as dysbiosis, leads to an imbalance in the SCFA production that contributes to the proinflammatory state characteristic of chronic-metabolic diseases (18,23). For the SCFA production it is important that the gut microbiota function as a community, and have symbiotic associations with the guest, since during the process, hydronium ions concentrations will be increased, which will be used by other bacteria in the microbiota to avoid variations in the pH. SCFA absorption by the colonocyte requires an exchange with bicarbonate ions, which neutralizes the hydronium ions that are produced during the SCFA formation (25). Changes in the SCFA production generate variations in the colon pH that has an important influence on the composition and population of the intestinal microbiota. A lower SCFA absorption implies lower bicarbonate concentrations at the colonic level and hydronium ions accumulation, leading to decreases in colonic pH (24). 5

A higher SFCA concentration promotes a low pH (5.5) in ileum and cecum that prevents the excessive pathogenic bacteria growth sensitive to pH (as enterobacteria and clostridium), and allows the butyrate producing bacteria growth (Firmicutes phylum) who come to understand up to 20% of the gut microbiota total population. As the luminal pH increases to 6.5 in more distal colonic sites, due to lower SFCA production (fermentable dietary fibers are less available in distal colon) and changes in its absorption, the butyrate generation producing bacteria virtually disappears along with an increase in acetate and propionate-producing bacteria (Bacteroidetes phylum) (26). Due high metabolic rate of the gut microbiota, one of the most widely studied functions, is the bidirectional connection between the gut and the brain (gut-brain axis), postulated as a possible explanation to some of the most frequent neurological disorders in our environment (22), and in a special way, the role that the SCFA could play in the neurodegenerative genesis (27). Especially, SFCA act as neuromodulators, inhibiting neuroinflammation and regulating the enteric neuroendocrine system, present functions on the integrity of the hemato-tissue barrier, neuroplasticity, brain function and behavior, modulate the neurotransmitters synthesis and the receptors expression, such as dopamine and GABA receptors (28,29). In such a way that imbalances in the SFCA production, are a possible risk factor in the development of neurodegenerative disorders and on the contrary, its homeostasis a possible therapeutic and neuroprotective target (Figure 1).

Insert figure 1

Gut microbiota and neurological interactions There is a bidirectional communication between gut and brain, in which the microbiota, the enteric nervous system, the autonomic nervous system, the neuroendocrine system, the neuroimmune system and the CNS, known as the gut-brain axis, participate (30). This complex axis forms a bidirectional neurohumoral communication system whose alteration is related to diseases such as hepatic encephalopathy, anxiety, autism and even irritable bowel (31). This relationship has communication channels such as the vagus nerve, the circulatory system and the immune system (30). The vagus nerve is one of the main ways to transmit information from the microbiota to the CNS, since it represents the most predominant neuronal effector of the parasympathetic nervous system, comprising 75% of all its nerve fibers. Vagus is the longest cranial nerve, at birth of the medulla oblongata and interacting especially with the immune system and the CNS, with motor functions in the larynx, diaphragm, stomach and heart, as well as sensory functions in the ears, 6

tongue and visceral organs such as the liver (9). Thus, the vagus nerve is the main constitutive communication path that bi-directionally modulates the interactions of the microbiota and the brain. In this regard, Bravo et al. (32) states that, the administration of Lactobacillus rhamnosus to mice of the BALB/c strain favors the γ-aminobutyric acid (GABA) transcription in the hippocampus and reduces corticosterone induced by stress and anxiety, behaviors related to depression. The previous thing, is translated in a modification of the behavior depending on the vagal integrity, given that vagotomized mice do not exhibit the previous behavior, after the L. rhamnosus consumption. Dysbiosis is a common denominator of gastrointestinal disorders, chronic-metabolic diseases and ND. Dysbiosis represents changes in the bacteria number that produce SCFA, such as reduction of the Faecalibacterium, Roseburia and Eubacterium fylum (main butyrate producers), and in parallel increase of harmful microorganisms (lipopolysaccharide (LPS) producers endotoxin that causes inflammation), and microorganisms that are resistant to oxygen, that favors the damage of the epithelial cells that line the mucosa of the intestine (24). LPS is responsible for the activation of immune system cells, mainly those of the innate system (macrophages, neutrophils and dendritic cells), through the Toll-like receptors recognition (23). After its activation, proinflammatory cytokines (interleukin-1 (IL1, interleukin1IL1, tumor necrosis factor alpha (TNF) and interleukin-6 (IL6)) with potential capacity are produced to cross the blood-brain barrier (BBB). In the brain, these cytokines act on receptors expressed in neurons and glial cells, specifically microglia, leading to microgliosis and the onset of a low-grade inflammatory process, known as neuroinflammation. Also, cytokines can act on the receptors of different afferent nerves, generating alterations in neurological signals from the digestive tract to the CNS (33). In these circumstances there is also alteration of the neuroendocrine and immunological cells that modify the neurotransmitters release, and it translates into the different clinical manifestations that characterize ND (30). Dysbiosis causes are multiple, although hygiene and the widespread use of antibiotics are among the most important, currently, the Western diet represents one of the main alterations causes of the gut microbiota composition (34). The most important Western diet characteristics is the excessive consumption of simple sugars, saturated fats, animal proteins and a reduced intake of vegetable fibers. The people of this century are characterized by consuming abundant and daily ultra-processed foods and have less time for a quality food that ensures an adequate supply of antioxidants, essential fatty acids and fiber (35). Such factors, which go hand in hand with an increase in risk factors for the metabolic disease’s development, they are also an important factor in the dysbiosis generation (36). In this way, the lifestyle and culture of the 21st century, are a limiting

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factor in the microbial homeostasis maintenance, being an important axis of study for the ND development, through its connection with the gut microbiota.

