Dysbiosis, Probiotics, Synbiotics and Human Health

Abstract

The manuscript aims to project handy information on intricacies and interwoven of the ecosystem of gut-dysbiosis, and probiotics and synbiotics, with human health. Information collected from diverse source including databases. Presented information might insight and paves the way for better management of human health with probiotics and synbiotics therapy, in diverse domain.

Keywords: Dysbiosis; Effect; Health; Probiotics; Symbiotic; Therapy

Abbreviations

GIT: Gastrointestinal Tract; SCFA: Short-Chain Fatty Acid; DC: Dendritic Cell; MHE: Minimal Hepatic Encephalopathy; LAB: Lactic Acid Bacteria; AchR: Acetylcholine Receptor; NF-kB: Nuclear Factor Kappa-light-chain-enhancer of activated B-cells; TNF: Tumor Necrosis Factor; Th-cell: T helper cell; Tr-cell: T regulatory cell; and NK-cell: Natural Killer Cell

Introduction

The human GIT colonizes thousands species of microbes and enriched with many molecules, be using as nutrients by microbes. It possesses potentiality to be colonizing by microbes, to highest diversity. In fact, billions of bacteria inhabit the human digestive system, referred to as the GIT-microflora. They contribute over a kilo of body weight. Biotic species-/strain-diversity of the GIT-microflora is over 1000, which are beneficial (non-pathogenic) and pathogenic (potentially harmful) [1-5].

The mucosa of the GIT is continuously exposing to an environment that enriched in foreign substances, food particles, and microbial antigens. Within GIT, the large intestine or colon is the site preferred by microbes for colonization. Thus, the gut-microbiota play a key role in efficient nutrient absorption thus has a crucial role in disease and maintaining human health. Through metabolic process, the intestinal microbes metabolizes diverse nutritional substrates to terminating metabolites like organic acids, vitamins, SCFAs, etc [4].

Consensus on roles of the intestinal-microbiota in human health and disease is expanding rapidly. The gut-microbiota appears to be contributing to nearly every aspect of the host's growth and development. The gut-health in is a key sector for maintaining overall health, of people whose gut-microbiota plays key role in metabolism and nutrient absorption. Consensus is that tremendous arrays of diseases and dysfunctions associated with an imbalance in composition, numbers, or habitat of the gut-microbiota. Hence, dynamic balance between the host gut and its microbiota is prerequisite [1-8].

Perturbation of the gut-microflora/ecosystem may leads to different gut/functional-bowel disorders, certain illness, or chronic diseases like autoimmune diseases, colon cancers, gastric ulcers, cardiovascular disease, and obesity. Circumstances like diet, medication, stress, age and inhabiting conditions perturb this balance. This perturbation, alteration or imbalances of the microflora are outcomes gut-dysbiosis. This state events the colonization of pathogenic species, manifested, consequences diseases and disorders, aforesaid [3-9].

Restoration of the gut-microbiota may difficult to be accomplishing. However, therapies of dietary supplement, especially probiotics/prebiotics/synbiotics, are able to manipulate composition of the gut-microbiota in infants and adults [10-11]. The therapy comprises a large heterogeneous group of bacteria, the normal inhabitants of the human GIT. These enables in maintaining a balance between the beneficial and harmful bacteria. Related promising results had been establishing in a large number of well-designed studies, clinical one [1-3].

Probiotics (the beneficial/friendly bacteria) and prebiotics (the indigestible food ingredients) maintain intestinal health and deliver specific health benefits. In symbiotic [combination of probiotics and prebiotics], a synergistic chemopreventive actions is exerted with combinations of the two. Here the probiotics uses the prebiotics as a food source that enables in extending their survival within the intestine than would be possible otherwise [1-3,12-15].

