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CNS & Neurological Disorders - Drug Targets, 2014, 13, 1325-1333 1325
Implication of Gut Microbiota in Human Health
Imran Khan
1, Muhammad Yasir
*,2, Esam I. Azhar
2,3, Taha Kumosani
1,4, Elie K. Barbour
5, Fehmida Bibi
2and Mohammad A. Kamal
61Biochemistry Department, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia
2Special Infectious Agents Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia
3Medical Laboratory Technology Department, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
4Experimental Biochemistry Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia
5Department of Animal and Veterinary Sciences, Faculty of Agricultural and Food Sciences, American University of Beirut (AUB), Beirut, Lebanon; Adjunct Professor at Biochemistry Department, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia
6Metabolomics & Enzymology Unit, Fundamental and Applied Biology Group, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia
Abstract: Gut-microbiota (GM) is considered a hidden metabolic organ of the human body, providing biochemical pathways which are absent in the host. Balanced diet with calorie restriction (CR) promotes growth of healthy microbiota, leading to longevity by down-regulating inflammatory responses. While, dysbiosis leads to body dysfunction, inducing metabolic disorders, causing poor epithelial architecture, and impeding the development of mucosal-associated lymphoid tissue, resulting in with reduced T and B cell populations, rendering the body prone to infections, cancer and allergy.The GM enzymes activity is a new risk factor for cancer whilegut-derived interleukin-6 is associated withhepatocellular carcinomadevelopment. GM can also influence the brain biochemistry and emotional behavior. The altered GM affects the genes involved in second messenger pathway and long-term potentiation, leading to their differential expression in the hippocampus, cortex, striatum and cerebellum.In addition, the dysbiotic GM is associated with autistic disorder.Living with dysbiotic GM is possible with consequences of serious impairments.
Keywords: Allergy, cancer, gut-microbiota, metabolism, immunity, heart diseases, nervous system.
INTRODUCTION
We are evolved in symbiotic association with trillions of microbes and their highest density is present in the gut known as gut microbiota (GM) [1]. GM evolved into lineages, assisting host’s digestion, providing vitamins [1, 2]
and short‐chain fatty acids (SCFAs) [3], replacing pathogens by competitive exclusion, and regulating metabolism and the immune system [1, 4]. GM is composed of fungal, protozoan and hundreds of bacterial species [5], with a collective metagenome that is 150-fold larger than the human genome [6]. Bacteria constitute 99% of the total GM, in which 90%
fall under two main phyla, Firmicutes and Bacteroidetes [7], while a small population belong to the phyla Proteobacteria, Actinobacteria, Verrucomicrobia and Fusobacteria [7]. GM composition varies along the gut segments with an established increasing gradient between stomach and colon [8], and forming site specific microbial signatures [9]. A small fraction of GM, known as core, remains constant, through the gut [10]; however, the overall GM composition
*Address correspondence to this author at the Special Infectious Agents Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia; Tel: +966-26401000/25303; Fax: +966-26952076;
E-mail: [email protected]
varies from person to person [9], mainly due to the large portion of fluctuating transient microbiota [10]. GM could be considered as the last discovered body organ [11], with a responsiveness nature similar to any other organs of the body [12].
The GM-host association is facing unique challenges by urbanization, rapid global mobility, introduction of new processed foods, various levels of sanitation and hygiene, non- familial children care, and medical therapies [1]. Dietary changes, antimicrobial treatments and gut infections [4] induce aberrant shifts or imbalances in GM composition, known as dysbiosis [13], imposing drastic health problems including infections, atopy, inflammatory bowel disease, obesity, diabetes and arthritis, etc. (Fig. 1) [12, 14]. Beside all these factors, host genome can also influence GM shape [15]. Mucosal architecture of the gut becomes more susceptible to infection whenever the normal gut microbiota is disturbed [16]. It is estimated that around one fifth of the world populations is suffering from digestive track problems [17]. GM communities are like the gold mines, which drove the scientists for deeper investigations into GM compositional changes during different diseases and environmental circumstances, and the impact of such changes on human health. In this review, we have highlighted the importance of GM and its impact on human health, with special
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emphasis on metabolism, cancer, heart diseases, allergy, nervous system, immune system and longevity.
GM AND METABOLISM
Diet is one of the driving forces that shapes the GM composition [18]; the plant polysaccharides (e.g. starch) promote growth of Ruminococcus bromii and Eubacterium recta and Bacteroidetes. The prebiotic inulin increases the levels of Faecalibacterium prausnitzii and Bifidobacterium
sp. [l2]. A toxic metabolic compound named p-cresol, that has a damaging effect on the DNA of epithelial cells, accumulates in the body when the carbohydrate is missing from diet [19]. These facts demonstrate the importance of balanced diet. Impact of changing the amount of food intake in CR treatment on GM shift in densities of its taxa is still under investigation [18].
GM is a major contributor in digestion and metabolism [18], promoting health [19] and providing biochemical pathways that are not present in the host [20]. GM can degrade resistant Fig. (1). The GM-Host interaction and the factors that influence the GM composition. A: External and internal host factors contribute to influence GM composition B: GM role in host physiology: mainly involve in metabolism, regulate energy and nurture immune system. C:
GM dysbiosis, particularly of certain bacteria groups showed association with several multi-factorial health disorders.