Ultra-processed food and its impact on the gut microbiota According to the PAHO, ultra-processed foods are formulated mostly from industrial ingredients and contain little or no natural food, with the aim of extending their shelf life, making them highly appetizing and lucrative. Most of the ingredients that make up an ultra-processed food are additives as preservatives, stabilizers, emulsifiers, solvents, binders, boosters, sweeteners, sensory enhancers, flavorings and dyes (37). Although international organizations such as the WHO, the American Heart Association (AHA), the National Health System of the United Kingdom and the Dietary Guidelines Advisory Committee have focused their objectives on the generation of public policies, for the reduction of the ultra-processed foods consumption, sales of industrially processed food products, including fast food and sugary beverages, have increased in the last century around the world, being a factor of importance of the increasing chronic-metabolic diseases prevalence (4). Such trends are the result of changes in economic systems, globalization and market dysregulation, opening greater access to the ultra-processed foods consumption than natural foods (38). Also, the high added sugars consumption, characteristic and present in ultra-processed foods, it is a factor of importance in the obesity development (39), type 2 diabetes mellitus (40), elevation of triglycerides and serum cholesterol, increase in blood pressure and coronary disease (41) and, recently cancer (42) and ND (43). Aggregated sugars are defined as sugars that are added to food during processing, manufacturing or food preparation. The most recent term, "free sugars," also includes the sugars naturally present in fruit juices without sugar (40). Foods with a higher added sugars content are usually an empty calories source with an essential nutrients minimum or dietary fiber, displacing foods of greater nutritious contribution and favoring the fat in tissues accumulation, which can lead to diseases such as non-alcoholic fatty liver disease and obesity (44). Currently, the food industry has led to the production of various sources of refined sugar such as cane, beet, corn derivatives and even cheaper products, such as high fructose corn syrup (HFCS) (mixture of 55% fructose and 45% free glucose), present in a wide ultra-processed foods variety (45). In developed and underdeveloped countries, such as Canada, the United States and Mexico, there is a high consumption of products with HFCS present in ultra-processed foods (46). This substantial increase in fructose consumption, has been parallel to the increase in the incidence of obesity, that also represents an increase in caloric intake (47,35). On the other hand, changes in the 8

source and sugar load, directly affect the regulation and gut microbiota homeostatic maintenance, by contributing to variations in pH, microorganism’s composition and SCFA production. The reduction of complex carbohydrates consumption and fiber and the increase in the simple sugar’s consumption, characteristic in the Western diet, confers substantial evolutionary pressure on the gut microbiota. Bifidobacterium and some Clostridium subgroups (Roseburia and Eubacterium rectale), exhibit a significant reduction with reduced or limited fiber intake directly related to the butyrate levels reduction in feces (48). Microorganisms such as lactic acid bacteria, particularly the Lactobacillus, and the genus Faecalibacterium of Clostridium cluster IV, they are fruitful microorganisms (49), so a high ultra-processed foods consumption leads to the increase of this bacterial population. Likewise, the genus Firmicutes grows substantially in Western diets, which reduces the Bacteroidetes genus. Unlike the Firmicutes, the Bacteroidetes present an enzymatic machinery for the metabolism of non-digestible polysaccharides by the host, this leads to their growth and survival. The loss or Bacteroides reduction as a result of the conditioning of Western diet substrates, results in the dysbiosis and the loss of several specific microbial niches in the intestine, leading to the differences observed in the microbial phylogenies of people with chronic-metabolic diseases (50). Another characteristic of Western diets is their high saturated fats content. The high-fat diet consumption also affects the modulation of the gut bacterial population, leading to a reduction of up to 50% in the group of Bacteroides, Verrucomicrobia, E. rectal, C. coccoides and Bifidobacterium and a proportional increase of Firmicutes and Proteobacteria, in addition, it induces the proinflammatory cytokines generation (IL1, IL6 and TNF, favoring hyperinsulinemia and excessive storage of lipids in liver and adipose tissue. Relationship between the high-fat diet consumption with low-grade inflammation and the metabolic diseases development, has been attributed to the reduction of the number of Bifidobacterium and a higher concentration of plasma endotoxin (LPS derived from Gram-negative bacteria) (19,51).

Western diet and neurodegenerative disease Diet is the main factor that influences the composition and gut microbiota diversity. Dietary impact has been studied extensively in recent years, being the De Fillipo et al. (52) group research, the first to report differences in the microbial profile of two populations with different dietary characteristics. These variations could be observed in rural community children in Africa with a diet based on grains with a high consumption of fiber and an abundant microbiota in Bacteroidetes, especially in the Prevotella genera; while Italian children with an ultra-processed diet, it was characterized for 9