Nowadays consumers are interested in intake of food that needs to be healthy and or alleviates illness. Since their introduction, probiotics, prebiotics, and synbiotics have been attracted much attention for ameliorating health. These are becoming increasingly popular, evidenced from rapidly expanding research support and an ever-widening choice of products. Their products presented commercially in diverse forms like foods, dietary supplements, and clinical therapeutics (oral or non-oral delivery). Scientific communities nowadays engaged in searching for different prebiotics as well as effective synbiotics combinations, for maintaining the beneficial microbiota of human GIT. Knowledge of gut-microflora and its interactions may lead to development of the dietary strategies that serve to sustain or even improve the healthier gut-microflora [1- 5,10-15].

There is therefore needs to have an exhaustive handy reference on the functions of the gut-microbiota, occurrence of gut-dysbiosis, intricate and interwoven the ecosystem of gut-dysbiosis with human health, probiotics and synbiotics, and future perspectives. In addition presenting is how gut-microbiota triggers development of disease in gut-dysbiosis state and synbiotics alleviating it.

Human Gut-Microbiota

The term "microbiota," "microflora," or "normal-flora" had been using to designate the vast host of microbes coexisting with the host [3,16-18]. An estimate is that the human-microbiota contains as many as 1014 microbial cells, a number 10 times greater than the number of cells present in human bodies [19-21]. Said microbiota comprises bacteria, unicellular eukaryotes, and other organisms, in large numbers. Every surface of the human body starting from skin surface to genitourinary tract, oral cavity, respiratory tract, ear, and GIT colonized heavily with diverse species of bacteria [18,22-24]. Amongst them, the gut is most heavily colonized organ that houses a huge microbial ecosystem, having biotic species-/strain-diversity over 1000. The colon alone contains over 70% of the human-microbiota, as estimated. The gut dominated by several bacterial phyla including Bacteroidetes, Firmicutes, and Actinobacteria [3,7-8,19,21,25].

The GIT is a sterile environment at birth. Colonization of it begins during the delivery process, from the maternal genital-flora and/or environment. Later on, it colonizes from the surroundings or environment [26]. Factors like microbiota of the maternal-genital-tract, obstetric techniques (vaginal or caesarean delivery), sanitary conditions, and type of feeding have an immediate effect on the level and frequency at which various species colonizes the infant's gut [3,25].

The gut initially colonizes with the facultative anaerobes like Escherichia coli and Streptococcus spp. These first colonizers metabolize any traces of oxygen in the gut, thereby transforming the environment towards strong anaerobic conditions. The feeding profile of the infant determines largely the subsequently colonizing microbes. Weaning of baby to solid foods changes the composition and complexity of the gut-microbiota, and final phase of microbiota acquisition. Dietary changes in the adulthood are significantly responsible for the composition and complexity of intestinal-microbiota. The gut-microbiota of adult has majorly non-sporing anaerobes. Most numerically predominant are species of Bacteroides and Bifidobacterium, Clostridium, Eubacterium, Fusobacterium, Lactobacillus, and various gram-positive cocci. Bacteria numerically non-predominant include Enterococcus spp., Enterobacteriaceae, and methanogens and dissimilatory sulfate-reducing bacteria [3,7-8,25].

Role in functions

Gut-microorganisms are able readily to degrade available substrates, derived may be from the diet or endogenous secretions. Substrates available majorly for colonic fermentation are starches and soluble dietary fibers. Substrates of other carbohydrate, available in lower concentrations, are oligosaccharides and portions of non-absorbable sugars and sugar alcohols. Proteins and amino acids can be the substrates for effective growth of colonic microbes. Other substrates that may contribute are bacterial secretions, lysis-products, sloughed epithelial cells, mucins, etc. Diverse microbial enzymes degrade these materials. Gut-microbes eventually able to ferment these intermediates to terminate-products like carbon dioxide, histamine, organic acids, and other products, neutral, acidic, and basic. Said fermentation processes progress through a series of energy-yielding reactions that do not use oxygen in the respiratory chains [7-8,25].