Microbiota Gut
Medical Practices
Antibiotics
Hygiene
Vaccination
Dysbiosis Host Genotype
Age Diseases
Host Immune System Host Physiology
Geographic Provenance Early Colonization
Birth Mode
Environment
(Hospitalization, parents life style)
Life Style
Dietary Habits
Probiotics
Prebiotics
Normal Functions
Energy Homeostasis
Host Protection Metabolism
Cancer
Activate Autoimmunity
Cardiovascular Diseases
Nervous System Disorders
Provide Vitamins
Help in Digestion
Ferment non-digestible substances
Provide Signaling Molecules
Provide Protection to Host
Nurture Innate and Adaptive Immunity
Play role in Mucus development
Helicobacter pylori Salmonella typhi Streptococcus gallolyticus
Helicobacter pylori Chlamydia pneumonia Yersinia enterocolitica Treponema pallidum Haemophilus influenzae Streptococcus pneumoniae Neisseria meningitidisis Campylobacter jejuni Shigella
Salmonella
Allergy
Staphylococus aureus Clostridium difficile Other Gram-negative bacteria Hepatocellular Carcinoma
Inflammatory Bowel Disease Enterobacteriacae Alcaligeneceae Lachnospiraceae
Faecalibacterium prausnitzii Proteobacteria
Bifidobacteria A
B C
Implication of Gut Microbiota in Human Health CNS & Neurological Disorders - Drug Targets, 2014, Vol. 13, No. 8 1327
carbohydrate helping in extraction of energy and in releasing beneficial SCFAs [19]. Moreover, the absence of normal GM ecological balance causes energy deprivation in liver and colonic epithelial cells [2]. In addition, an altered GM composition leads into metabolic disorders [19]. Metabolic products of GM act as signaling molecules, affecting the intestine, liver, brain, adipose and muscular tissues [2]; some products of GM, such as the propionate and butyrate have anti- inflammatory and anti-cancerous potentials [19]. The dysbiosis of GM can deteriorate the host’s health causing diarrhea or constipation, releasing carcinogenic and toxic compounds, raising susceptibility of the host to intestinal infections [19]. The condition of having a GM with low density of gamma- Proteobacteria, and a high level of Erysipelotrichi is linked to hepatic steatosis [19]. Moreover, there are profound evidences that microbial metabolic products affect the level of obesity [21].
GM, CANCER AND HEPATOCELLULAR CARCINOMA Enzymes activities of GM toward specific types of ingested food is one of the most recent identified risk factors for cancer (the leading cause of mortality) [20]. Genotoxic and carcinogenic types of byproducts are produced from metabolism of nitro aromatics, nitrate and azo compounds [20].
Moreover, the involvement of gamma-Proteobacteria and Peptococcus sp. in N-nitroso synthesis, a carcinogenic agent, strengthens the association of GM and cancer development [19].
For example, the anaerobic GM bacteria, such as Eubacterium spp., Butyrivibrio sp., Bacteroides sp. and Clostridium sp., encode an enzyme called azoreductase [22]. This enzyme deconjugates methylazoxymethanol glucuronide, excreted via bile, and further metabolize into electrophilic methyldiazonium ion. This ion generates carbonium ion which methylate nucleic acids and can trigger colon carcinogenesis [23]. Moreover, it has been reported that gut flora could also facilitate the pathogenesis of a tumor-causing virus, known as mouse mammary tumor virus [24]. Chronic inflammation, immune evasion and immune suppression are the actual mechanisms behind the GM role in cancer onset [9]. Changes in GM composition and population trigger cancer. It has been documented that patients with pancreatic cancer have an increase in 31 and a reduction in 25 salivary bacterial strains [9].
The strains Capnocytophaga gingivalis, Prevotella melaninogenica and Streptococcus mitis are used as markers to detect oral squamous cell carcinoma [9]. Furthermore, certain strains may develop colon cancer by overproducing H2S [19]. It is shown that an increase in Desulfovibrio sp., Enterococcus faecalis, Bacteroides vulgatus, Ruminococcus spp., Streptococcus hansenii, Bifidobacterium spp., Faecalibacterium prausnitzii [25] and Fusobacterium nucleatum [9] are linked with high risk of chronic rectal cancer, while others, such as Lactobacillus S06 and Eubacteriumaero faciens impede chronic rectal cancer [25]. The bacteria like Helicobacter pylori [26], Salmonella typhi [27] and Streptococcus gallolyticus [28] are associated with different types of cancer (Fig. 1).
Nevertheless, GM is also associated with down regulating the risk of cancer development. For instance, the GM can metabolize thymidine kinase, an enzyme involved in cancerous cell division. This enzyme activity was 50% less in normal GM- colonized mice compared to germ free (GF) mice [9]. Some probiotic bacteria, especially Bacillus polyfermenticus can
restrain colon cancer by intercepting the ErbB2 and ErbB3 inhibition [9]. Furthermore, Lactobacillus acidophilus and Bifidobacterium longum can inhibit the development of carcinogen-induced colon tumor [29]. The restoration of GM through fecal transplantation and bowel lavage infusion [30], and its modulation through antimicrobials probiotics and probiotics provide good promises in future cures of several diseases [9], including cancer [31].
Hepatocellular carcinoma (HCC) is a liver cancer with unresolved inflammation and cirrhosis [32]. HCC frequently results from synergism between chemical and infectious liver carcinogens [33], is more common and the key reason of death among cirrhotic patients [34]. HCC is the sixth most common neoplasm which is continuously steeping around the world and more than 750,000 new cases diagnosed each year [35]. Around 80 - 90% chronic liver disease, hepatic fibrosis and cirrhosis cases lead to HCCs [36]. Microbial metabolites are the most recent identified risk factor for HCC [36]. It is becoming apparent that GM is a central component of hepatic pathophysiology [34]. GM may have an active involvement in the development of nonalcoholic type fatty liver disease [37], hepatic encephalopathy [38] and HCC [32, 36]. Pro-inflammatory cytokines that are released as result of intestinal inflammation, may be another possible cause of HCC among patients suffering from chronic inflammatory liver disorders; however, the exact mechanism remains unresolved [32]. The pro-inflammatory cytokines, particularly interleukin-6 (IL-6) that are produced in the sinusoidal endothelial cell and Kupffer cell at the time of liver diseases [32] are considered to play important role in HCC development [32]. Recently, Zhang et al., (2012) reported that gut-derived IL-6 can also develop HCC [32].
Unfortunately, the IL-10, the inhibitor of IL-6 secretion, level remains alters during liver injuries [32].
GM dysbiosis and liver damages are inter-connected [39].
