Introduction

The human gastrointestinal tract consists of a diverse collection of microbes which are considered to be non-pathogenic and essential for intestinal homeostasis.¹ Human intestinal microbiome is an anaerobic environment made up of trillions of microorganisms that have co-evolved with the host with unique functional characteristics.² Reports suggest the presence of over 10⁴ microorganisms in the gastro-intestinal tract, which is comparatively ten times higher than the cells that exist in the human body.³ Apart from beneficial microorganisms, anaerobic or facultative pathogens may also invade, colonize the gut and cause diseases.⁴ Colonized microbes may assist in the digestion of food through two main catabolic pathways viz., Saccharolytic and Proteolytic. In the saccharolytic pathway, gut microbiota breaks down sugars and produce vital short chain fatty acids (SCFAs). On the other hand, the proteolytic pathway is characterized by protein fermentation leading to the synthesis of substances such as ammonia, amines, thiols, phenols, and indoles apart from SCFAs. Accumulation of certain microbial metabolic by-products disrupts the intestinal tolerance, triggering severe health problems in the human system.⁵ Microbial metabolites regulate and activate host immunity to defend the body from pathogens. Antimicrobial peptides (AMPs) which are encoded from the host’s genes are a component of the host’s innate immune response against pathogenic infections. The expression of AMPs surges when bacteria colonize the gut in order to control the spreading of pathogenic bacteria. Maintaining a homeostatic state in the gut microbiome is a crucial factor in gut health as its imbalance may lead to many metabolic diseases such as metabolic endotoxemia, type 2 diabetes, inflammatory bowel disease or obesity.⁶ The equilibrium between the activation of the innate immune system and the microbial factors that regulate multifaceted functions is restored by gut microbes. Disappearance of microbial diversity results in the suppression of the innate immune system and higher incidence of non- communicable diseases.^7,8,9 In a diseased condition, intestinal barrier turns leaky allowing the gut microbes to navigate into distant organs causing inflammation leading to conditions such as alcoholic fatty liver disease, non-alcoholic fatty liver disease, or cardiovascular diseases.^10,11 Colonization of the gut starts when a fetus is in the lower uterus but an infant’s gut microbiota is established only after birth through two transitions in infancy. The first transition occurs after birth, during the period of lactation whereby dominance of the gut microbiota by Bifidobacterium is reported. The second transition occurs during the weaning period, where the introduction of solid foods contribute in the establishment of an adult-type complex microbiome dominated by the Bacteroidetes and Firmicutes phyla.¹²  Bacteroidetes and Firmicutes represent more than 90% of the adult gut microbiome with the ratio between the two phyla varying from person to person depending on the dietary, environmental and lifestyle factors.^13,14 Early establishment of the gut microbiota is affected by various factors such as the mode of delivery (C-section or vaginal delivery), mode of milk intake (breastfeeding or formula feeding), and administration of antibiotics. Metagenomic analysis of fecal samples from a group of Swedish infants and their mothers reported that the mode of birth was one of the most important factors in shaping the gut microbiota of infants. Vaginally delivered newborns shared a 72% match in microbial diversity between the early colonizers of the newborn’s gut and the species found in the stool of their own mothers suggesting a possibility for an effective vertical mother-neonate microbial transfer. However, newborns delivered by C-section had only 41% of species match with their mother, indicating that mother-infant transmission was compromised during a C-section birth.¹⁵ The gut microbiota exhibit a vital  role in maintaining the overall functioning of the newborn by contributing to digestion (metabolizing polysaccharides which are barely digestible), vitamin synthesis, barrier development against potentially pathogenic bacteria, detoxifying bacteria by aiding in the development of the host immune system, and the regulation of mood and behaviour by influencing the development of the nervous system.^16,17 Maintenance of intestinal homeostasis by gut microbiome is of utmost importance in order to prevent gastro-intestinal diseases and in regulating disease conditions such as obesity and depression.^178,181 Many approaches that include administration of probiotics, prebiotics, Fecal Microbial Transplant (FMT), antibiotic administration, supplementation of engineered bacteria capable of secreting metabolites have been studied for restoring the homeostatic condition. This review discusses the state of eubiosis, dysbiosis, their role in maintaining gut health and prevention of diseases.

Intestinal Epithelial Barrier

The intestinal barrier is made of a single layer of internal epithelial lining that maintains the integrity of the gut. The epithelial cells collectively form a polarized layer to establish a tight barrier with the help of intercellular tight junctions, adherens junctions and desmosomes effectively separating the luminal bacteria from the immune cells that are present in the intestinal mucosa. Lamina propria, a thin layer of connective tissue present below the epithelial layer contribute for a healthy communication between the gut microbiome and the internal mucosal immune cells (dendritic cells, T cells, B cells and macrophages) through the pattern recognition receptors (PRRs). Receptors present on the intestinal epithelial cells (IECs) are either Toll like receptors (TLRs) or nuclear oligomerization domain-like receptors (NLRs) that are responsible in recognizing bacterial components such as microbe associated molecular patterns (MAMPs) or pathogen associated molecular patterns (PAMPs) namely the microbial liposaccharides or peptidoglycans.^18,19 Upon the interaction of TLRs with a PAMP, the innate immune system is activated thereby triggering signaling pathways leading to the production of inflammatory mediators such as interleukin-6 or tumor necrosis factor.²⁰ Signaling of TLR also induce the synthesis of  antimicrobial peptides and interferons that influence the responses of adaptive immunity. The interaction of TLRs with MAMP helps in promoting gut homeostasis by maintaining the integrity of the intestinal barrier in turn reducing the host’s inflammatory responses. The permeability of IECs ensures selective absorption of essential ions and allows nutrient passage through the barrier. Transportation of vital molecules occurs through three main pathways viz., trans-cellular pathway, carrier mediated pathway and paracellular pathway. The tight junction protein seals the gaps between the intestinal cells and selectively allows the transport of solute molecules and essential ions while restricting the movement of hydrophilic molecules and non-essential microbial-derived peptides. Alterations in the structure of the tight junctions lead to disruption of the epithelial integrity, allowing random to and fro movement of bacterial toxins affecting the gut permeability, epithelial physiology and immune homeostasis.²¹ IECs continuously interact with commensal bacteria in the GI tract and provide instruction to mucosal immune system to activate an immunological balance between active and quiescent state that ultimately contribute in intestinal homeostasis.¹⁷⁹