Basing upon the metabolic activities of gut-microbiota and their fermentation terminate-products, these can be categorizing either beneficial or pathogenic. Their health promoting effects are improved digestion and absorption, pathogen growth inhibition, immunostimulation, vitamin synthesis, and cholesterol and flatulence reduction. Harmful effects are toxin and carcinogen production, diarrhea/constipation, intestinal putrefaction/infections, liver damage, etc [7-8,25].

Role in histological functions

The gut-microbiota ensures function of intestine and intestinal structure, as possesses role in cell and tissue development. Colonic microbes secrete butyrate, a SCFA, which reinforces defense barrier in the colon. This butyrate regulates cell differentiation and growth, inhibits cell transformation, promotes cell reversal from a neoplastic to a nonneoplastic phenotype, and induces secretion of mucin, antimicrobial peptides, and other factors [3,27-28]. Mucin secretion and degradation balances the intestinal mucus layer that obstructs pro-inflammatory compounds and antigen uptake [29]. In addition, development of the microvasculature of intestinal villi depends on indigenous microbes [30]. All these signify the importance of the gut-microbes in developing morphology and structure of the gut [3,8].

Role in metabolic and protective functions

The colonic bacterium synthesizes amino acids, produce group B vitamins, and biotransforms bile. Enzymatic biotransformation of bile is important for the metabolism of glucose and cholesterol [31]. These microbiomes provide needful biochemical pathways for the fermentation or metabolism of non-digestible substrates like fibers and endogenous mucus. Said metabolism promotes their growth and production of SCFAs and gases [32]. SCFAs produced majorly are acetate, propionate, and butyrate. Other terminating metabolites are lactate, ethanol, succinate, formate, caproate, isobutyrate, 2-methyl-butyrate, valerate, and isovalerate [3,8].

Many of the beneficial gut-organisms produce antimicrobial compounds, and compete for nutrients and attachment sites, in the gut-lining, preventing colonization by pathogens. They demote production of peptidoglycans and lipopolysaccharides, all can be detrimental to the host [3,14-15,33-35].

Development of B cells, Tr-cell, and Th-cells (1, 2, and 17) is dependent on the signals from the gut-microbiota [36-40]. Butyrate, have been shown to inhibit NF-kB in patients with ulcerative colitis thus exerting immunomodulatory effects [41-42]. They also inhibit DNA synthesis, stimulate apoptosis, and may play significantly in preventing cancer of the GIT [8,25].

Immune system development is governing also by the nature of the indigenous gut-microflora, immature at birth, develops gradually upon exposure to the gut-microbiota [3,6,43]. The innate immune system allows the host in sensing a concrete microbial environment, prerequisite to promote the release of signaling molecules (cytokines and chemokines) for initiating an immune response [25]. These concepts illustrate a dynamic relationship between the immune system and the microbiota [4]. The gut-mucosa averts menaces by signaling to the innate immune system through toll-like receptors. These receptors recognize and bind to specific microbial macromolecules like lipopolysaccharides, flagellin, peptidoglycans, and N-formylated peptides. Activation of these receptors initiates NF-kB pathways, mitogen-activated protein kinase, and caspase-dependent signaling cascades. These consequences are in production and release of protective peptides, cytokines, chemokines, and phagocytes. Thus resulting can be a protective response to non-pathogenic bacteria, an inflammatory response to pathogens, or a trigger of apoptosis [3,8].

Microbial metabolism takes place in the cecum and colon, the site where SCFAs are absorbed. SCFAs have a protective effect on the intestinal epithelium [32]. Fermentation of carbohydrate and production of SCFAs significantly stimulates absorption of magnesium, salts, water, calcium, and phosphorus [25]. As most of the butyrate completely metabolized, the colonic bacterium prefers it as the sole source of energy. Acetates serve as a substrate in cholesterol biosynthesis. Likewise, the gut-microbiota performs diverse and essential metabolic activities in the hosts [3,8].