Liver damages are associated with decrease blood flow rate at gut-liver axis, impaired bile secretion and altered peristalsis, which result into GM dysbiosis; whereas GM also influence liver function indirectly through metabolites [39]. GM is an important contributor in obesity development [21] and increasing obesity has become a key risk factor for several types of cancer including HCC [40]. The senescence-associated secretory phenotype promotes obesity-associated HCC development in mice [40]. Obesity affects inflammatory cytokines secretion in senescence-associated secretory phenotype and GM composition, as well as changes the GM metabolites [40]. Several studies indicated increase in Enterobacteriacae, Enterococcus [39] and Alcaligeneceae [38]
in the stool of cirrhotic patients [39]. A decrease in Ruminococcaceae and Lachnospiraceae count has been observed in cirrhotic patients [38]. The probiotics can restore GM composition and thus may reduce the gut-derived IL-6 production [32]. Furthermore, probiotics can elevate gut-derived IL-10 level in rats [32]. The high dose of Lactobacillus casei induce IL-10 [41]. This strain is found in yogurt [42], Poto poto (Congo tradition food) and dégué (a fermented food of Burkina Faso) [43]. These foods could be a potential probiotic to overcome the liver injuries. Both liver health and GM normal composition is important for good health. However, very limited studies are available about the GM – HCC interaction and need deep investigation to unmask the underline mechanism.
GM AND IMMUNITY
The gastrointestinal tract, in terms of mass and cellularity, is the largest immune organ in the body; it harbors the highest microbial density that nurtures the immune system by presenting to it a whole spectrum of antigens [4], stimulating the maturation of lymphoid tissues in the mucosa (peyers patchesand lamina propria) and systemic lymphoids including the spleen, thymus and lymph nodes [13]. The stable differentiation, expansion, and maintenance of immune cells in these lymphoid tissues are dependent upon GM [13]. GM can activate innate immune receptors and generate regulatory T cells that promote immunologic tolerance through complex signaling pathways [10]. GM is proven to induce repair of
damaged intestinal epithelium [44], and to use this barrier to interact with the immune system [45]. GM follows several pathways in its interaction with the immune system; some bacterial species penetrate directly into the mucus and contact the epithelial cell layer [45] via germline encoded pattern recognition receptors, such as the toll-like receptors, cytosolic RIG-I-like receptors, Nodlike receptors and HIN-200 family members [46]. However, other bacterial species are presented to the immune system through dendritic cells (DC), which phagocytize antigens from the intestinal lumen, and by M cells overlaying the Peyers Patches (PP), forming a dome like structure below the epithelium (Fig. 2) [45].
The GM-immune system interaction is of a mutual understanding nature. GM sensitizes the immune system by
Fig. (2). The GM Nurture Immune System Which Subsequently Regulate the GM Density. A: The bacterial flora present antigens to dendritic cells either directly in lamina propria [79] or indirectly through M-cells in payer’s patches. The endocytosed dentrict cells prime and polarize T cells (known as effectors T cells) in payer’s patches and mesenteric lymphoid nodes [4]. The dendritic and immune cells can exit payer’s patches through afferent lymphatic into mesenteric lymph nodes– which is considered an intersection between the peripheral and mucosal recirculation pathways [4]. The effectors T cells leave the mesenteric lymphoid nodes through efferent lymphatic and diffuse into the circulatory system for effector function [80]. These effector cells home back to mucosal lining when their surface proteins interact with agonist, and then neutralize antigens and protect host against pathogen [81]. For instance α4β7-integrin express on T cells which agonist with MAdCAM1, an endothelial cell receptor [81]. B: Regenerating islet-derived protein 3γ (REG3γ) is controlled through Toll-like receptors (TLRs), express in epithelial cells. The REG3γ expression also require MYD88 [82, 83] and IL 22-mediated signals from innate lymphoid cells [82]. The α-defensins are highly expressed by Paneth cells in the small intestine. Unlike α-defensins, which kill both Gram-positive and negative bacteria [84], REG3γ is active more specifically against Gram-positive bacteria [82]. C: The GM can induce IgA expression by presenting potential antigens [85] to dendritic cells which subsequently induce B cells to produce IgA [86]. The IgA are secreted to epithelial layer and contributing to maintain mucosa-associated bacterial density and composition [86, 87].
Epithelial Cell Layer GM Antigens
M cell MADCAM1
Lamina Propria
Efferent Lymphatic
Afferent Lymphatic
Payer’s Patche
Peripheral Immune MLN
System The matured immune cells home back to mucosal lining for effecter function
Dendritic Cell
IgA
Mucosal B Cell
IgA-Secreting Plasma Cell Regulate GM
Regulate GM
Innate Lymphoid Cell IL-22
Reg3γ α-Defensins A
Bacteria
T Cell
B Cell
Paneth Cells TLR
Epithelial Cell B
C
Implication of Gut Microbiota in Human Health CNS & Neurological Disorders - Drug Targets, 2014, Vol. 13, No. 8 1329
presenting bacterial components such as lipopolysaccharide, flagellin and muramyl dipeptide, inducing acquire local and systemic responses [45]; in reward, GM gets shelter and nutrition by the Gastrointestinal tract. Beside symbiotic association, the immune system keeps a check on GM density and composition, controlled by the Regenerating islet-derived protein 3γ (REG3γ), an antibacterial lectin that is expressed in epithelial cells [44]. This lectin regulates the number of bacteria that contact the epithelial surface [44].
Immunoglobulin A (IgA) is secreted into the intestinal lumen, contributing to microbiota composition; also, dependent changes in GM community was related to α- defensin [44], (Fig. 2). The hosts can sense a shift in GM composition by detecting microbial byproducts such as the SCFAs, including butyrate and propionate [45]. The dysbiosis has substantial effects on host body, leading to poor epithelial architecture [45], deficient antimicrobial defense by IgA and CD8αβ [44], and immature development of the mucosal-associated lymphoid tissue associated with reduced IgA levels and drop in T and B cell populations [45]. The absence of GM caused limited generation of the TH17 cells in the gut and spleen; these cells are known to action mucosal linings by recruiting monocytes and neutrophils in response to infection [47].
GM contributes to systemic autoimmune and allergy conditions [44]. The GF mice show increased susceptibility to invariant natural killer T cell–mediated oxazolone-induced colitis and ovalbumin-induced asthma [44]. The altered expression of NF-κB, a transcription factor involved in inflammatory and immune responses of the gut, are linked to pathologies of chronic inflammatory bowel disease or obesity [46]. It is expected that future GM research could find solutions to intestinal immune pathologies and systemic immune diseases.