Eubiosis and Dysbiosis

Establishment of the microbial pattern during host development is crucial as the gut microbiome plays a vital role in maintaining gut homeostasis. The gut microbiota established during infancy provides a qualitative and quantitative balance of various microorganisms that are required for metabolite synthesis and normal functioning of the host.^24,25,26 Metabolic byproduct of gut bacteria regulate a diverse intestinal function such as digestion, permeability secretion, visceral sensing, motility, mucosal immunity, barrier effectiveness, etc.¹⁷ This state of a balanced gut microbiome is called as Eubiosis. Eubiotic state is generally characterized by the presence of beneficial species belonging mainly to Firmicutes, Bacteroidetes, Actinobacteria and Proteobacteria phyla. Firmicutes and Bacteroidetes are the main dominant phyla, while the others are sub dominant. Firmicutes include Lactobacillus, Mycoplasma, Streptococcus and Clostridium.²² Firmicutes are gram-positive bacteria composed mainly of Bacilli (facultative aerobes) and Clostridia (anaerobes) classes which are characterized with a low GC content and possess the ability to produce endospores that enable them to survive in adverse aerobic conditions.²³ Bacteroidetes are anaerobic, gram negative bacteria belonging to about 20 genera and species that can tolerate the presence of oxygen but do not utilize it for its growth.²² The host and the microbiome share a mutually beneficial relationship wherein the host provides shelter and nutrients to the microbiota and in turn the microbes and their secretory metabolites protect the host from pathogens, minimise immune disorders by immunomodulation and improve various body functions. Association between the host and its microbiota is referred to as symbiosis.  The microbiome and the host communicate through a crosstalk with the intestinal niche harboring its own microbial community.³⁰ Gnotobiotic mice colonized with a single bacterial strain, Bacteroides thetaiotaomicron VPI-5482 exhibited relatively lesser weight gain and fat deposition compared to the germ free mice suggesting that even a single microbial species can influence the host metabolism.^18,28 Upon addition of one more microbe (Methanobrevibacter smithii), the host showed an enhancement in the fat storage indicating the existence of microbial interaction between species in the gut. The metabolic products obtained from Bacteroides thetaiotaomicron’s fermentation were utilized by Methanobrevibacter smithii to produce methane that made the fermentation reaction thermodynamically favourable.²⁹ Quantitative analysis of gene expression revealed the interactions between the host and the gut microbiome or between the various microbes colonising the gut. The complete genome analysis of Bacteroides thetaiotaomicron and Methanobrevibacter smithii afford evidences regarding the microbial adaptation in the human gut. However, the pathways of such interactions are not yet completely understood.¹⁸ Perturbations to the structure of the complex commensal microbial communities allow microbes to move to the peritoneal cavity and enter blood circulation causing few microbes to become pathogenic. Ali Metchnikoff suggested that most diseases begin in the digestive tract when the “good” bacteria are no longer able to control the “bad” ones. This condition where the bacteria no longer live together in mutual harmony is known as Dysbiosis, a widely used term that was originally defined as ‘difficult living’ or ‘life in distress’.^17,31 The eubiotic and dysbiotic states are clearly depicted in Fig.1.

Figure 1: Differences in Eubiotic and Dysbiotic States of the Gut. Click here to view Figure

Gut Microbiota and Eubiosis

Several factors viz., host-dependent factors (e.g., genetic background, age, sex, immune system and gut motility), treatment (e.g., antibiotics) and diet (e.g., non-digestible carbohydrates, fat) influence the microbial richness in the gut.³² Most of the dietary microbiota modulations are affected by the consumption of a wide range of fibres, administration of probiotics (live beneficial bacteria) and prebiotics (food which enhance the growth of probiotics).³³ The microbes present in the gut are capable of digesting the indigestible dietary fibres like polysaccharides, oligosaccharides, proteins, peptides and glycoprotein by converting them into products such as short chain fatty acids (SCFAs) namely acetate, propionate, butyrate and other signaling molecules which can be easily absorbed by the host.³⁴ The short chain fatty acids maintain the integrity of the intestinal epithelial barrier, reduce the translocation of bacteria, increase the expressions of hunger-suppressing hormones and also reduces inflammation. A decreased expression of the short chain fatty acids is associated with the alteration of the gut microbiota indicating an imbalanced state.³⁵ Glycoside hydrolases coded by the gut microbiota genome are employed in breaking down plant polysaccharides rich in xylan, pectin and arabinose containing carbohydrate structures into an usable energy sources.³⁶ Glycans present in the food cannot be degraded by the enzymes coded in the human genome. The gut microbiota ferment glycans into short chain fatty acids and obtain energy.¹⁸ Synthesised SCFAs serve as nutrients for colonocytes and the other gut epithelial cells. Bacteroides thetaiotaomicron, a common bacterium in the human gut flora, is known to produce high levels of digestive enzymes required for the breakdown of carbohydrates.²⁴ The cross talk between the microbes or between the microbes and the host is maintained or can be enhanced by the various products secreted by the intestinal microbes.³³ Indole is identified to be a major signaling molecule involved in the crosstalk between the microbiota and the gut wall which works by increasing epithelial cell tight junctions.²² Indole also helps in regulating the secretion of GLP-1(Glucagon like peptide) from the enteroendocrine cells (specialized cells found within the gastrointestinal tract, stomach and pancreas) that helps in maintaining the glucose levels.³⁷ Genome of Proteobacteria, one of the few identified in the human gut contains high levels of antibiotic resistance genes against bacitracin, tetracycline and macrolides. Resistance against such antibiotics increases with age.^38,39 Bifidobacterium, a gram positive bacterium is known to produce vitamin K, B₁₂, Biotin, Folate, Thiamine, which help in preventing infections by pathogenic bacteria.^40,41 Reduction of intestinal endotoxin levels and improved mucosal barrier in rodents are noted in groups supplemented with Bifidobacterium spp.^42,43 A number of studies have shown that the intestinal bacteria and their metabolites play a key role in the activation of the immune system, proliferation and differentiation of the T cells. Anti-inflammatory compounds produced by the gut microbes also help in preventing inflammation due to the production of LPS, a component of cell walls of gram-negative bacteria.⁴⁴