Role in hepatic encephalopathy

Endotoxemia causes inflammation leading to cirrhosis of the liver. MHE is a complication of cirrhosis characterized by neurological manifestations where neurotoxic substances accumulate in the bloodstream. The exact pathogenesis of MHE is unclear but hypothesized that gut-derived-nitrogenous substance, specifically ammonia derived primarily from enteric bacteria, plays central role [3,8,44-45].

Role in diabetes and obesity

Patients with diabetes mellitus have different gut-microbiota comparing non-diabetic adults. Diabetic individuals had a lower number of Faecalibacterium prausnitzii with an increase in inflammatory markers. This concept establishes correlations between the gut-microbiota composition, and inflammation happenings and metabolic alterations, in obese individuals. The gut-microbiota maintains metabolic equilibrium of the host whilst obesity is associated with large changes in the abundances of diverse bacteria from different taxa [3,46-50]. In addition, they increase production of angiopoetin-related protein-4, a lipoprotein lipase inhibitor that inhibits the uptake of fatty acids from circulating triglyceride-rich lipoproteins in muscle and white adipose tissues [3,8,51].

Role in brain and behavior

The mechanistic influence of gut-microbiota on the brain and behavior is still unclear but an explanation could involve immune-mediated neural or humeral mechanisms. Presence of catecholamine biosynthetic pathways in probiotics indicates the possibility that cell-to-cell signaling in vertebrates may be due to late horizontal gene transfer from bacteria [52]. There were also elevated levels of TNF-α in the Central Nervous System [7-8,53].

DCs embedded in the gut-wall are in close proximity to sheaths of neurons. The function of DCs is modulating by the sensory neuropeptide, calcitonin-gene-related peptide [54]. DCs might signal about gut-microbiota to the brain through the vagus nerve [55]. This nerve has principal role in signaling between GIT and brain. The vagal response can be stimulating by endotoxins and inflammatory cytokines like interleukin-1β and TNF-α [56]. Vagal response also demotes proinflammatory cytokine release from intestinal macrophages [3,7-8,56-57].

Dysbiosis

Factors like pH of the gut contents, nutrient availability, redox potential within the tissue, age and health of the host, bacterial adhesion and cooperation, mucin secretions containing immunoglobulins, bacterial antagonism, and transit time may affect the diversity and quantity of microbiota present in the segments of the GIT [3,6,25,58].

The signal of the intestinal microbes determines normal physiology of the host. The gut-lumen consist gastric acid, digestive enzymes, and immunoglobulin-A. These constituting the first line of defense are lethal to invading and ingested pathogens. The indigenous gut-microbe degrades intra-luminal antigens and inhibits the pathogens from adherence and colonization. They are necessary also for induction of B-cells and T-cells (regulatory and helper) [59]. Any imbalance or perturbation in gut-microbial ecosystem could outcome deregulation of its microbiota (dysbiosis) [4]. Dysbiosis often associated with various disease states ranging from the most common inflammatory bowel disease [60,61] and irritable bowel syndrome [4,9,62-66] to the more unexpected activation of chronic HIV infection and atopy [3,67-70]. It seems associated with other diseases, particularly prevalent in the 21st century. These consensuses complex/dynamic relationship between human health and the human microbiome and might pave the way for better management of health [3,4].

Dysbiosis Alleviation

Microbiomics has spurred a dramatic increase in scientific, industrial, and public interest in probiotics and prebiotics as potential agents for managing and controlling gut-microflora. Genomics and bioinformatics, as tools may let in establishing mechanistic relationships among gut-microbiota, health status, and effects of drugs in the individual. Hope this will provide perspectives for individualized gut-microbiota management [3].

Therefore, important is restoring the bacterial homeostasis, may have been disturbed by any or several factors. One of the ways to alter the gut-microbiota favorably is by using of select intestinal-microbiota. Consensus is that select microbiota may involved in diverse clinical states like preventing or treating various GIT disorders, promoting gastrointestinal health, produce vitamins and minerals, contribute to protein homeostasis, and preventing metabolic syndrome. However, their precise role is unclear and additional research is prerequisite to determine their causal or associative relationship [3,6,25,58].