GM AND CARDIOVASCULAR DISEASES
The food we eat is converted into various active compounds by GM which are affecting the heart, with some causing cardiovascular diseases (CVD), that are behind one third of the global human mortality [48]. GM facilitates mono-saccharides absorption, increasing fat storage and directly contributing to CVD development mainly from high fat diet [49]. Furthermore, GM converts dietary lecithin and choline, the molecules which help in cell membrane building and transmittance of nerve impulses, into trimethylamine N- oxide – which promotes atherosclerosis [50]. In addition, some pathogens are also involved in CVD development by altering the GM profile through inflammatory responses to Helicobactor pylori and Salmonella infections [51].
Chlamydia pneumonia [52] and Yersinia enterocolitica [53]
can develop cardiac problems, (Fig. 1). Researchers are trying to reduce CVD risks by manipulating GM through probiotics [51] and various food products [48].
Angiotensin converting enzyme (ACE) catalyzes angiotensin-I to the angiotensin-II (a vasoconstrictor), resulting in hypertension by inhibiting bradykinin (a vasodilator). Lactobacillus, a probiotic bacterium, produces bioactive peptides, possessing an anti-ACE activity, a therapeutic approach that alleviates hypertension [51, 54].
The friendly Lactobacillus bulgaricus-51probiotic and its fermentation products are proven to decline ventricular
arrhythmia by attenuating the prostacyclin that protects the tissue during myocardial ischemia, and by their effect on norepinephrine [51]. Fermented milk with Lactobacillus helveticus-CM4 can reduce blood pressure [51]. The probiotics may hold therapeutic promises, with a possibility to cure CVD by GM manipulation.
GM AND ALLERGY
Allergy is a common health problem, affecting approximately 25% to 35% of industrialized populations with serious implications on infants and pregnant women.
The children born into atopic families are prone to allergy (50%–80% of risk). Inspite of all preventive measures against potent allergens present in milk, egg products, pet furry, dust, and mattress, still the allergic diseases are continuously escalating [31]. The discovery of allergy and asthma genes did not help in finding a cure for allergic patients [10], forcing the scientists to search for other possible remedy approaches.
Lifestyle and environmental changes contribute to the increasing propensity of allergic disease [55]. Allergic diseases, such as atopy, hay fever, and asthma have low prevalence among more sibling, farmer’s children and children in contact with pets [56]. Children contacts with microbes might skew the immune responses away of the path that leads to allergy, i.e. towards responses by the TH1 instead of TH2. Microbial exposure has inverse relationship to the prevalence of hay fever [57], asthma and atopy [10]. It has been identified that Eurotium, Penicillium, Bacillus and Staphylococcus bacteria have allergy-preventive effects [57].
For example, endotoxins, β(1-3) glucans, extracellular polysaccharides and muramic acid from molds and bacteria protect the host against allergy and asthma [10].
Acinetobacter, a soil bacterium is linked to high levels of an anti-inflammatory marker in the blood of healthy individuals, confirming its protective role in the asthma [58].
The early neonatal microbiota, normally transmitted from maternal vaginal microbiota, is essential in establishing a healthy GM in the host. The infants born by caesarean section are inhabited only by epidermal rather than vaginal microbiota, rendering them vulnerable to allergies and asthma [4]. This fact re-emphasizes the importance of balanced GM in human health [10]. Altered GM contributes to allergic disorders. It is now confirmed that allergic infants have high count of Staphylococus aureus, Clostridium difficile and lower prevalence of Bacteriodes and Bifidobacteria [31]. Isocaproic acid, a Clostridium difficile metabolic product was found in high concentration in allergic infant’s stool, while healthy infants have higher level of isobutyric acid, revealing the importance of lactating gut microbiota [31]. The factors that disrupt the GM can trigger allergic reactions, including antimicrobials use during infancy that disturbs the GM and increases the caspase-1 expression, a most common cause of drug allergy [59]. The gram-negative bacteria cell wall components, endotoxin or lipopolysaccharide, can increase the severity of asthma [60].
Probiotics are emerging therapeutics that can be used in cure of several diseases including allergy. The Lactobacillus rhamnosus was first time used successfully in curing atopic dermatitis in the year 1997 [10, 31].
GM AND NERVOUS SYSTEM
The GM can influence brain biochemistry and emotional behavior through metabolic products. The amino acid metabolites, SCFAs and neuroactive substances are known to have a significant influence on the brain functions [61].
Pathogens and inflammation are associated with cytokine- induced sickness behavior, and can develop depression, cognitive dysfunction and anxiety [62]. Polysaccharide-A, an antigen of Bacteroides fragilis mediates trafficking and migration of gut derived antigen presenting cells to CNS- associated lymphoid tissue, demonstrating the GM and CNS association [63]. The brain-gut axis is defined as “the connection between CNS and intestine [64], comprised of neural, both central and enteric nervous systems, endocrine, and immune systems” [65].
The alternation in GM can have a damaging effect on the CNS. This damage can be due to direct pathogen-induced antibodies that can develop acute flaccid paralysis as result of its cross reactivity with neural surface antigens [63]. The Treponema pallidum [66], Haemophilus influenzae, Streptococ- cus pneumonia and Neisseria meningitidisis [67] can cause damage to CNS (Fig. 1). Damage can be indirect, in which genes in the absence of GM can differentially be expressed in the hippocampus, cortex, striatum and cerebellum. Most probably these genes are involved in second messenger pathway and long term potentiation [68]. The influence of GM on genes function is still under investigation, trying to reach into more
solid conclusions. Dysbiosis is a suspected contributing factor in the onset of autistic disorders. Recently, a study reported a high density of Clostridium spp. in the feces of children suffering from autistic disorder [63]. Furthermore, GF mice showed motor dysfunction and anxiety, a common feature of Angelman’s syndrome. The GF mice expressed modulated density of postsynaptic density protein (PSD95) and synaptophysin proteins that are important in synaptogenesis [68]. These studies lead to a recommendation that the GM diversity and composition should be analyzed in patients suffering from genetic and neuro-disorders.