Factors Causing Dysbiosis

Lifestyle, antibiotic treatments, psychological and physical stress, pathogens, consumption of alcohol, and smoking are some of the factors that can disturb the balance of intestinal microbiota.⁴⁵ Strong correlation between dysbiosis of the gut microbiota and disease etiology is observed in several metabolic diseases such as obesity where an increase in the number of Firmicutes and a decrease in the number of Bacteroidetes have been reported in human and animal models.^46,47 Lifestyle factors that includes geographical location, sleep pattern, personal fitness, and hygiene practices influence the rate of eubiosis and dysbiosis.^33,48 An alteration in the functioning of the gut barrier leads to a leaky gut that changes the gut microbiota composition reported to be associated with diet-induced obesity and genetic obesity.⁴⁹ Antibiotic treatments disrupt the microbial assemblages and affect the functionality of gut microbes resulting in antibiotic associated diarrhea.  Duration of the treatment, concentration of the antibiotic and the spectrum of the antibiotic are probable factors that can have an impact on the integrity of the intestinal barrier.⁵⁰ Inflammatory response produced by the host cause a significant decrease in the beneficial bacteria population that leads to pathogen colonization in intestinal niche. Furthermore, substances such as nitrate, S-oxides, and N-oxides generated as by-products of inflammation, potentially colonize pathogenic Escherichia coli in mice model.⁴⁵ Imbalances in the gut microbiome are known to influence the brain, including the mood of an individual.⁵¹ Studies show that individuals exposed to psychological stress have a significant decrease in the production of mucin and mucopolysaccharide layer lining in the mucosal surface.⁵² It is known that the mucopolysaccharide layer and mucous inhibits the growth of the pathogenic organisms thereby acting as a defensive barrier. Stress can also be one of the reasons for an individual to suffer from inflammatory bowel syndrome.³³ Stress acts as a factor that causes gut impermeability allowing bacteria and bacterial antigens to cross the epithelial barrier thus altering the composition of the microbiome.¹⁸² Alcohol consumption is a another major factor that can have an impact on the gut microbiota. Ethanol can also affect intestinal cells by targeting many pre and post-transcriptional regulators, that mainly includes circadian clock genes and microRNA (short ribonucleic acid molecules of 22 nucleotides attached to complementary sequences of miRNA causing translational repression).⁵³ Ethanol is metabolized by the microbes present in the intestine to produce acetaldehyde that causes disruption of the tight junction integrity resulting in significant decrease in the ‘good’ bacteria.⁵³ According to a study by Chen (2015) in humans and mice, alcohol induce intestinal dysbiosis resulting in limiting the production of LCFA (long chain fatty acid). However, exogenous administration of fatty acids stabilized the intestinal barrier resulting in restoration of eubiosis condition.¹⁸⁰ The changes induced due to smoking can lead to an increase in the count of Bacteroides-Prevotella in individuals that can lead to the increased risk of Crohn’s disease. Fermentation of high protein rich food by colonic microbes results in the synthesis of potentially harmful by-products that affect the morphology and functionality of the mucosal cells. Emergence of indole, ammonia, phenols, and amines in relation to high protein diet consumption also affects the intestinal homeostasis.⁵⁰

Consequences of Dysbiosis

Dysbiosis is a major factor that is associated with the pathogenesis of many intestinal and extra-intestinal disorders. Intestinal disorders such as inflammatory bowel disease, irritable bowel syndrome (IBS), celiac disease, and extra-intestinal disorders such as allergy, asthma, metabolic syndrome, cardiovascular disease, and obesity are associated with dysbiosis. The malfunctioning of the microbiota turns the intestinal barrier leaky thereby allowing the gut microbes to progress into other organs. The bacterial composition varies from one location to another in the gastrointestinal tract with the higher microbial diversity reported in the distal large intestine and in fecal microbiota.⁵⁴ Primarily, the changes caused as a result of dysbiosis cause an imbalance to the homeostatic state leading to an overall loss of the diverse microbial community present in the intestinal region. The alteration in the intestinal region allows translocation of pathogenic organisms to the gut. The decrease in the bacterial diversity favors the recognition of the pathogenic bacteria by the Pattern Recognition Receptor (PRR) system. Host response to such infectious agents might further affect the host metabolism and energy homeostasis. Re-localization of Nuclear Factor Kappa B (NF-kB) in the nucleus and increase in the cellular oxidative stress are responses related to disruption of host metabolism. Diseases including type 2 diabetes, atherosclerosis, Crohn’s disease are linked with low grade chronic inflammation.⁵⁵ Loss of bacterial diversity causes a decrease in the load of beneficial bacteria and an increase in the pathogenic strains. Resulting imbalance in the microbial consortia has been linked with various diseases such as inflammatory bowel disease, crohn’s disease, obesity, metabolic syndrome, fatty liver disease, parkinson’s diseases etc. Fig. 2 summarizes the diseases associated with a leaky gut.

Inflammatory Bowel Disease

Inflammatory Bowel Disease (IBD) is a chronic condition wherein patients suffer from severe inflammation in the gastrointestinal tract.⁵⁶ The disease has two clinical forms; Ulcerative colitis (UC) which is restricted to the rectum and the colon excluding the small intestine and Crohn’s disease (CD) wherein any part of the intestine can have inflammation including the small intestine and large intestine.²¹ Expression of abnormal Toll like receptors (TLR4) of the intestine is known to be associated with inflammatory bowel disease. Increased expression of TLRs, pro-inflammatory cytokines viz., tumor necrosis factor (TNF)-a, interleukin (IL)- 1b, IL-6, and IL-8 activates the intestinal inflammatory responses.⁵⁶ Another cause of IBD is the loss of intestinal integrity caused due to the defect resulting from mucosal tolerance. Due to this imbalance, microbes and their metabolites continuously move in and out through the leaky gut causing uncontrollable inflammatory signal cascades.²¹ Extensive research is however required to prove that dysbiosis is one of the major causes of IBD. Pathogenesis is still not clear as to whether dysbiosis seen in IBD patients is an effect of the disease or a risk factor. It is observed that IBD patients have a decreased number of butyrate producing bacteria (Faecalibacterium prausnitzii) and also a decline in the diversity of Firmicutes.⁵⁷ An increase in the number of sulphate reducing bacteria is also observed in patients with IBD. These bacteria metabolize sulphate to hydrogen sulphide which can block the utilization of butyrate by the intestinal epithelial cells, and decreases the expression of the tight junction proteins which in turn increases the permeability of the intestinal barrier resulting in the translocation of bacteria.⁵⁷ The increase in sulphate reducing bacteria also inhibits phagocytosis and killing of bacteria. It has also been reported that healthy individuals have many obligate anaerobic populations but the IBD patients have a decreased population of obligate anaerobes and an increased population of facultative anaerobes. This change from obligate to facultative anaerobes in the intestine led to the hypothesis that oxygen may be a major factor that causes dysbiosis in IBD patients. An oxygen hypothesis was made which suggested that due to an increase in the reactive oxygen species, the anaerobic environment of the gut is disrupted which favors the facultative anaerobes causing dysbiosis.⁵⁸ Metagenomic analysis of the gut microbiota in IBD patients exhibited a decreased expression of genes responsible for carbohydrate and amino acid metabolism and an increase in the oxidative stress pathway in IBD patients.⁵⁹ Furthermore, a bulk of the studies focus on microbiome census and obliterate the role of viruses and fungi that is even less understood.¹⁸⁵ There hasn’t been any specific pathogen fulfilling the Koch’s postulates identified in patients of IBD. Hence, dysbiosis leading to functional changes in the gut microbiota may be responsible for the pathophysiology of IBD. Research for improvement of epithelial integrity and correction of abnormal micro-host interaction are currently in progress to supplement anti-inflammatory and immune therapies for IBD patients. Moreover, interventions in bacterial engineering, next generation probiotics, microbe-specific bactericidal antibiotics and fecal microbiota transplantation therapy have promising results for IBD treatment.