being high in fat and animal protein, it had a microbial Firmicutes predominance (mainly Faecalibacterium). From the above, several research groups have shown an important association between a diet high in ultra-processed foods and variations in the composition and gut microbiota diversity (36) and even, important epigenetic changes (53,54). The marked increase in the ultra-processed foods consumption in recent decades is directly associated with the obesity incidence (55,56), a low-grade systemic inflammatory disease which is characterized by high levels of circulating free fatty acids (FFA), dysbiosis, endotoxins (LPS) and inflammatory mediators, that lead to the homeostatic various organs alteration (57). This favors a neuroinflammatory state at the level of the nervous system, where obesity involves various CNS structures (58). Term neuroinflammation describes a vast process of mechanisms and physiopathological phenomena mediated by alterations in the glial cells morphology, it is a reactive state of the CNS immunological component that encompasses the response or the set of responses that are given to some damage occurred in the tissue (59). Changes in dietary patterns, characterized by an elevation in the intake of simple carbohydrates and saturated fatty acids and low antioxidants consumption from fresh vegetables, not only leads to changes in the gut microbiota composition (dysbiosis) but also proinflammatory systemic state promotion related to the ND development (11,60,61) According to a meta-analysis conducted by Teasdale et al. (62) where the quality of the diet of people with severe mental illness is analyzed, a caloric and sodium consumption was found, higher than the international recommendations. Situation that is related to the high consumption of ultra-processed foods of the current population. High fat and simple carbohydrates diets, such as occurs with chronic ultra-processed foods consumption, is associated with a reduction in cognitive function (63), where the hippocampus is one of the regions most compromised to tissue damage by the saturated fats action, since its neuronal population presents a particularly high metabolic demand (64). Several studies in animal models have shown the impact of high fat diets on aging in microglial function (65), cognitive deterioration and neuroinflammation (66), as well as its contribution in the ND development such as Alzheimer's (67). Such interactions between diet-gut microbiota, influences the neurotransmitters production and compromising CNS homeostasis (10). In the PD particular case, LPS produces local inflammation and oxidative stress in the intestine, thus initiating the α-synuclein (αSyn) deposition that disseminates to the CNS. Hypothetically, pathological αSyn can lead to neuronal death, microglial activation and subsequent activation of TLRs. This would trigger a vicious circle of neuroinflammation that could explain why the pathology of PD develops in the specific pattern proposed by the Braak hypothesis, which 10

specifically affects regions interconnected with vulnerable neurons such as the dorsal motor nucleus of the vagus (DMV). It is known that neurons in the affected areas have specific characteristics that cause a high metabolic load, which seems to make these neurons especially sensitive to oxidative stress and the wrong folding of αSyn (68,69). The spread of pathological αSyn from the ENS to the CNS through the vagus nerve and DMV, it leads to its grouping and the formation of Lewy pathology (LP), clinically related to its accumulation in the neurons of the olfactory tract and the ENS, leading to gastrointestinal problems such as dysphagia, nausea, constipation and defecation difficulty and loss of smell, characteristic in PD and described in the prion hypothesis (70,71). To date, few clinical studies correlate changes in intestinal microbiota due to a prolonged and constant ultra-processed foods consumption and they associate it with the ND development. De la Cuesta et al. (72), carried out a cross-sectional study where the gut microbiota of 441 Colombian adults was characterized by sequencing the 16S rRNA gene and determined its relationship with demographic, health and dietetic parameters, concluding that a Western diet favors the development and establishment of microbial consortiums associated with the chronic-metabolic diseases development. Diets high in saturated fats and simple sugars are associated with an increased risk of developing Alzheimer's disease (73). Liu et al. (74), conducted a systematic review that included sixteen studies with a total sample size of 381 patients with autism in relation to 283 healthy people (control group), showing systematic alterations of the gut microbiota in groups with autism compared to control groups. This reinforces the evidence that dysbiosis of the gut microbiota can be correlated with behavioral abnormalities in autism, being the diet the main trigger of dysbiosis. On the other hand, according to Houser & Tansey (75), Parkinson's disease is a multisystemic disorder originating in the gut microbiota alterations associated not only with neurodegenerative processes but also to a systemic inflammation, as is the obesity case. Adherence to the Mediterranean diet (diet characterized by its high fiber content, antioxidants and omega 3) is associated with a lower probability of prodromal Parkinson's (disease phase characterized by the absence of motor disorders and presence of smell disturbance, constipation, depression and REM sleep behavior disorder) in the elderly, although more studies are still needed to elucidate the factors involved, it is clear that dietary components (fiber and antioxidants) contribute to the gut microbiota homeostasis, which reduces the neurodegenerative effects in the nervous system (76). In a parallel way, in a meta-analysis and systematized review carried out by Wu & Sun (77), identified 9 cohort studies with 34,168 participants and conclude that the Mediterranean diet is inversely related to the risk of cognitive disorders incidence. Although there is no direct association with the microbiota dysregulation, De Filippis et al. (78) state that adherence to the Mediterranean diet is associated with metabolic profiles related to beneficial microbiomes unlike subjects who 11

consume a Western diet, this as a result of the gut microbiota study and the 153 people metabolome with high adherence to the Mediterranean diet. Bioactive compounds present in the diet (vegetables), mainly in plants, have a positive influence on gut microbiota disturbances (79) and changes in brain volume (80). Countries that consume a diet high in fiber, compared to a Western diet, have a lower dementia incidence (81). Morris et al. (82), indicated that dietary fiber consumption through green leafy vegetables (consumption of approximately one serving per day of green leafy vegetables and foods rich in phylloquinone, lutein, nitrate, folate, α-tocopherol and kaempferol), it was associated with a slower cognitive decline in 960 elderly people, after improvements in the state of the gut microbiota. In this way, it could be inferred that a proper diet in fiber and antioxidants, influences the gut microbiota regulation, what contributes to less neurodegeneration and neuroinflammation, reducing the dementias symptoms or preventing the ND development. High-fiber diets favor the maintenance of beneficial gut bacteria that produce anti-inflammatory SCFA. Although there is still a need for a greater research numbers that assert the direct relationship between the ultra-processes consumption – gut microbiota – neurodegeneration, the current evidence supports that a high and chronic ultra-processed foods consumption its influences the gut microbiota functions (Table 1) with systemic repercussions that impact at the neurological level. Figure 2, summarizes the coexisting relationship between a diet high in ultra-processed foods, dysbiosis and the development of neuroinflammation.