Moreover, it was proven that certain probiotics helped patients with nervous system disorders [63]. Probiotics, containing Bifidobacterium longum, was able to normalize the mouse behavior and to modulate the hippocampal brain- derived neurotrophic factor expression [62]. The Bifidobacterium animalis and Lactobacillus plantarum can augment neurotransmitters, affecting the excitatory and inhibitory balance of nerve impulses [69]. The role of GM in brain development and subsequent behavior is merging microbiology and neuroscience into a new discipline [68].
Table 1 enlists the bacterial species which can contribute to central nervous system – gastrointestinal axis.
GM AND LONGEVITY
Ageing is defined as “the regression of physiological function accompanied by the development of age” [70]. The Table 1. The interaction of bacterial species to central nervous system/gastrointestinal axis.
Microbiota Strain Host-Microbes Interaction
Bifidobacterium Lactobacilli The strain is contributing in development of autism and depressive disorder [63].
Campylobacter jejuni The strain is noticed in poultry, and can cause enteritis, diarrhea, abdominal pain, fever, malaise, carditis, appendicitis and Guillain-Barre´ syndrome [63].
Haemophilus pneumoniae The strain play a role in processing of gastrointestinal sensory information in mice [65]. It can cause Guillain-Barre´
syndrome [63].
Mycoplasma pneumonia Strain can cause Guillain-Barre´ syndrome [63].
Clostridium tetani
Clostridium botulinum These strains excrete neurotoxin which can damage nervous system [68].
Listeria monocytogenes This strain is the major cause of food borne disease and can damage the CNS [88].
Lactobacillus helveticus
Bifidobacteriumlongum Both of these strains are used in combination to reduce anxiety, enhance psychology and decrease serum cortisol [65].
Lactobacillus reuteri Used as probiotic to reduce anxiety and stress-induced increase of corticosterone in mice [65].
Trichurismuris Infection of this strain can cause alteration in anxiety-like behavior and hippocampal brain derived neurotrophic factor (BDNF) level [65].
Citrobacter rodentium Induces anxiety-like behavior (CF1 mice) [65].
Lactobacillus rhamnosus
Lactobacillus helveticus The strain can prevent anxiety-like behavior, learning and memory deficit in C. rodentium-infected mice [69]. It can also effect the brain biochemistry [62].
Bifidobacterium longum Prevent anxiety-like behavior [69].
Lactobacillus farciminis
Bifidobacteriuminfantis Helped the host mice to abolish colorectal distension hyeralgesia by reducing Fos expression, which is a general neuronal activation marker triggered by colorectal distention [69].
Lactobacillus reuteri Used as probiotic to reduce visceral pain [69].
Lactobacillus paracasei The strain showed protection against antibiotic-induced visceral sensitivity in mice [69].
Lactobacillus plantarum The strain can increase BDNF level [69]. BDNF support neuronal survival, facilitate the growth and differentiation of nerve cells and synapses and contribute in various aspects of emotional and cognitive behaviors [65].
Implication of Gut Microbiota in Human Health CNS & Neurological Disorders - Drug Targets, 2014, Vol. 13, No. 8 1331
aging process affects significantly the GM diversity and composition [71], either through immune responses or progressive diseases in centenarians [70]. The Firmicutes/Bacteroidetes ratio is used to evaluate the status of GM [70], a ratio that decreases with ageing [18].
However, Bacteroides, Enterococci, Enterobacteria and Clostridia levels remain constant through life [71]. These changes are also restricted to geographic origin [71]. It is hypothesized that healthy GM leads to longevity by delaying or preventing the inflamm-ageing, an increased inflammatory status [70] that is linked with ageing [71].
Bacterial species of genera Faecalibacterium, Bifidobacterium and Lactobacillus are well-known for down-regulating the pro-inflammatory responses [70, 72].
Lactobacillus rhamnosus CNCM I-3690, normally use to ferment camel milk called Suusac (Eastern African food) [73], increased 20% the average life of Caenorhabditis elegans [74], a model organism for ageing study [75].
Similarly, Lactobacillus paracasei Fn032, use to ferment foxtail millet [76], prevent free radicals (one of the causes behind ageing and death [77]. The anti-ageing effect of fermented milk was first observed by Metchnikoff in 1908 [75]. Beside these probiotics bacteria, CR – a dietary regimen, is thought to lengthen lifespan through affecting the progression of GM during aging [18], which is quite a controversial topic in nutritional science. The impact of CR on GM sustainability was first observed in urinary bacterial metabolites in mice under CR experiments [18]. The CR promotes healthy GM, more specifically the sustainability of the genus Lactobacillus, associated with longevity and abases the abundance of bacteria that negatively correlate with lifespan [18]. This triangle of CR, GM and ageing is driving scientists towards investigations that could uncover new reasons behind longevity.
CONCLUSION AND PROSPECTIVE
Microbiologists from the previous century identified the linkage between the host and gut microbes. However, recent development in DNA technology has revolutionized our ability in investigating the host-microbes interaction, and revealed that only 70-90% of the bacteria can be cultured under the present laboratory conditions. The current development in metagenomic, and the availability of sequencing and bioinformatics tools allow to go deep in analysis of the gut’s microbial community composition and their metabolic potential [20, 46].
Microbiota is considered the hidden metabolic organ of the body that contributes to normal functioning. The host- bacterial association can either be beneficial (symbiosis and commensalism) or pathogenic [31]. GM provide enzymes and biochemical pathways that are absent in the host [20].
Recently, it was discovered that microbial changes in Firmicutes and Bacteroidetes in the human gut could be one of the possible causes of obesity. The metabolism of nitroaromatics and azo compounds by Peptococcus sp. and other gut species can lead to the generation of genotoxic and carcinogenic agents [20]. The involvement of GM in brain development and subsequent behavior is providing a base for a new area of research, merging microbiology and neuroscience [64, 68]. The GM dysbiosis deteriorates the health of the host causing diarrhea or constipation, releasing
carcinogenic and toxic compounds [19, 44, 49]. Dysbiosis is associated with allergy, immunity related disorders, higher susceptibility of the host to intestinal infection [19, 78]. It can be concluded, that advancement in GM research will most likely increase our understanding of both the intestinal immune pathologies and systemic immune diseases.