Crohn’s Disease (CD)

Dysbiosis in patients of Crohn’s disease has been identified using both culture-dependent and culture-independent techniques. Studies have reported that the common sites of inflammation seen in CD patients are present in the human gut. The inflammation could be the result of a poor diet or long antibiotic courses in childhood.⁶⁰ Biopsies of the colonic or small intestinal tissue of CD patients provide evidence that they have a reduced ability of killing pathogenic microbes compared to the control.⁶¹ The pathogenesis of bacteria in CD is well established in patients and dysbiosis is mainly associated with a lower number of Firmicutes and Clostridium cluster IV along with a higher amount of Bacteroidetes. Lower levels of Faecalibacterium prausnitzii has been commonly determined in fecal samples and biopsies in most of the CD patients. Mycobacterium avium subspecies paratuberculosis (MAP) and Escherichia coli strain LF82 are also reported to be more in number in CD patients.^62,63,64 In the cohort studies, the predominant faecal microbiota which is believed to cause dysbiosis in CD was Dialister invisus, Faecalibacterium prausnitzii, Bifidobacterium adolescentis and Ruminococcus gnavus. A multifaceted interplay between host genetics and microbial assemblage is identified in the pathogenesis of CD. Genetic variants exhibit a varied inflammatory response related to membrane permeability, microbial sensing, and impediment in autophagy pathways causing increased inflammation in CD.⁶⁵ Single nucleotide polymorphism in Mucin-19 has been associated with intestinal inflammation in CD, where intestinal mucus layer face structural anomalies. Typical dysbiosis signature of bacterial consortia viz., Faecalibacterium prausnitzii, Ruminococcus spp., Dialister invisus, Bifidobacterium spp., Clostridium spp. associated with CD were reported in fecal samples.⁶⁶ Varied effects are observed due to altered luminal defensins and modified permeability in the brush border of the intestinal lining. Studies also show that even the unaffected relatives of patients had an entirely different microbiota compared to healthy controls. An analysis of biopsies in CD patients revealed that the alpha diversity of the tissue-associated intestinal microbiome remained lower which might be associated with continuous diarrhea that signifies marked alterations in intestinal microbiome of patients.¹⁸⁶ A detailed study in CD-associated dysbiosis will help in understanding and untangling the role of bacteria involved in causing CD.

Obesity, Metabolic Endotoxemia and Type 2 Diabetes

Obesity is characterized by a cluster of many metabolic disorders that may be caused because of factors such as high fat diet, reduction in physical activities etc.¹⁸³ Apart from these factors, a large shift in the abundance of certain microbes belonging to the intestine also play a very important role in the development of metabolic diseases associated with obesity.¹ In a study on obese mice, a significant decrease of Bacteroidetes and an increase of Firmicutes were observed in the cecal microbiota.⁴⁶ The development of obesity in mice affects the relative abundance of major gut bacteria derived from maternal inoculum. The mechanism responsible for the direct microbial changes in the gut is still undefined. It has also been reported that obesity due to the alteration of the diet leads to a decrease in Bifidobacterium spp. and a Bacteroidetes related bacteria, Eubacterium rectale-Blautia Coccoides.⁶⁷ One of the key mechanisms known for the development of obesity is the inhibition of fasting-induced adipose factor (FIAF). FIAF inhibits lipoprotein lipase, promoting the release of triglycerides such as very low-density lipoprotein (VLDL) and chylomicrons. Limiting FIAF regulate obesity related disorders by controlling the release of triglycerides. Levels of short chain fatty acids in obese individuals are significantly lower than lean individuals. SCFAs inhibit the accumulation of fat in the adipose tissue by reducing energy intake and by increasing energy expenditure. Hence, decrease in SCFA leads to accumulation of fat. SCFAs, primarily propionate and butyrate reduce food intake by activating gut hormones through the free fatty acid receptor 2 and 3 (FFAR2; FFAR3). However, the same study reported the action of SCFAs independent of FFAR activation in food intake and body weight gain subjects.⁶⁸ Propionate supplementation activated gut hormones, Peptide tyrosine kinase and glucagon like peptide (GLP-1) which in turn exhibited a profound effect in reducing food intake and reduced weight gain by limiting adipose tissue accumulation.⁶⁹ Obesity and diabetes are associated with higher gut permeability leading to metabolic endotoxemia, initiation of low grade inflammation and insulin resistance in the liver, muscles and adipose tissue.⁴⁹ Metabolic endotoxemia is characterized by an increase in the levels of LPS in the bloodstream. Lipopolysaccharide (LPS), a structural component of the cell wall of gram-negative bacteria contain Lipid A which causes an initiation of a signaling cascade to activate the pro-inflammatory pathways, increasing the oxidative stress as it binds to Toll Like Receptor 4.^10,70 Many studies have been performed on CD14/TLR4 receptor knockout mice to observe the contribution of gut microbiota in regulating the pathophysiology of diseases such as obesity, type 2 diabetes, and metabolic endotoxemia as it is considered that high fat content in the diet causes an increase in the LPS levels. The LPS binds to the CD14/TLR4 receptors and cause secretion of pro-inflammatory cytokines which are closely associated with these diseases. Experimental mice that do not have CD14/TLR4 receptor were found to be resistant to high fat diet induced metabolic disorders. Simultaneously, studies carried out with various other combinations of high fat diet and LPS in CD14/TLR4 receptor knockout mice exhibited resistance to high fat diet induced metabolic disorders at lower LPS concentration. The conclusion drawn from the various studies reflected that high fat feeding induced low-grade inflammation, which was originated from intestinal absorption of LPS. ^1,71,72  Various reports of higher levels of plasma LPS were found to be associated with metabolic endotoxemia and low-grade inflammation.^73,74 Many studies have reported that an imbalance of specific microbes of the intestine is related to the increase in LPS levels.⁴⁹ Mice that were fed with high fat diet had a significant decrease in the levels of Bifidobacterium spp. and Eubacterium rectale / Clostridium Coccoides compared to the ones that were fed with a standard high carbohydrate diet suggesting that high fat diet increased the proportion of LPS containing microbiota in the gut which leads to signaling of proinflammatory cytokines thereby leading to high fat diet-induced metabolic diseases. ⁶⁷ Few experimental studies suggest that the development of low-grade inflammation is due to metabolic endotoxemia which is involved with insulin resistance and type 2 diabetes. Data also suggests that increased plasma LPS has a negative effect on glucose metabolism. Alteration of the microbiota can cause endotoxemia leading to insulin resistance. A decrease in the number of butyrate-producing bacteria and an increase in the number of Lactobacillus spp. is associated with type 2 diabetes.⁵ Butyrate is a short chain fatty acid which is an energy substrate for the epithelial cells of the gut.^75,76 The epithelial cells will increase in number due to the increased production of butyrate thereby involved in the secretion of Glucagon-like peptide 1 (GLP-1). GLP-1 plays an important role in maintaining levels of glucose in the body by stimulating the secretion of insulin to convert glucose to glycogen. Impaired GLP-1 secretion can lead to an imbalance in the glucose levels causing diabetes. Metabolic syndrome is an amalgam of heart diseases, stroke and type 2 diabetes. Problems such as increased blood pressure, excess body fat around the waist, abnormal cholesterol or triglyceride levels and high blood sugar levels are associated with metabolic disorders.⁷⁷ Increase in metabolic syndrome is attributed to increased food consumption and change in lifestyle activity.⁷⁸ The gut microbiota regulates the host metabolism by regulating the composition of bile acid pools. The changes in the bile acid pool activates ligand binding to Farnesoid X Receptor leading to the transcription of genes that affects the glucose and lipid metabolism.⁷⁹