LAB and non-LAB have shown to positively influence health. Common and well-known beneficial bacteria belong to the genus Lactobacillus and Bifidobacterium. These can be introducing into the gut and/or encouraged to multiply through ingestion of appropriate probiotic strain(s) or by making provision of growth substrates, known as prebiotics or soluble fibers. Hence, restoring the balance by using these bacteria or materials for preventing and treating disease should be advantageous. Prebiotics along with probiotics and synbiotics can favorably influence microbial interactions with the immune system and gut-epithelium. These had been studied and using in diverse sickness [3,25].

Synbiotics

Several members of the gut-microbiota produce vitamins and minerals and provide them to the host, maintain protein homeostasis, and inhibit adhesion and displacement of pathogens. In addition, they compete for nutrients and some of the attachment sites same as of pathogens, acidification of the gut-environment and production of antimicrobial compounds inhibiting the growth of pathogens, and the production of toxic compounds such as ammonia and amines. Germ-free animals are susceptible to infections and require 30% more energy in their diet and supplementation with vitamins (K and B), mandatory to maintain their body weight. Exposure to the gut-microbiota is prerequisite for developing the innate immune system [5,25].

Oral ingestion of beneficial living intestinal microbes increases the amount of health-promoting microbes in the gut. Certain limitations, including nutrient availability and the ability of beneficial gut-microbes to survive in the physiochemical protective barriers of the host in order to reach the lower GIT must be overcome before an ecological niche can be become established. Accomplishments of said limitations mean the selected gut-microbiota may have a number of remarkable postulated health effects on acute and chronic disease in humans [5,10-11,25].

Pharmaceuticals been unable to decrease global morbidity and mortality (associating acute and or chronic diseases) is growing awareness for search and exploiting potential of alternative agents, as preventative and therapeutic. Amongst them probiotics, prebiotics, and synbiotics ought to have direct and or indirect effects on the pathogenesis and disease progression. Nowadays these are proposing as novel therapeutic option. Progression in the concepts is, first probiotics followed by prebiotics and then synbiotics [1,2].

These facts evolutes are the emerging concepts of probiotics, prebiotics and synbiotics, to modulate the targeted gut-microflora/ ecology. Using of living organisms in the diet to increase amount of health-promoting bacteria in the gut, postulates probiotic approach. The selective promotion of these bacteria by the intake of certain non-digestible carbohydrates postulates prebiotics. Both probiotics and prebiotics can fortify the lactate-producing microbes of the human or animal gut [5,10-11,25].

Synbiotics are combination of probiotics and prebiotics useful in alleviating disease and ailments. Synergistic chemopreventive actions exerted with combinations of the two, which together be called synbiotics. It may define as "the nutritional supplements that are combinations of probiotic bacteria and prebiotic food ingredients" [1,10-11,71-75].

Synbiotics therapies enables in manipulating composition of gut-microbiota and reducing the levels of pathogenic microorganisms. In synbiotics, the probiotics uses the prebiotics as a food source, which enables them to survive for extended period within the intestine than would otherwise be possible. Thus enables in improving the viability of probiotics and delivering projected health benefits. These in consequence decreases intestinal inflammation, alleviates allergy and diarrhea, produce antimicrobials, enhances and regulates immune function, elicit antitumorigenic or anticarcinogenic activity, binds to potential food carcinogens and toxins, and demotes bacterial enzymes which hydrolyse precarcinogenic compounds, such as beta-glucuronidase [1,71-75].

True probiotic, without its prebiotic food, does not survive well in the digestive system, the main reason for using a synbiotics. In absence of necessary food source, the probiotics will have a greater intolerance for oxygen, low pH, and temperature. The prebiotics provides a great place for probiotics to thrive thus conserving the population of these beneficial bacteria [1-5]. Examples of synbiotics provided with Table 1.