The comprehensive studies in investigating the composition of GM and its interaction with the host are two important issues in future prospective for the development of alternative therapies. Probiotic bacteria, especially Lactobacillus, produce bioactive peptides that possess an anti-ACE activity, and are considered new therapies in alleviation of hypertension [51, 54]. Probiotics, containing Bifidobacterium longum were able to normalize the mouse behavior and to modulate the hippocampal brain-derived neurotrophic factor expression [62]. The Bifidobacterium animalis and Lactobacillus plantarum were able to augment neurotransmitters [69]. The use of supplemented food or prebiotics, and fecal infusion can be a potential future therapeutics for intestinal problems, helping in restoration of the GM composition [2].
AUTHORS' CONTRIBUTIONS
Imran Khan, Muhammad Yasir, Fehmida Bibi and Esam I. Azhar contributed in the designing, reviewing of literature and drafting the manuscript. Imran Khan and Muhammad Yasir prepared the tables and figures. Prof. Taha Kumosani, Elie K. Barbour and Mohammad A. Kamal critically reviewed the manuscript.
LIST OF ABBREVIATIONS
BDNF = Brain-derived neurotrophic factor CNS = Central nervous system
CR = Calorie restriction CVD = Cardiovascular diseases GF = Germ free
GM = Gut microbiota
HCC = Hepatocellular carcinoma IgA = Immunoglobulin A IL = Interleukin
SCFAs = Short‐chain fatty acids
CONFLICT OF INTEREST
There is no conflict of interest for this study.
ACKNOWLEDGEMENTS
This work was supported by a research grant no. 84-34-
طﻁ -
آﺁ from King Abdulaziz City for Science and Technology (KACST), Saudi Arabia.
REFERENCES
[1] Dethlefsen L, Relman DA. Incomplete recovery and individualized responses of the human distal gut microbiota to repeated antibiotic perturbation. Proc Natl Acad Sci USA 2011; 108(1): 4554-61.
[2] Tremaroli V, Backhed F. Functional interactions between the gut microbiota and host metabolism. Nature 2012; 489: 242-9.
[3] Kolida S, Saulnier DM, Gibson GR. Gastrointestinal microflora:
probiotics. Adv Appl Microbiol 2006; 59: 187-219.
[4] Maynard CL, Elson CO, Hatton RD, Weaver CT. Reciprocal interactions of the intestinal microbiota and immune system.
Nature 2012; 489: 231-41.
[5] Ferreira RB, Gill N, Willing BP, et al. The intestinal microbiota plays a role in Salmonella-induced colitis independent of pathogen colonization. PloS One 2011; 6: e20338.
[6] Ley RE, Peterson DA, Gordon JI. Ecological and evolutionary forces shaping microbial diversity in the human intestine. Cell 2006; 124: 837-48.
[7] Rajilic-Stojanovic M, Smidt H, de Vos WM. Diversity of the human gastrointestinal tract microbiota revisited. Environ Microbiol 2007; 9: 2125-36.
[8] Larsson E, Tremaroli V, Lee YS, et al. Analysis of gut microbial regulation of host gene expression along the length of the gut and regulation of gut microbial ecology through MyD88. Gut 2011; 61:
1124-31.
[9] Khan AA, Shrivastava A, Khurshid M. Normal to cancer microbiome transformation and its implication in cancer diagnosis.
Biochim Biophys Acta 2012; 1826: 331-7.
[10] Heederik D, von Mutius E. Does diversity of environmental microbial exposure matter for the occurrence of allergy and asthma? J Allergy Clin Immunol 2012; 130: 44-50.
[11] Tyakht AV, Kostryukova ES, Popenko AS, et al. Human gut microbiota community structures in urban and rural populations in Russia. Nat Commun 2013; 4: 2469.
[12] Rescigno M. The Pathogenic Role of Intestinal Flora in IBD and Colon Cancer. Curr Drug Targets 2008; 9: 395-403.
[13] Lamouse-Smith ES, Tzeng A, Starnbach MN. The intestinal flora is required to support antibody responses to systemic immunization in infant and germ free mice. PloS One 2011; 6: e27662.
[14] Ubeda C, Pamer EG. Antibiotics, microbiota, and immune defense.
Trends Immunol 2012; 33: 459-66.
[15] Jermy A. Host genes shape the gut microbiota. Nat Rev Microbiol 2010; 8: 838.
[16] Weinstock GM. Genomic approaches to studying the human microbiota. Nature 2012; 489: 250-6.
[17] Tappenden KA, Deutsch AS. The physiological relevance of the intestinal microbiota--contributions to human health. J Am Coll Nutr 2007; 26: 679S-83S.
[18] Zhang C, Li S, Yang L, et al. Structural modulation of gut microbiota in life-long calorie-restricted mice. Nat Commun 2013;
4: 2163.
[19] Rajilic-Stojanovic M. Function of the microbiota. Best Pract Res Clin Gastroenterol 2013; 27: 5-16.
[20] Pandeya DR, D’Souza R, Rahman MM, et al. Host-microbial interaction in the mammalian intestine and their metabolic role inside. Biomed Res 2012; 23: 9-21.
[21] Kovatcheva-Datchary P, Arora T. Nutrition, the gut microbiome and the metabolic syndrome. Best Pract Res Clin Gastroenterol 2013; 27: 59-72.
[22] Rafii F, Franklin W, Cerniglia CE. Azoreductase activity of anaerobic bacteria isolated from human intestinal microflora. Appl Environ Microbiol 1990; 56: 2146-51.
[23] Rosenberg DW, Giardina C, Tanaka T. Mouse models for the study of colon carcinogenesis. Carcinogenesis 2009; 30: 183-96.
[24] Pennisi E. Microbiology. Gut bacteria lend a molecular hand to viruses. Science 2011; 334: 168.
[25] Wang T, Cai G, Qiu Y, et al. Structural segregation of gut microbiota between colorectal cancer patients and healthy volunteers. ISME J 2012; 6: 320-9.
[26] Kodaman N, Pazos A, Schneider BG, et al. Human and Helicobacter pylori coevolution shapes the risk of gastric disease.