Fatty Liver Disease (Non-Alcoholic and Alcoholic)

Non-Alcoholic Fatty Liver Disease (NAFLD) has become the most common chronic liver disease in the world¹⁸⁴. Individuals who are usually obese and insulin resistant are in high-risk groups for NAFLD.¹⁶ Gut microbes connect to the liver through the portal vein and confer positive and negative effects. Pathways involving the gut–liver axis are influenced by the microbiome and their homeostatic state. In eubiotic state, butyrate secreting Faecalibacterium prausnitzii maintain the membrane integrity and tight junction formation. In dysbiotic state, damage causing bacteria such as Bilophila wadsworthia, forms a secondary layer above beneficial microbes and hinders metabolite synthesis. Dysbiosis related symptoms include systemic endotoxin levels, endogenous ethanol quantity and augmented intestinal permeability. In addition, the existence of harmful Klebsiella pneumonia in the gut synthesises endogenous alcohol which activates the reactive oxygen species chain in the liver, causing progression of NAFLD. Mechanisms that lead to endotoxemia and inflammation include diet induced intestinal bacterial overgrowth, leaky gut and the movement of endotoxins to distant parts that are similarly associated with NAFLD. Enhanced permeability and accumulation of bacterial metabolites in the liver is observed due to damages in the intestinal barrier by the triggering of TLR 4, TLR 5 and TLR 9 receptors causing abnormal retention of fats and hindering the metabolism of lipids.⁸⁰ One of the mechanisms that relate the microbiota to NAFLD is the bacterial metabolism of choline. The deficiency of choline causes accumulation of triglycerides in the liver and further progressing to steatohepatitis, fibrosis, cirrhosis and liver cancer.⁸¹ Metabolism of choline also has an influence on obesity and insulin resistance.⁸²  Mice susceptible to NAFLD, fed with a high fat diet had reduced expression of choline due its conversion into methylamines by microbiota, resulting in the inability to synthesize phosphatidylcholine causing subsequent accumulation of triglycerides in the liver.⁸² Accumulation of triglycerides further causes complications in the liver making individuals susceptible to NAFLD. Disruption of the gut barrier eventually leads to translocation of the gut microbes and their metabolites causing the activation of immune system leading to liver inflammation and injury.⁸³ With respect to alcoholic fatty liver disease, consumption of alcohol leads to alterations of gut microbiota further causing a leaky gut and thereby allowing the microbes and their metabolites to translocate to the liver. Studies carried out in mice fed with ethanol showed a decrease in the population of phylum Firmicutes and genus Lactobacillus spp. Incidence of higher levels of few species belonging to Verrucomicrobia (genus Akkermansia muciniphila), Actinobacteria (genus Corynebacterium spp.) and Proteobacteria (genus Alcaligenes spp.) were observed.⁸⁴ In the Tsukamoto-French model of alcoholic liver disease, a group of mice were given specific liquid diets and intra-gastric infusions of ethanol. On the other hand the control group was given the same liquid diet but was fed with dextrose instead of alcohol.  Quantitative changes through real-time PCR and qualitative changes in the reduction of probiotic bacteria such as Lactobacillus, Pediococcus, Leuconostoc and Lactococcus in the gut of the experimental mice was observed.⁸⁵ Recent lifestyle and dietary trends have added on the prevalence of non-alcoholic fatty liver disease / steatohepatitis (NAFLD/NASH) around the globe. Even-though non-invasive biomarker and imaging modalities are employed in the detection of individuals with high risk of rapid disease progression and low fibrosis stages, early detection will help to deliver efficient single or combination treatment that will have maximum benefits and fewer adverse events.¹⁸⁷

Parkinson’s Disease

Parkinson’s disease (PD) is a multi-centric neurodegenerative disorder characterized by the accumulation and aggregation of alpha synuclein in the substantia nigra of the central nervous system and in other neural structures.^86,87 Studies have found that gut microbiota can influence the central nervous system (CNS) and enteric nervous system and possess the potential to alter the CNS through the microbiota-gut-brain axis. Modulatory regulation involves immunological, neuro endocrine and direct neural mechanisms.⁸⁸ Gastrointestinal (GI) dysfunction has been reported in PD patients which are considered to be the initial symptoms of PD, prior to the characteristic motor symptoms.⁸⁹ Various dysbiosis symptoms have also been reported to be related to the PD associated GI dysfunction.^90,91 Gut dysbiosis, small intestinal bacterial overgrowth or increased gut permeability will cause excessive stimulation of the innate immune system which may eventually produce systemic and/or CNS inflammation.⁹² Germ free animal with low or depleting microbiota showed compromise in microglia cell shape and maturation, leading to improper immune responses. Restoring the microbiota second time exhibited partial recovery of microglia cells.⁹³ Deficiency of short chain fatty acids such as butyrate, propionate, acetate have also been directly linked to the deficiency in the inhibitory neurotransmitter GABA (gamma-aminobutyric acid).⁹⁴ High numbers of Helicobacter pylori infections were reported in patients for a decade.⁹⁵ Similarly a 50% increase of Helicobacter pylori related dysbiosis cases have been reported among Indian PD patients.⁹⁶ Pathogenesis of PD related gut dysbiosis showed alterations in gut microbiome. Higher count of opportunistic pathogens such as Proteus and Enterobacter spp. and a lower count of Peptostreptococcus, Lactobacillus and Butyricicoccus spp. were noted.⁹⁷ Manipulation of fecal microbial community, better and complete bowel movement was observed in PD subjects supplemented with fermented milk containing 250 * 10⁹ of multiple probiotics comprising Streptococcus salivarius, Lactobacillus rhamnosus, Lactobacillus delbrueckii, Lactobacillus paracasei, Bifidobacterium etc., and prebiotic fibers.⁹⁸ Commensal gut microbiota maintains stable neural and emotional indices exerting better cognitive and emotional improvement.⁹⁹ Psychobiotic effects of Lactobacillus helveticus and Bifidobacterium longum conferring better psychological balance and mental health has been reported in rat and human volunteers.¹⁰⁰ The imbalance of specific bacteria and its consequences pertaining to each of the diseases discussed in the previous section is depicted in Table 1.

