A microbiome is defined as the set of microorganisms living on or inside living organisms. This microbiome includes bacteria, fungi, viruses, and protozoa that consist of 150 time’s greater genetic material than that of the host.¹ The well-studied niche microflora is inside the human gut, where about tens of trillions of microbes live symbiotically. Phyla, Firmicutes, Bacteroidetes, Proteobacteria, and Actinobacteria are, more prominent in healthy adults.² When the species of different class of microbes are deregulated, it contributes to several complication related to the health. In human body, colon contains the highest microbial diversity that is present on earth. In human gut Bifidobacterium, Bacteroides, Prevotella, Fusobacterium, Eubacterium, Peptococcus, Peptostreptococcus Ruminococcus, class of microbes abundant. Escherichia and Lactobacillus. Bacteroides alone constitute about 30% of all microbes in GI tract.³ Innate and adaptive immune systems of host also contributed by microbiome.^4,5 Dysboisis of microbiome cause inflammation and autoimmune diseases.^6-8 Intestinal dysbiosis deregulates metabolic activities which are highly associated with host factors like age, diet, and environmental conditions.⁹ Accompanying mechanistic exploration toward host microbe interaction, in 2007 human microbiome project (hmpdacc.org) started focused on identifying and characterizing human microbial flora.¹⁰ Hence intestinal microbe can be major target for health improvement.¹¹

Microbiome specific disease diagnosis, monitoring and treatment may revolutionize much incurable drug dependent disease worth anticipating. Microbiome technologies are expected to play a crucial role in the development of new drug discovery platforms and companion diagnostics in the precision medicine era (Figure 1).

Common Enterotype in Gut Ecology
Human gut microbiome has been classified into three distinct enterotypes (Bacteroides, Prevotella, and Ruminococcus). Gut microbial enterotypes are associated with specific fooding habits and drug intake patterns. Prevotella– are enriched in people consume carbohydrate diet. While high protein and fat diet intake dominate Bacteroides– population. Ruminococcus-dominant enterotype is associated with grain Lovers. 16S rRNA gene of human intestinal tract microflora explores diversity measurement.^12,13 Metagenomics studies also characterized functional microbiome among American and Japanese individuals. The intestinal flora includes Lactobacillus, Bifidiobacteria, Peptostreptococci Propionibacteria and Enterococci.^14,15 Primary function of these microorganisms is to live in commensal and protect gut after secreting antibiotic substance that inhibit the growth of harmful microorganism and maintain pH that is essential for intestinal wall to perform protective barrier, and provide an environment where microbe cannot colonize.^16-20 Opportunistic flora, of intestinal include Clostridia, Bacteroides, Staphylococci, Streptococci, Bacilli, Yeasts, Peptococci Enterobacteria, Fusobacteria, Eubacteria, Catenobacteria and others. The flora which enters the body through food and drink constitutes the transitional flora.²¹ Dysbioisis of microbiome cause inflammation and autoimmune diseases,^6-8 promoted by loss of intestinal barrier function, against which an immune cascade get activated (Figure 2).

Psoriasis and Psoriatic Arthritis
Psoriasis is an autoimmune disease in which skin cells grow faster than normal and formed a bumpy red patch covered with white scales.²² Several studies on surface or skin microbiota confirmed the elevated Staphylococcus and Streptococcus genus.²³ In psoriatic patient bacterial DNA has been isolated both locally and systemically, and altogether evidence a central role of bacteria in psoriatic disease.²⁴

Prolonged psoriasis illness cause damage of tissues and bone which resulted in psoriatic arthritis.²² Gut microbiota study of psoriatic patient clear the abundance of Prevotella copri.²³ Decrease Bacteroides genus and an increase in the numbers of Faecalibacterium, Akkermansia, and Ruminocuccus genera is also a characteristic findings in the gut microbiome of patients with psoriasis.¹¹ African cluster study found that prevotella species, predominantly contributes to the joint inflammation in the intestine. Auto reactive T cells turn out to be highly reactive to auto antigens, including arthritis specific antigens, via activation of innate immunity.^24,25 These T cells populations can then exacerbate joint inflammation. Presence of bacterial DNA in psoriatic patient plasma confirmed.²⁶ This increased bacterial load in blood arose from intestinal barrier disruption, along with their metabolite access to blood stream and skin homeostasis impairment.^27,28 These findings established a correlation between the gut microbiome and skin homeostasis. Psoriatic skin had less Propionibacterium and Corynebacterium had less Ruminococcaceae and Akkermansia but more Bacteroides and Faecalibacterium.^28,29 Intake of oral probiotic of Bifidobacterium infantis35624 reduced the plasma levels of TNF-a as compare to control.³⁰ Oral administration of L. salivarius LA307 and L. rhamnosus LA305 showed reduction of eczema and inflammation marker.³¹ In imiquimod-induced psoriasis mouse model L. pentosus GMNL-77 and Lactobacillus sporogenes administration (as a probiotic) were able to suppress TNF-a, IL-6, and proinflammatory cytokines in the IL-23/IL-17 cytokine.³²