Proc Natl Acad Sci USA 2014; 111: 1455-60.
[27] Lax AJ, Thomas W. How bacteria could cause cancer: one step at a time. Trends Microbiol 2002; 10: 293-9.
[28] Boleij A, Roelofs R, Danne C, et al. Selective antibody response to Streptococcus gallolyticus pilus proteins in colorectal cancer patients. Cancer Prevent Res 2012; 5: 260-5.
[29] Chang JH, Shim YY, Cha SK, Reaney MJ, Chee KM. Effect of Lactobacillus acidophilus KFRI342 on the development of chemically induced precancerous growths in the rat colon. J Med Microbiol 2012; 61: 361-8.
[30] van Nood E, Vrieze A, Nieuwdorp M, et al. Duodenal infusion of donor feces for recurrent Clostridium difficile. N Engl J Med 2013;
368: 407-15.
[31] Bjorksten B. Effects of intestinal microflora and the environment on the development of asthma and allergy. Springer Semin Immunopathol 2004; 25: 257-70.
[32] Zhang HL, Yu LX, Yang W, et al. Profound impact of gut homeostasis on chemically-induced pro-tumorigenic inflammation and hepatocarcinogenesis in rats. J Hepatol 2012; 57: 803-12.
[33] Fox JG, Feng Y, Theve EJ, et al. Gut microbes define liver cancer risk in mice exposed to chemical and viral transgenic hepatocarcinogens. Gut 2010; 59: 88-97.
[34] Scarpellini E, Ponziani FR, Tortora A, et al. P.11.18 Gut Microbiota Alteration: The Link between “Leaky Gut” and Spontaneous Bacterial Peritonitis in Liver Cirrhotic Patients?
Digest Liver Dis 2013; 45: S170-S1.
[35] Jemal A, Bray F, Center MM, et al. Global cancer statistics. Cancer J Clin 2011; 61: 69-90.
[36] Dapito DH, Mencin A, Gwak GY, et al. Promotion of hepatocellular carcinoma by the intestinal microbiota and TLR4.
Cancer Cell 2012; 21: 504-16.
[37] Wang Z, Klipfell E, Bennett BJ, et al. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature 2011;
472: 57-63.
[38] Bajaj JS, Ridlon JM, Hylemon PB, et al. Linkage of gut microbiome with cognition in hepatic encephalopathy. Am J Physiol Gastrointest Liver Physiol 2012; 302: G168-75.
[39] Usami M, Miyoshi M, Kanbara Y, et al. Analysis of fecal microbiota, organic acids and plasma lipids in hepatic cancer patients with or without liver cirrhosis. Clin Nutr 2013; 32: 444-51.
[40] Yoshimoto S, Loo TM, Atarashi K, et al. Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome. Nature 2013; 499: 97-101.
[41] Feyisetan O, Tracey C, Hellawell GO. Probiotics, dendritic cells and bladder cancer. BJU Int 2012; 109: 1594-7.
[42] Erdoğrul Ö, Erbilir F. Isolation and Characterization of Lactobacillus bulgaricus and Lactobacillus casei from Various Foods. Turk J Biol 2006; 30: 39-44.
[43] Abriouel H, Ben Omar N, Lopez RL, et al. Culture-independent analysis of the microbial composition of the African traditional fermented foods poto poto and degue by using three different DNA extraction methods. Int J Food Microbiol 2006; 111: 228-33.
[44] Hooper LV, Littman DR, Macpherson AJ. Interactions between the microbiota and the immune system. Science 2012; 336: 1268-73.
[45] Salzman NH. Microbiota-immune system interaction: an uneasy alliance. Curr Opin Microbiol 2011; 14: 99-105.
[46] Lakhdari O, Cultrone A, Tap J, et al. Functional metagenomics: a high throughput screening method to decipher microbiota-driven NF-kappaB modulation in the human gut. PloS One 2010; 5.
[47] Bangsgaard Bendtsen KM, Krych L, Sorensen DB, et al. Gut microbiota composition is correlated to grid floor induced stress and behavior in the BALB/c mouse. PloS One 2012; 7: e46231.
[48] Fava F, Lovegrove JA, Gitau R, Jackson KG, Tuohy KM. The gut microbiota and lipid metabolism: implications for human health and coronary heart disease. Curr Med Chem 2006; 13: 3005-21.
[49] Backhed F, Ding H, Wang T, et al. The gut microbiota as an environmental factor that regulates fat storage. Proc Natl Acad Sci USA 2004; 101: 15718-23.
[50] Wang Z, Klipfell E, Bennett BJ, et al. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature 2011;
472: 57-63.
[51] Hanning I, Lingbeck J, Ricke SC. Probiotics and heart health:
reduction of risk factors associated with cardiovascular disease and complications due to foodborne disease. Watson RR, Preedy VR, Eds.; San Diego: Elsevier, 2010.
[52] Rupprecht HJ, Blankenberg S, Bickel C, et al. Impact of viral and bacterial infectious burden on long-term prognosis in patients with coronary artery disease. Circulation 2001; 104: 25-31.
[53] Bonnet E, Archambaud M, Sommabere A, et al. Endocarditis due to Yersinia enterocolitica. Infection 1998; 26: 320-1.
[54] Yamamoto N, Akino A, Takano T. Antihypertensive effect of the peptides derived from casein by an extracellular proteinase from Lactobacillus helveticus CP790. J Dairy Sci 1994; 77: 917-22.
[55] Prescott SL, Tang ML. The Australasian Society of Clinical Immunology and Allergy position statement: Summary of allergy prevention in children. Med J Austr 2005; 182: 464-7.
Implication of Gut Microbiota in Human Health CNS & Neurological Disorders - Drug Targets, 2014, Vol. 13, No. 8 1333 [56] von Mutius E, Vercelli D. Farm living: effects on childhood asthma
and allergy. Nat Rev Immunol 2010; 10: 861-8.
[57] Ege MJ, Mayer M, Normand AC, et al. Exposure to environmental microorganisms and childhood asthma. N Engl J Med 2011; 364:
701-9.
[58] Hanski I, von Hertzen L, Fyhrquist N, et al. Environmental biodiversity, human microbiota, and allergy are interrelated. Proc Natl Acad Sci USA 2012; 109: 8334-9.