Table 1: Microbial Imbalance in Gut Ecosystem and their Consequence.

Figure 2: Diseases Associated with a Leaky Gut. Click here to view Figure

Preventive and Therapeutic Approaches

Many approaches are proposed to restore the normal intestinal homeostasis in the gut. Assessment of gut microbial cascade is an essential factor towards designing a prophylactic treatment to treat dysbiosis.¹⁰¹ Employing probiotics, prebiotics, synbiotics, amino acids and carbohydrate as dietary interventions, fecal microbial transplantation, use of engineered bacteria, antibiotic administration, bacterial consortium transplantation and phage therapy are gaining importance to modulate the intestinal dysbiosis.¹⁰¹

Use of Probiotics, Prebiotics and Synbiotics

According to the World Health Organization, probiotics are “live microorganisms which when administered in adequate amounts confer a health benefit to the host”.⁴⁹ The gastrointestinal tract is composed of beneficial microorganisms belonging to genus Lactobacilli and Bifidobacteria and other organisms such as Saccharomyces boulardii, Escherichia coli Nissle 1917, Streptococcus thermophilus, Faecalibacterium parausnitzi and Bacillus polyfermenticus.⁴ Lactobacillus reuteri is known to promote the release of incretin (GLP-1) which will in turn cause an increase in the secretion of insulin in obese glucose-tolerant subjects.¹⁰² Probiotics adhere to the intestinal walls and physically block the adhesion of pathogenic bacterial species onto the epithelial cells. The microorganisms also induce anti-inflammatory T_{regs cells} and lower the pH which helps in preventing the pathogenic bacteria from adhering to the inner lining of the gut. Probiotics help in increasing the mucus layer, enhancing the number of the epithelial cells and in the elongation of microvilli thereby increasing the surface area.^103,104 Administration of certain Lactobacillus sp. has been observed to decrease the production of toxins such as dimethylamine and nitrosodimethylamine in patients with Chronic Kidney Disease (CKD). The gut microbes are also involved in the secretion of mucin and in the formation of muco-polysaccharides, which protects the intestinal cells. Administration of Bifidobacterium infantis in obese mice showed a decrease in the production of pro-inflammatory cytokines and white adipose tissue.^67,68 Microbes such as Lactobacillus rhamnosus , Lactobacillus gasseri BNR17 and Bifidobacterium lactis isolated from human breast milk were reported to be beneficial in treating adiposity and obesity in which, mRNA levels of genes that are related to fatty acid oxidation, including Acyl-CoA oxidase (ACO), carnitine palmitoyle-transferase1 (CPT1) and peroxisome proliferator-activated receptor α and δ (PPAR-α and δ) were undoubtedly expressed higher. In addition, lower levels of fatty acid synthesis such as sterol regulatory element-binding protein-1c (SREBP-1c) and acetyl-CoA carboxylase (ACC) were noted. ACO and CPT1 are the enzymes that play key roles in energy homeostasis and adipogenesis, Therefore, increased expression of fatty acid metabolism gene and alternatively reduced fatty acid synthesis were responsible for antiobesity effect in the mice.^105,188 Prebiotics are non-digestible substances that play an important role in maintaining the nutritional, physiological and immunological status of the host and are used as an alternative constituent to improve the activity of probiotics. Fruits, vegetables, and cereals are potential sources of prebiotics.^106,107 Artificially synthesized prebiotics that include lactulose, galacto-oligosaccharides, malto-oligosaccharides, fructo-oligosaccharides, inulin and oligosaccharides have gained attention in intestinal homeostasis.¹⁰⁸ Prebiotics are fermented by the gut bacteria thereby producing products such as SCFAs which play an essential role in preventing many ailments such as metabolic endotoxemia and type 2 diabetes. Inulin and fructo-oligosaccharides are prebiotic dietary fibres that are used to enhance the growth of bacterial species belonging to genera of Bifidobacterium and Lactobacillus.¹ Prebiotic treatment also helps in increasing the number of enteroendocrine cells that produce GLP-1 and GLP-2 (L-cells) in the jejunum and colon.¹⁰⁹ Changes in the gut microbiota of the mouse with the inclusion of prebiotics helped in increasing the plasma GLP-2 levels and hence can improve systemic and hepatic inflammation. It has also been reported that apart from maintaining the integrity of the gut barrier and enhancing the immune function, GLP-2 also enhances hepatic insulin sensitivity and is also known to play a key role in controlling glucose homeostasis.¹⁰⁴ An approach was suggested to use prebiotic dietary fibres (oligofructose) to increase the number of Bifidobacterium spp.¹¹⁰ Hence, the dietary supplementation of prebiotics helps in improving glucose-tolerance, glucose-induced insulin-secretion and normalising low-grade inflammation (decreased endotoxemia, plasma and adipose tissue pro-inflammatory cytokines).¹¹¹ Synbiotics, a combination of probiotics and prebiotics, is another therapeutic approach to restore intestinal homeostasis.¹¹² Some examples of synbiotics include a combination of Lactobacillus rhamnosus GG, Bifidobacteria and Lactobacilli with fructo-oligosaccharides or inulin.¹¹³ Symbiotic effect of the prebiotics and probiotics contribute for a synergistic effect that complement higher tolerance to various environmental conditions of the host’s intestine such as oxygenation, pH and temperature.¹¹³ Synbiotics help in reducing the concentration of undesirable metabolites and also leads to an increase in the levels of short chain fatty acids, ketones, carbon disulphides and methyl acetates which have a positive effect on the host’s health.¹¹⁴ The use of a synbiotic product consisting of Lactobacillus rhamnosus and Bifidobacterium lactis as probiotics and inulin and oligofructose as prebiotics in the diet helped in increasing the levels of intestinal IgA. Synbiotics reduce the levels of blood cholesterol, blood pressure and also improve the absorption of calcium, magnesium, and phosphorus.¹¹⁵ Table 2 provides the list of probiotics, prebiotics and synbiotics with the respective function.