Insert figure 2

Conclusions and future directions Although the food science is in search of therapeutic alternatives that affect the high chronicmetabolic diseases prevalence, the food industry increasingly puts more access food with lower nutritional quality and extremely economic, that in the face of current food crises and globalization, they are mostly consumed by the population. Current lifestyle is driving the population to an increasingly industrialized and less natural diet, situation that contributes to higher chronicmetabolic diseases prevalence’s which in turn are related to neuroinflammatory states, neurodegeneration and cognitive deterioration. Diet plays an important role in the chronic- metabolic diseases development since it is made up of diverse factors that together are potential triggers of a pro-oxidative and proinflammatory systemic state. Close connection between diet, dysbiosis and the chronic-metabolic diseases development reveals that health systems are not ready for the growing ND epidemiological demand. 12

Future research, should aim to better identify what food processing aspects can impose negative effects on health, being of importance for the stricter food policies generation on the access and ultra-processed foods development. Likewise, the health sector should redirect its public health policies towards the ND prevention, through the ultra-processed food consumption regulation and the timely detection of cognitive decline signs in vulnerable populations, as is the people with obesity case. Gut microbiota dysregulation is a possible clinical marker candidate in the assessment of the association between neuroinflammation, cognitive decline and ultra-processed foods consumption, therefore the current trend in diagnosis points to the microbiota evaluation through the feces analysis (89); however, the above is not yet a routine method indicated by the clinical practice guidelines. Changes in the diagnostic and intervention models, based on the coexisting relationship between diet- gut microbiota and ND, will be the principle for effective prevention models for the ND.

References 1. Nardocci M, Leclerc B, Louzada M, Monteiro C, Batal M, Moubarac J. Consumption of ultra-processed foods and obesity in Canada. Can J Public Health. 2019; 110: 4–14 https://doi.org/10.17269/s41997-018-0130-x. 2. Noncommunicable Diseases Progress Monitor, 2017. Geneva: World Health Organization; 2017.

Licence:

CC

BY-NC-SA

3.0

IGO.

https://apps.who.int/iris/bitstream/handle/10665/258940/9789241513029eng.pdf?sequence=1 3. Development Initiatives. Global Nutrition Report 2017: Nourishing the SDGs. Bristol, UK: Development

Initiatives.

2017.

https://globalnutritionreport.org/reports/2017-global-

nutrition-report/ 4. Pan American Health Organization. Ultra-processed food and drink products in Latin America: Trends, impact on obesity, policy implications. Washington, DC. 2015; ISBN 978-92-75-11864-1. http://iris.paho.org/xmlui/bitstream/handle/123456789/7699/9789275118641_eng.pdf?sequ ence=5&isAllowed=y&ua=1&ua=1 5. Monteiro C, Moubarac J, Cannon G, Ng S, Popkin B. Ultra-processed products are becoming dominant in the global food system. Obesity rev. 2014; 2: 21- 28 http://dx.doi.org/10.1111/obr.12107.

13

6. Martínez-Leo E, Acevedo J, Segura-Campos M. Biopeptides with antioxidant and antiinflammatory potential in the prevention and treatment of diabesity disease. Biomed Pharmacother. 2016; 83: 816–826 http://dx.doi.org/10.1016/j.biopha.2016.07.051. 7. Martínez-Leo E, Martín A, Segura-Campos M. Gut Microbiota Alterations in People With Obesity and Effect of Probiotics Treatment. In: Grumezescu A, Holban AM, editors. Diet, Microbiome and Health. 1st edition. Vol. 11. Elsevier; 2018. p. 111-129. 8. Cuevas A, Ramos O, Riezu J, Milagro F, Martínez J. Diet, Gut Microbiota, and Obesity: Links with Host Genetics and Epigenetics and Potential Applications. Adv Nutr. 2019; 10 (1): S17–S30 https://doi.org/10.1093/advances/nmy078. 9. Borre YE, O´Keeffe GW, Clarke G et al. Microbiota and neurodevelopmental Windows: implications

for

brain

disorders.

Trends

Mol

Med.

2014;

20(9):

509-18.

https://doi.org/10.1016/j.molmed.2014.05.002. 10. De-Paula V, Forlenza A, Forlenza O. Relevance of gutmicrobiota in cognition, behaviour and

Alzheimer’s

disease.

Pharmacol

Res.

2018;

136:

29-34

https://doi.org/10.1016/j.phrs.2018.07.007. 11. Roy-Sarkar S, Banerjee S. Gut microbiota in neurodegenerative disorders. J Neuroimmunol. 2019; 328 (15): 98-104 https://doi.org/10.1016/j.jneuroim.2019.01.004. 12. National Institute of Neurological Disorders and Stroke. Neurodegenerative diseases; 2017. [accessed

2019

Jan

28]

https://www.ninds.nih.gov/Current-Research/Focus-

Disorders/Alzheimers-Related-Dementias 13. Joint Programme- Neurodegenerative Disease (JPND) Research; 2017. [accessed 2019 Jan 28]

http://www.neurodegenerationresearch.eu/es/acerca-del-jpnd/que-es-una-enfermedad-

neurodegenerativa/ 14. Klimenko N, Tyakht A, Popenko A, Vasiliev A, Altukhov I, Ischenko D. Microbiome Responses to an Uncontrolled Short-Term Diet Intervention in the Frame of the Citizen Science Project. Nutrients. 2018; 10(5): 3-18. https://doi.org/10.3390/nu10050576. 15. Petrosino J, Highlander S, Luna R, Gibbs R, Versalovic J. Metagenomic Pyrosequencing and

Microbial

Identification.

Clin

Chem.

2009;

55(5):

856–866

https://doi.org/10.1373/clinchem.2008.107565. 16. Thomas T, Moitinho-Silva L, Lurgi M, Björk J, Easson C, Astudillo-García C. Diversity, structure and convergent evolution of the global sponge microbiome. Nat Commun. 2016; 7 (11870): 1-12 https://doi.org/10.1038/ncomms11870.