[59] Han NR, Kim HM, Jeong HJ. Kanamycin activates caspase-1 in NC/Nga mice. Exp Dermatol 2011; 20: 659-63.
[60] Schwartz DA. Does Inhalation of Endotoxin Cause Asthma? Am J Resp Crit Care Med 2001; 163: 305-6.
[61] Gassem MA. Study of the micro-organisms associated with the fermented bread (khamir) produced from sorghum in Gizan region, Saudi Arabia. J Appl Microbiol 1999; 86: 221-5.
[62] Bercik P. The microbiota-gut-brain axis: learning from intestinal bacteria? Gut 2011; 60: 288-9.
[63] Ochoa-Reparaz J, Mielcarz DW, Begum-Haque S, Kasper LH. Gut, bugs, and brain: role of commensal bacteria in the control of central nervous system disease. Ann Neurol 2011; 69: 240-7.
[64] de Jonge WJ. The Gut's Little Brain in Control of Intestinal Immunity. ISRN Gastroenterol 2013; 2013: 630159.
[65] Cryan JF, O'Mahony SM. The microbiome-gut-brain axis: from bowel to behavior. Neurogastroenterol Motil 2011; 23: 187-92.
[66] Michelow IC, Wendel GD, Norgard MV, et al. Central Nervous System Infection in Congenital Syphilis. N Engl J Med 2002; 346:
1792-8.
[67] Coyle PK. GLucocorticoids in central nervous system bacterial infection. Arch Neurol 1999; 56: 796-801.
[68] Diaz Heijtz R, Wang S, Anuar F, et al. Normal gut microbiota modulates brain development and behavior. Proc Natl Acad Sci USA 2011; 108: 3047-52.
[69] Bested AC, Logan AC, Selhub EM. Intestinal microbiota, probiotics and mental health: from Metchnikoff to modern advances: part III - convergence toward clinical trials. Gut Pathogens 2013; 5: 4.
[70] Biagi E, Candela M, Fairweather-Tait S, Franceschi C, Brigidi P.
Aging of the human metaorganism: the microbial counterpart. Age 2012; 34: 247-67.
[71] Biagi E, Nylund L, Candela M, et al. Through ageing, and beyond:
gut microbiota and inflammatory status in seniors and centenarians.
PloS One 2010; 5: e10667.
[72] van Baarlen P, Troost FJ, van Hemert S, et al. Differential NF- kappaB pathways induction by Lactobacillus plantarum in the duodenum of healthy humans correlating with immune tolerance.
Proc Natl Acad Sci USA 2009; 106: 2371-6.
[73] Jans C, Bugnard J, Njage PMK, Lacroix C, Meile L. Lactic acid bacteria diversity of African raw and fermented camel milk products reveals a highly competitive, potentially health-
threatening predominant microflora. Food Sci Technol 2012; 47:
371-9.
[74] Grompone G, Martorell P, Llopis S, et al. Anti-inflammatory Lactobacillus rhamnosus CNCM I-3690 strain protects against oxidative stress and increases lifespan in Caenorhabditis elegans.
PloS One 2012; 7: e52493.
[75] Zhao Y, Zhao L, Zheng X, et al. Lactobacillus salivarius strain FDB89 induced longevity in Caenorhabditis elegans by dietary restriction. J Microbiol 2013; 51: 183-8.
[76] Amadou I, Le G-W, Shi Y-H. Evaluation of Antimicrobial, Antioxidant Activities, and Nutritional Values of Fermented Foxtail Millet Extracts by Lactobacillus paracasei Fn032. Int J Food Prop 2013; 16: 1179-90.
[77] Kaushal D, Kansal VK. Probiotic Dahi containing Lactobacillus acidophilus and Bifidobacterium bifidum alleviates age-inflicted oxidative stress and improves expression of biomarkers of ageing in mice. Mol Biol Rep 2012; 39: 1791-9.
[78] Bindels LB, Porporato P, Dewulf EM, et al. Gut microbiota- derived propionate reduces cancer cell proliferation in the liver. Br J Cancer 2012; 107: 1337-44.
[79] Cerf-Bensussan N, Gaboriau-Routhiau V. The immune system and the gut microbiota: friends or foes? Nat Rev Immunol 2010; 10:
735-44.
[80] Koboziev I, Karlsson F, Grisham MB. Gut-associated lymphoid tissue, T cell trafficking, and chronic intestinal inflammation. Ann NY Acad Sci 2010; 1207(Suppl 1): E86-93.
[81] Mehandru S. The Gastrointestinal Tract in HIV-1 Infection:
Questions, Answers, and More Questions! PRN Notebook 2007;
12: 1-10.
[82] Gallo RL, Hooper LV. Epithelial antimicrobial defence of the skin and intestine. Nat Rev Immunol 2012; 12: 503-16.
[83] Vaishnava S, Yamamoto M, Severson KM, et al. The antibacterial lectin RegIIIgamma promotes the spatial segregation of microbiota and host in the intestine. Science 2011; 334: 255-8.
[84] Salzman NH, Underwood MA, Bevins CL. Paneth cells, defensins, and the commensal microbiota: a hypothesis on intimate interplay at the intestinal mucosa. Semin Immunol 2007; 19: 70-83.
[85] Kosiewicz MM, Zirnheld AL, Alard P. Gut microbiota, immunity, and disease: a complex relationship. Front Microbiol 2011; 2: 180.
[86] Duerkop BA, Vaishnava S, Hooper LV. Immune responses to the microbiota at the intestinal mucosal surface. Immunity 2009; 31:
368-76.
[87] Guarner F, Malagelada J-R. Gut flora in health and disease. Lancet 2003; 361: 512-9.
[88] Mukherjee K, Hain T, Fischer R, Chakraborty T, Vilcinskas A.
Brain infection and activation of neuronal repair mechanisms by the human pathogen Listeria monocytogenes in the lepidopteran model host Galleria mellonella. Virulence 2013; 4: 324-32.
Received: March 30, 2014 Revised: May 16, 2014 Accepted: May 16, 2014
PMID: 25345506