Table 2: Nutraceuticals and their Functions with Respect to Gastrointestinal Related Diseases.

Dietary Induced Interventions

Change in dietary patterns is found to be the reason for dysbiosis in patients whose microbiota development was driven by diet. ^137,138 Studies have found a correlation between improved health due to consumption of dietary fibers and lowering of IBD and colorectal cancer.^139,140 Western diets with high amounts of protein and fat content and a very minimal fiber intake increases the incidence of colon related diseases. Consumption of less fiber content has been proven to hinder gut microbial establishment, while a diet with high fiber content mediates SCFA (Short-Chain fatty acids) synthesis by intestinal microbes. A severe reduction in faecal butyrate levels in obese individuals was observed, when the individuals were put on a low carbohydrate diet. Reduction in butyrate production may be due to lower number of butyrate producing Firmicutes sp. along with a sudden change in diet pattern.¹⁴¹

Fatty Acids

SCFAs like acetate, butyrate, pentanoate and propionate have two to five carbon atoms that are mainly produced through microbial fermentation of large complex polysaccharides inside the colon.⁷⁶ SCFAs enter into the bloodstream of the host and transverse to the distal colon, from which they are transported to respective tissues.¹⁴² Microbes in the gut produce 99% of the blood SCFAs (acetate and PPA), that act on regulatory receptor Olfr78 and Gpr41 in physiologically opposite roles in response to the same SCFAs stimulus at different concentration levels to maintain appropriate blood pressure regulation. SCFAs produced by the bacteria in the gut interact with olfactory receptors, Olfr78 and Gpr41 in the kidney, that are key regulators of blood pressure. Activation of Olfr78 stimulate renin and prevent the blood pressure from lowering to dangerous levels.¹⁴³ Maintaining the appropriate level of SCFAs (acetate and propionate) in the blood is important to prevent neuro degeneration. Mice treated with butyrate synthesized by Bifidobacterium helped in the restoration of microbial homeostasis inside the gut, thus improving gut integrity compared to control mice.¹⁴⁴ Butyrate, a bacterial metabolic end product, constitutes 20% of SCFA in the human colon. Butyrate is the primary metabolite preferred by the intestinal epithelial cells (IECs) that enhance the IEC barrier by stabilising the hypoxia-inducible factor (HIF). Butyrate suppresses colonic inflammation and carcinogenesis by activating GPR109a receptors that promote anti-inflammatory properties in colonic macrophages and dendritic cells. Butyrate stimulates anti-inflammatory mechanisms that helps in mucosal barrier restoration by limiting inflammatory cytokine production.¹⁴⁴ Similarly, another study reported that introduction of SCFAs such as Propionate (PA) into a mice model showed enhancement of CD25, CD4, Foxp3, Treg cells and ameliorated autoimmune encephalomyelitis. PA has the capacity to restore altered Treg cell: effector T cell balance in Multiple sclerosis (MS) patients by restraining CNS autoimmunity. ¹⁴⁵

Amino Acids and Carbohydrate Supplements in Food

Introduction of amino acids and carbohydrates would help the depleting and dormant bacterial spores to get activated and transform into a vegetative state.Colonic microbiota to a large extent depends on the availability of microbiota-accessible carbohydrates (MACs) that is found in the dietary fibre. Diet with highly rich in resistance starch or non-starch polysaccharide fibre can enrich the gut with diverging bacterial growth. Microbial digestion releases the finest food particle in to blood stream and serve as an antioxidant material.¹⁸⁸ Similarly, amino acid play a major role in supporting the growth and survival of gut bacteria that regulate energy and protein homeostasis in organism. Many elements of tryptophan catabolism would be extremely beneficial for maintaining gut homeostasis¹⁴⁶. Tryptophan helps in the regulation of tight junction proteins in intestinal epithelial cells that aids in building a barrier inside the gut¹⁴⁷. Studies suggest that N-acetylcysteine helps in increasing the barrier inside the gut and also stops endothelial cells from premature senescence.^148,149 N-acetylcysteine is also known to increase the growth of fibroblast cells by reducing ROS levels and by increasing ATP production in fibroblast.¹⁵⁰ However, in vitro studies show that over usage of amino acids like N-acetylcysteine and tryptophan could cause inflammation.¹⁵¹ The mTORC1 pathway activates pro-oxidant and pro-inflammatory proteins in the blood cells forming branched chain amino acids (BCAAs), Leucine, Isoleucine and Valine, thus could lead to daily elevation of blood levels from 3-6 m mol/l concentration.¹⁵¹

Engineered Bacteria and Antibiotic Administration

The eubiotic state can be restored by supplementing engineered bacteria that are capable of producing biomolecules possessing the potential to alter human metabolism.¹⁵² The engineered probiotic species include Escherichia coli Nissle, Lactococcus lactis, Bacteroides ovatus and Lactobacillus casei.^153,154,155 Nanobodies specific to eukaryotic targets are infused in synthetic microbiota that strongly anchor the engineered bacteria in the challenging gastrointestinal epithelial cells.¹⁵⁶ Engineered bacteria packed in the synthetic consortia are used for delivering therapeutic antimicrobial substances and immune-modulators to minimise inflammation. Appropriate modification of microbiome by incorporation of genetically engineered Escherichia coli Nissle 1917, capable of bio-synthesising N-acyl-phosphatidylethanolamines (NAPEs) in the intestinal tract reduces obesity related disorders. Daily administration of engineered Escherichia coli exhibited elevated levels of NAPEs that limits development of obesity.¹⁵⁷Antibiotic administration is also another therapeutic approach used to manipulate the microbial community to restore eubiotic state. Though antibiotics are reported to decreases the species richness and the microbial mass in the human gut, they carry the advantage for eliminating gut pathogens and confer resistance to beneficial microbes as a collateral effect. Selective antibiotics such as rifaximin also retard the inflammatory response exerted by the gut microbes by inhibiting the expression of nuclear factor (NF)-κB. Response of gut microbes to antibiotics are species specific. Incidence of higher Lactobacilli count was observed in mouse model treated with rifaximin whereas similar effect was not noticed in neomycin supplemented groups.²⁷ Antibiotics are also effective for primary treatment of Crohn’s disease at a dosage of 10 to 20 mg/kg/day.¹⁵⁸ Tylosin is another antibiotic which is used to treat chronic enteropathies in dogs. A study showed that the effect of this antibiotic in healthy dogs helped in reducing the bacterial content in the jejunum and caused an increase in the number of beneficial Enterococcus species and the study did not report any short term clinical abnormality of intestinal diseases in the treated groups ¹⁵⁹. Furthermore, treatment with polymyxin B helps in specifically eliminating Gram-negative bacteria and thereby further quenching LPS which results in diminishing hepatic steatosis¹⁶⁰. In a cohort of dogs with inflammatory bowel disease, administration of rifaximin helped in significantly improving the clinical signs by either decreasing the pathogenic strains or by increasing the beneficial microbes.^161,162