14

17. Tagliabue A, Elli M. The role of gut microbiota in human obesity: recent findings and future

perspectives.

Nutr

Metab

Cardiovasc

Dis.

2013;

23:160-168

https://doi.org/10.1016/j.numecd.2012.09.002. 18. Sanz Y, Santacruz A, Gauffin P. Gut microbiota in obesity and metabolic disorders. Proc Nutr Soc. 2010; 69: 434-441 https://doi.org/10.1017/S0029665110001813. 19. Lee YK. Effects of Diet on Gut Microbiota Profile and the Implications for Health and Disease.

Biosci

Microbiota

Food

Health.

2013;

32(1):

1–12

https://doi.org/10.12938/bmfh.32.1. 20. Rodríguez J, Murphy K, Stanton C, Ross R, Kober O, Juge N. The composition of the gut microbiota throughout life, with an emphasis on early life. Microb Ecol Health Dis. 2015; 26 (26050): 7-17 http://dx.doi.org/10.3402/mehd.v26.26050. 21. Frazier T, DiBaise J, McClain C. Gut Microbiota, Intestinal Permeability, Obesity‐ Induced Inflammation, and Liver Injury. J Parenter Enteral Nutr. 2011; 35(5S): 14S-20S https://doi.org/10.1177/0148607111413772. 22. Suárez J. Microbiota autóctona, probióticos y prebióticos. Nutr Hosp. 2013; 28: 38-41. 23. Di Lorenzo F, De Castro C, Silipo A, Molinaro A. Lipopolysaccharide structures of Gramnegative populations in the gut microbiota and effects on host interactions. FEMS Microbiol Rev. 2019; https://doi.org/10.1093/femsre/fuz002 24. Chakraborti CK. New-found link between microbiota and obesity. World J Gastrointest Pathophysiol. 2015; 6(4): 110-119 https://doi.org/10.4291/wjgp.v6.i4.110. 25. den Besten G, van Eunen K, Groen AK, Venema K, Reijngoud DJ, Bakker BM. The role of short-chain fatty acids in the interplay between diet, gut microbiota, and host energy metabolism. J Lip Res. 2013; 54(9): 2325-40 https://doi.org/10.1194/jlr.R036012. 26. Brahe LK, Astrup A, Larsen LH. Is butyrate the link between diet, intestinal microbiota and obesity-related

metabolic

diseases?

Obesity

Rev.

2013;

14:

950-959

https://doi.org/10.1111/obr.12068. 27. Lei E, Vacy K, Boon WC. Fatty acids and their therapeutic potential in neurological disorders. Neurochem Int. 2016; 95: 75‐ 84. https://doi.org/10.1016/j.neuint.2016.02.014. 28. Jena P, Sheng L, Di Lucente J, Jin L, Maezawa I, Wan YJ. Dysregulated bile acid synthesis and dysbiosis are implicated in Western diet–induced systemic inflammation, microglial activation,

and

reduced

neuroplasticity.

FASEB

J.

2018;

32(5):

2866-2877

https://doi.org/10.1096/fj.201700984RR 29. Nankova BB, Agarwal R, MacFabe DF, La Gamma EF. Enteric bacterial metabolites propionic and butyric acid modulate gene expression, including CREB‐ dependent 15

catecholaminergic neurotransmission, in PC12 cells ‐ spectrum

disorders.

PLoS

One

possible relevance to autism 2014;

9:

e103740

https://doi.org/10.1371/journal.pone.0103740. 30. Zhou L, Foster J. Psychobiotics and the gut–brain axis: in the pursuit of happiness. Neuropsychiatr Dis Treat. 2015; 11: 715–723 https://doi.org/10.2147/NDT.S61997. 31. Wang Y, Kasper LH. The role of microbiome in central nervous system disorders. Brain Behav Immun. 2014; 38: 1-12 https://doi.org/10.1016/j.bbi.2013.12.015. 32. Bravo JA, Forsythe P, Chew MV, Escaravage E, Savignac HM, Dinan TG, et al. Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expresión in a mouse via the vagus nerve. Proc Natl Acad Sci U S A. 2011; 108: 16050-5 https://doi.org/10.1073/pnas.1102999108. 33. Yoshikawa K, Kurihara C, Furuhashi H, Takajo T, Maruta K, Yasutake Y, et al. Psychological stress exacerbates NSAID induced small bowel injury by inducing changes in intestinal microbiota and permeability via glucocorticoid receptor signaling. J Gastroenterol 2017; 52: 61-71 https://doi.org/10.1007/s00535-016-1205-1. 34. Zinöcker M, Lindseth I. The Western Diet–Microbiome-Host Interaction and Its Role in Metabolic Disease. Nutrients. 2018; 10 (365): 1-15 https://doi.org/10.3390/nu10030365. 35. Monteiro C, Bertazzi R, Moreira R, Ribeiro I, Cannon G. Increasing consumption of ultraprocessed foods and likely impact on human health: evidence from Brazil. Public Health Nutr. 2010; 14(1): 5-13 https://doi.org/10.1017/S1368980010003241. 36. Brown K, DeCoffe D, Molcan E, Gibson D. Diet-Induced Dysbiosis of the Intestinal Microbiota and the Effects on Immunity and Disease. Nutrients. 2012; 4: 1095-1119; https://doi.org/10.3390/nu4081095. 37. Monteiro CA, Levy RB, Claro RM, Castro IRR, Cannon G. A new classification of foods based on the extent and purpose of their processing. Cad. Saúde Pública, Rio de Janeiro, 2010; 26(11): 2039-2049. 38. Baraldi LG, Martinez E, Canella DS, Monteiro C. Consumption of ultra-processed foods and associated sociodemographic factors in the USA between 2007 and 2012: evidence from a nationally representative cross-sectional study. Bris Med J. 2018; 8: 1-9 http://dx.doi.org/10.1136/bmjopen-2017-020574. 39. Guideline: Sugars intake for adults and children. Geneva: World Health Organization; 2015. https://apps.who.int/iris/bitstream/handle/10665/149782/9789241549028_eng.pdf?sequence =1 16

40. Ludwig, D., Hu, F, Tappy, L., Brand-Miller, J. (2018). Dietary carbohydrates: role of quality and quantity in chronic disease. BMJ. 361: 1-6. https://doi.org/10.1136/bmj.k2340. 41. Johnson RK, Appel LJ, Brands M, Howard BV, Lefevre M, Lustig RH, et al. Dietary sugars intake and cardiovascular health: a scientific statement from the American Heart Association.

Circulation.

2009;

120:

1011–20.

https://doi.org/10.1161/CIRCULATIONAHA.109.192627. 42. Makarem N, Bandera E, Nicholson J, Parekh N. Consumption of Sugars, Sugary Foods, and Sugary Beverages in Relation to Cancer Risk: A Systematic Review of Longitudinal Studies. Annu Rev Nutr. 2018; 38: 17-39. https://doi.org/10.1146/annurev-nutr-082117051805 43. Gu Y, Manly JJ, Schupf N, Mayeux R. Sugary beverage consumption and risk of Alzheimer’s disease in a community-based multiethnic population. Alzheimers Dement. 2018; 14(7): P645. https://doi.org/1 0.1016/j.jalz.2018.06.2696. 44. Jensen T, Abdelmalek MF, Sullivan S, Nadeau KJ, Green M, Roncal C, et al. Fructose and sugar: A major mediator of non-alcoholic fatty liver disease. J Hepatol. 2018; 68(5): 10631075. https://doi.org/10.1016/j.jhep.2018.01.019. 45. Tappy L, Le KA, Tran C, Paquot N. Fructose and metabolic diseases: new findings, new questions. Nutr. 2010; 26: 1044–1049 https://doi.org/10.1016/j.nut.2010.02.014. 46. Moodie R, Stuckler D, Monteiro C, Sheron N, Neal B, Thamarangsi T. et al. Profits and pandemics: prevention of harmful effects of tobacco, alcohol, and ultra-processed food and drink industries. The Lancet. 2013; 381(9867): 670- 679. https://doi.org/10.1016/S01406736(12)62089-3. 47. Bray GA, Nielsen SJ, Popkin BM. Consumption of highfructose corn syrup in beverages may play a role in the epidemic of obesity. Am J Clin Nutr. 2004; 79: 537–543. https://doi.org/10.1093/ajcn/79.4.537. 48. Lopez-Legarrea P, Fuller N.R, Zulet M.A, Martinez J.A, Caterson I.D. The influence of microbiota and small intestinal physiology before and after the onset of obesity. Biochimie. 2014; 141: 97-106 https://doi.org/10.1016/j.biochi.2017.05.019. 49. Endo A, Futagawa-Endo Y, Dicks LM. Isolation and characterization of fructophilic lactic acid bacteria from fructose-rich niches. Syst Appl Microbiol. 2009; 32: 593–600. https://doi.org/10.1016/j.syapm.2009.08.002. 50. Sonnenburg ED, Zheng H, Joglekar P, Higginbottom SK, Firbank SJ, Bolam DN, Sonnenburg JL. Specificity of polysaccharide use in intestinal bacteroides species

17

determines

diet-induced

microbiota

alterations.

Cell.

2010;

141:

1241–1252

https://doi.org/10.1016/j.cell.2010.05.005. 51. Araújo J.R, Tomas J, Brenner C, Sansonetti P.J. Impact of high-fat diet on the intestinal based on the extent and purpose of food processing. Cadernos de SaúdePública. 2017; 26: 2039-2049. 52. De Filippo C, Cavalieri D, Di Paola M, Ramazzotti M, Poullet J.B, Massart S, et al. Impact of diet in shaping gut microbiota revealed by a comparative study in children from Europe and

rural

Africa.

Proc.

Natl.

Acad.

Sci.

USA.

2010;

107:

14691–14696

https://doi.org/10.1073/pnas.1005963107. 53. Dore J, Blottiere H. The influence of diet on the gut microbiota and its consequences for health.

Curr

Opin

Biotechnol.

2015;

32:

195–199

https://doi.org/10.1016/j.copbio.2015.01.002. 54. Kau A.L, Ahern P.P, Griffin N.W, Goodman A.L, Gordon J.I. Human nutrition, the gut microbiome and the immune system. Nat. 2011; 474(7351): 327–36. 55. Juul F, Hemmingsson E. Trends in consumption of ultra-processed foods and obesity in Sweden between 1960 and 2010. Public Health Nutr. 2015; 18(17): 3096-3107 https://doi.org/10.1017/S1368980015000506P. 56. Juul F, Martinez-Steele E, Parekh N, Monteiro C. Ultra-processed food consumption and excess

weight

among

US

adults.

Bri

J

Nutr.

2018;

120(1):

90-100

https://doi.org/10.1017/S0007114518001046. 57. Mechanick J, Hurley D, Garvey W. Adiposity-based chronic disease as a new diagnostic term: The American Association of Clinical Endocrinologists and American College of Endocrinology

position

statement.

Endocr

Pract.

2017;

23(3):

372-378.

https://doi.org/10.4158/EP161688.PS. 58. Guillemot-Legris O, Muccioli G. Obesity- induced neuroinflammation: Beyond the hypothalamus.

Trends

Neurosci.