Fecal Microbial Treatment, Bacterial Consortium Treatment and Phage Therapy

Fecal microbial transplantation (FMT) is a process by which fecal bacteria is transplanted from a healthy donor to a diseased recipient’s gastrointestinal tract.³ Infusion of fecal microbiota exhibited clinical improvement in dysbiosis-associated diseases. Though colonization of microbial suspension varies from individuals, a stable intestinal ecosystem can be restored by employing a mixed bacterial consortium. A study using faecal microbiota transplantation (FMT) from lean donors to insulin-resistant patients with metabolic syndrome showed that faeces from lean subjects improved insulin sensitivity and was also enhanced the numbers of butyrate-producing bacteria.¹⁶³ In a randomized control study that was carried out between a group of people who were given FMT treatment and another group wherein the people were given antibiotics to treat the patients from recurrent Clostridium difficile infection showed that Clostridium difficile associated diarrhea in the FMT group resolved 81% of patients whereas, only 31% of the antibiotic group recovered. Infusion of donor feces to host system improved the microbial diversity by increasing the load of Bacteroidetes species and clostridium cluster IV and XIVa (Firmicutes) along with the decrease in the count of proteobacteria species. ¹⁶⁴ However, an infused bacterial consortium might not have similar clinical efficacy in restoring mucosal physiology. Contrasting results were observed in a randomized Ulcerative Colitis trial where patients did not show any significant changes in the gut microbiota after undergoing FMT therapy.¹⁶⁵ Few other studies carried out on adult Ulcerative Colitis patients following this approach failed but a lot of structural changes in the gut microbiota was observed.^166,167 It has also been reported that this approach helps to some extent in treating some of the gastro-intestine related disorders but it is unclear whether the benefits of this approach is derived from the transfer of viable microbes or through the delivery of a wide range of substances like proteins, SCFAs and many others which are present in the faeces. Possibly, this approach should be carried out periodically and repeatedly in order to maintain the eubiotic state in the donor to cure dysbiosis.¹⁶⁸ Clinical application of FMT therapy is limited due to poor colonisation of bacteria in the intestinal tract and non-standardization of the treatment process. The other therapeutic approach used to restore eubiosis is Bacterial Consortium Transplantation (BCT). Intestinal dysbiosis and TNBS induced colitis gets ameliorated upon supplementation of a bacterial consortium containing ten bacterial strains. Microbial equilibrium is re-established in the transplanted mice samples offering a therapeutic option for colitis and IBD diseases.¹⁶⁹ BCT is a more effective and safer approach as the bacterial consortium can be very specific based on the disease to be treated.¹⁷⁰ Disruption of microbial homeostasis in the intestine due to ceftriaxone sodium induced dysbiosis in BALB/c mice was restored by complementary supplementation of 1 × 10^9.8 bacterial cells collected from fresh faeces. Commensal bacteria in faecal sample that include Bifidobacterium thermophilum, Enterococcus hirae, Lactobacillus reuteri, Bacteroides alanitronis, Streptococcus thermophilus, Veillonella parvula, Peptococcus niger, Eubacterium siraeum, Escherichia coli str. Staphylococcus aureus subsp etc enhanced the intestinal permeability and re-established the disrupted mucosal barrier.¹⁷¹

Surface imprinted nanobodies that anchor on the surface of bacteria are utilised for the synthesis of synthetic consortia. Surface display of nanobody helps the target microbe to bind strongly on the target entities that include eukaryotic cells, viruses and bacteria.¹⁷² Intestinal phages directly influence the co-existing bacteriome which directly contribute to intestinal homeostasis. Phage bacteriome interaction and Phage host interaction influence gut equilibrium. Activation of host immune response by a phenomenon called phage tropism stimulates the TLR pathway and stimulates adaptive immune response.¹⁷³ The treatment of dysbiosis with respect to phage therapy is of great concern as many studies must be performed for the approval of phages as antibacterial drugs by Food and Drug Administration (FDA) and European Medicines Agency (EMA). It is known that phages are viruses that infect bacteria by recognizing the specific receptor proteins present on the bacterial surface and hence it is reported that these phages can be used for antimicrobial purposes. Phages can be genetically modified and can be used as “gene carriers” for the biosynthesis and degradation of nutrients and to modulate the intestinal microbiota.¹⁷⁴ Studies have reported that the use of lytic phages have shown positive results of decrease in Pseudomonas aeruginosa PA14. Phages aid in the disaggregation of the biofilm thereby allowing the antibiotics to diffuse at a much higher rate resulting in the elimination of the pathogenic bacteria.^175,176 Further studies need to be carried out to understand the mechanistic interaction of using phages as a therapeutic agent to manipulate the microbiota in order to attain eubiosis.¹⁷⁷

Conclusion

The importance of the microbes inhabiting the intestinal region directly influences the metabolic functioning and contributes for disease management.  Maintaining a eubiotic state will help in preventing the onset of gastro-intestinal diseases. Many therapeutic approaches are currently employed to restore the eubiotic state for a healthy gut homeostasis. Apart from the usage of prebiotics, probiotics and synbiotics, use of certain metabolites synthesized by the gut microbes aid in bringing back normalcy. The administration of gut peptides like GLP-1 and secretory products such as butyrate, short chain fatty acids help in maintaining homeostasis in the gut microbiome. Fasting Induced Adipocyte Factor (FIAF) activity can also be considered as a useful therapy to increase LPL-driven triglyceride clearance. Evidence based data will further help in considering the gut microbiota as a target to prevent intestinal dysbiosis and further robust investigation is required for it to be applicable in humans. This field involves great interest because there is no universal cure for an imbalance of the gut microbiota. Personalised medicine employing innovative approaches like bacteria therapy, phage therapy, next generation probiotics and bacterial consortium transplantation depends on the individual’s health condition, lifestyle, diet and other criteria.

Acknowledgement

The authors acknowledge the support received from the Department of Life Sciences and Centre for Research, CHRIST (Deemed to be University), India.

Conflict of Interest

The authors declare that they have no conflict of interest.

Funding Sources

The project is funded under MRP-DSC-1936 by CHRIST (Deemed To Be University), Bangalore, India.

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