2017;

40(4):

237-

253

https://doi.org/10.1016/j.tins.2017.02.005. 59. Becher B, Spath S, Goverman J. Cytokine networks in neuroinflammation. Nat Rev Immunol. 2016. https://doi.org/10.1038/nri.2016.123. 60. Guillemot-Legris O, Masquelier J, Everard A, Cani PD, Alhouayek M, Muccioli GG. Highfat diet feeding differentially affects the development of inflammation in the central nervous system. J Neuroinflammation. 2016; 13, 206 https://doi.org/10.1186/s12974-0160666-8.

18

61. Aguayo S, Calderon A. Old Fashioned vs. Ultra-Processed-Based Current Diets: Possible Implication in the Increased Susceptibility to Type 1 Diabetes and Celiac Disease in Childhood. Foods. 2017; 6(100): 1-16 https://doi.org/10.3390/foods6110100. 62. Teasdale S, Ward P, Samaras K, Firth J. Dietary intake of people with severe mental illness: systematic review and meta-analysis. The British Journal of Psychiatry. 2019; https://doi.org/10.1192/bjp.2019.20. 63. Prickett C, Brennan L, Stolwyk R. Examining the relationship between obesity and cognitive function: a systematic literature review. Obes Res Clin Pract. 2015; 9(2), 93–113 https://doi.org/10.1016/j.orcp.2014.05.001. 64. Wang X, Michaelis EK. Selective neuronal vulnerability to oxidative stress in the brain. Front Aging Neurosci. 2010; 2, 12 https://doi.org/10.3389/fnagi.2010.00012. 65. Spencer S, Basri B, Sominsky L, Soch A, Ayala M, Reineck P, Gibson B, Barrientos R. High-fat diet worsens the impact of aging on microglial function and morphology in a region-specific

manner.

Neurobiol

Aging.

2019;

74:

121-134

https://doi.org/10.1016/j.neurobiolaging.2018.10.018. 66. Duffy CM, Hofmeister J, Nixon JP, Butterick TA. High fat diet increases cognitive decline and neuroinflammation in a model of orexin loss. Neurobiol Learn Mem. 2019; 157: 41-44 https://doi.org/10.1016/j.nlm.2018.11.008. 67. Rollins PE, Gallino D, Kong V, Ayranci G, Devenyi G, Germann J, Chakravarty M. Contributions of a high-fat diet to Alzheimer's disease-related decline: A longitudinal behavioural and structural neuroimaging study in mouse models. NeuroImage Clin. 2019; 21: 1-15 https://doi.org/10.1016/j.nicl.2018.11.016. 68. Rietdijk C, Perez-Pardo P, Garssen J, van Wezel R, Kraneveld A. Exploring Braak’s Hypothesis

of

Parkinson’s

Disease.

Front

Neurol.

2017;

8:

37

https://doi.org/10.3389/fneur.2017.00037 69. Kim S, Kwon SH, Kam TI, Panicker N, Karuppagounder S, Lee S, et al. Transneuronal Propagation of Pathologic α-Synuclein from the Gut to the Brain Models Parkinson’s Disease. Neuron. 2019 https://doi.org/10.1016/j.neuron.2019.05.035 70. Visanji N, Brooks P, Hazrati L, Lang A. The prion hypothesis in Parkinson's disease: Braak to the future. Acta Neuropathol Commun. 2013; 1: 2 https://doi.org/10.1186/2051-5960-1-2 71. Duyckaerts C, Clavaguera F, Potier MC. The prion-like propagation hypothesis in Alzheimer's

and

Parkinson's

disease.

Curr

https://doi.org/10.1097/WCO.0000000000000672

19

Opin

Neurol.

2019;

32:

266-271

72. De la Cuesta J, Corrales-Agudelo V, Velásquez-Mejía E, Carmona J, Abad J, Escoba J. Gut microbiota is associated with obesity and cardiometabolic disease in a population in the midst of Westernization. Sci Rep. 2018; 8(11356): 1-14 https://doi.org/10.1038/s41598018-29687-x. 73. Liyanage SI, Vilekar P, Weaver D. Nutrients in Alzheimer’s Disease: The Interaction of Diet,

Drugs

and

Diseas.

Can

J

Neurol

Sci.

2019;

46:

23-34

https://doi.org/10.1017/cjn.2018.353. 74. Liu F, Li J, Wu F, Zheng H, Peng Q, Zhou H. Altered composition and function of intestinal microbiota in autism spectrum disorders: a systematic review. Transl Psychiatry. 2019; 9(43): 1- 13 https://doi.org/10.1038/s41398-019-0389-6. 75. Houser M, Tansery M. The gut-brain axis: is intestinal inflammation a silent driver of Parkinson’s

disease

pathogenesis?.

NPJ

Parkinsons

Dis.

2017;

3(3):

1-9

https://doi.org/10.1038/s41531-016-0002-0. 76. Maraki M, Yannakoulia M, Stamelou M, Stefanis L, Xiromerisiou G, Kosmidis M, et al. Mediterranean Diet Adherence Is Related to Reduced Probability of Prodromal Parkinson’s Disease. Mov Disord. 2019; 34(1): 48-57 https://doi.org/10.1002/mds.27489. 77. Wu L, Sun D. Adherence to Mediterranean diet and risk of developing cognitive disorders: an updated systematic review and meta-analysis of prospective cohort studies. Sci Rep. 2017; 7:41317. https://doi.org/10.1038/srep41317. 78. De Filippis F, Pellegrini N, Vannini L, Jeffery I, La Storia A, Laghi L, et al. High-level adherence to a Mediterranean diet beneficially impacts the gut microbiota and associated metabolome. Gut. 2016; 65:1812-1821 http://dx.doi.org/10.1136/gutjnl-2015-309957. 79. Mafra D, Borges N, Alvarenga L, Esgalhado M, Cardozo L, Lindholm B, et al. Dietary Components That May Influence the Disturbed Gut Microbiota in Chronic Kidney Disease. Nutrients. 2019; 11(496): 1-23 https://doi.org/10.3390/nu11030496. 80. Lee S, Kim EY, Shin C. Changes in Brain Volume Associated With Vegetable Intake in a General

Population,

J

Am

Coll

Nutr.

2019;

2-7.

https://doi.org/10.1080/07315724.2018.1563002. 81. van de Rest O, Berendsen AA, Haveman-Nies A, de Groot LC. Dietary patterns, cognitive decline,

and

dementia:

a

systematic

review.

Adv

Nutr.

2015;

6(2):154-168

https://doi.org/10.3945/an.114.007617. 82. Morris M, Wang Y, Barnes L, Bennett D, Dawson-Hughes B, Booth S. Nutrients and bioactives in green leafy vegetables and cognitive decline Prospective study. Neurology. 2018; 90(3): e214–e222 https://doi.org/10.1212/WNL.0000000000004815. 20

83. Garcia-Mantrana I, Selma-Royo M, Alcantara C, Collado M.C. Shifts on gut microbiota associated to mediterranean diet adherence and specific dietary intakes on general adult population. Front. Microbiol. 2018: 9: 1–11 https://doi.org/10.3389/fmicb.2018.00890. 84. Mitsou E.K, Kakali A, Antonopoulou S, Mountzouris K.C, Yannakoulia M, Panagiotakos D.B, Kyriacou A. Adherence to the Mediterranean diet is associated with the gut microbiota pattern and gastrointestinal characteristics in an adult population. Br. J. Nutr. 2017; 117: 1645–1655 https://doi.org/10.1017/S0007114517001593. 85. De Filippis F, Pellegrini N, Vannini L, Jeffery I.B, Storia A.L, Laghi L, et al. High-level adherence to a Mediterranean diet beneficially impacts the gut microbiota and associated metabolome. Gut. 2016; 65: 1812–1821 https://doi.org/10.1136/gutjnl-2015-309957. 86. Zhang M, Ma W, Zhang J, He Y, Wang J. Analysis of gut microbiota profiles and microbedisease associations in children with autism spectrum disorders in China. Sci Rep. 2018; 8:13981 https://doi.org/10.1038/s41598-018-32219-2. 87. Lindefeldt M, Eng A, Darban H, Bjerkner A, Zetterström C, Allander T, et al. The ketogenic diet influences taxonomic and functional composition of the gut microbiota in children

with

severe

epilepsy.

NPJ

Biofilm

Microbiom.

2019;

5:

1-13

https://doi.org/10.1038/s41522-018-0073-2. 88. Kang DW, Adams J, Coleman D, Pollard E, Maldonado J, McDonough-Means S, et al. Long-term benefit of Microbiota Transfer Therapy on autism symptoms and gut microbiota. Sci Rep. 2019; 9(5821): 1-9 https://doi.org/10.1038/s41598-019-42183-0. 89. Precup G, Vodnar D. Gut Prevotella as a possible biomarker of diet and its eubiotic versus dysbiotic roles-A comprehensive literature review. Br J Nutr. 2019; 29:1-24 https://doi.org/10.1017/S0007114519000680.

21

Figures

Figure 1. Molecular mechanisms involved by SCFA in neuroprotection

22

Figure 2. Connection between dysbiosis and the neurodegenerative disease development from a high ultra-processed foods consumption.

23

Table

Table 1. Summary of human studies involving different diets and their effects on the gut microbiota and neurodegeneration Study design

Variable

Results

References

Cross-sectional study; 27 healthy volunteers

Adherence to the Mediterranean diet

 Bifidobacterial counts,  concentration of acetate, propionate, and butyrate in fecal samples,  Bacteroidetes and a lower Firmicutes–Bacteroidetes ratio

(83)

Cross-sectional study, 120 healthy participants

Adherence to the Mediterranean diet

 Escherichia Coli counts,  Bifidobacteria

(84)

Cross-sectional survey; 51 vegetarians, 51 vegans, 51 omnivores

Adherence to the Mediterranean diet

Associations between consumption of vegetable-based diets and higher levels of short-chain fecal fatty acids, Prevotella and fiber-degrading Firmicutes.

(85)

Diet

Significant inverse associations between vegetable intake and brain gray matter volume change, particularly the change of temporal region.

(72)

Vegetables consumption

Consumption of approximately 1 serving per day of green leafy vegetables and foods rich in phylloquinone, lutein, nitrate, folate, αtocopherol, and kaempferol may help to slow cognitive decline with aging.

(74)

Prospective cohort study; 848 participants with chronic disease and cognitively healthy Prospective study; 960 participants of the Memory and Aging Project with chronic disease

 Bacteroidetes/Firmicutes ratio in ASD group.  Sutterella, Odoribacter and Butyricimonas in ASD group.  Veillonella and Streptococcus in control group.

Prospective cohort study; 35 children with autism spectrum disorder and control group (healthy).

Dysbiosis

Cross-sectional study; 441 Colombian adults

Western diet

 Prevotella copri, Treponema, Bacteroides, Bifidobacterium, Barnesiella and risk of cardiometabolic disease and obesity.

(72)

Prospective cohort study; 12 children with therapyresistant epilepsy

Ketogenic diet

 Bifidobacteria E. rectale, Dialister.  E. coli.

(87)

Cross-sectional study; 18 children with autism spectru disorder.

Microbiota Transfer

 Bifidobacteria, Prevotella.

(88)

24

(86)