Inflammatory Bowel Disease (IBD) and Colitis
Chronic Inflammation of small intestine, colon and Crohn’s disease (CD) and ulcerative colitis (UC) are called inflammatory bowel disease.³³ Gut dysbiosis, and dysfunctional immune responses cause intestinal tissue damage by activated Th1 and Th17.³⁴ Mucosal injury results in invasion of microbial antigens, TLR ligands that perpetuate the immune responses.³⁵ NOD2 gene present in human encodes intracellular pattern recognition receptor that recognizes bacterial peptidoglycan and stimulates immune system.³⁶ A report showed that NOD2 gene knockout in mice tends to decrease IL-10 and increased susceptibility to colitis, in human subjects with NOD2 mutations.³⁷ Increases in the Gammaproteobacteria and decreased abundances of bacterial taxa of Firmicutes and Bacteroides.^38,39 Most common microbes present in inflammatory bowel disease patient is Rhodotorula, which is capable of inducing intestinal inflammation.⁴⁰ transfer of these bacteria induces inflammation in healthy mice. In CD bacteria which produce short chain fatty acid Phascolarctobacterium and Roseburia are also reduced while Leuconostocaceae is depleted in UC along with enrichment of Escherichia species and a depletion of Faecalibacterium species.^41,42 Bacteroides vulgatus bacteria alter mucosal membrane function and turn on inflammatory genes.^43,44 Nonpathogenic strain of E. coli used as prebiotic has been shown effective in patients of ulcerative colitis.⁴⁵ B fragilis prevents colitis in mice by interacting with CD4 Foxp3 regulatory T cells which produce IL-10.⁴⁶

Therefore bacteria and fungi can penetrate mucosal barrier and activate TLRs, CARD9 and Decting-1 activation resulted in more severe phenotype in lamina propria.^47,48 When CARD9 knockout in mice, they got susceptible to colitis. This susceptibility was directly associated with tryptophan metabolism correlated to impaired microbial population.⁴⁹

Carbohydrate fermentation products, propionic acid, acetic acid and butyric acids which play important role in activation and regulation of multiple pathways specific to colon.⁵⁰ Among all metabolites butyrate significantly involved in colonocytes metabolism.⁵¹ This imparts anti-inflammatory action by inhibiting IL-12 and TNF-α cytokines and up regulating IL-10 in human monocyte.⁵² Expansion of T-Cell to mitigate intestine inflammation induces by Bacteroides and Clostridium species.⁵³ Previous studies on IBD suggest that combination probiotic of Bifidobacterium breve, Bifidobacterium infantis, B. longum, L. acidophilus, Lactobacillus plantarum, Lactobacillus paracasei, Streptococcus thermophiles, and Lactobacillus bulgaricus have potential to reverse ulcerative colitis.⁵⁴ Mesalamine, an anti-inflammatory drug decreases the Escherichia/Shigella in IBD and attenuates intestinal inflammation.^55,56

Liver Diseases
Liver is the major vital organ that detoxifies the body and support function of other organs. Failure of liver function can leads to serious health complication. Relation between liver diseases and gut microbiota has been well established.⁵⁷

Imbalance in pathobiont and beneficial bacteria is associated with deleterious effects on host and plays a critical role in the development of alcoholic liver disease,⁵⁸ nonalcoholic fatty liver disease,⁵⁹ nonalcoholic steatohepatitis,⁶⁰ acute (toxic) liver injury, fibrosis/cirrhosis, hepatic tumors,⁶¹ autoimmune hepatitis and autoimmune cholangiopathies.⁶² These disorders arise from translocation of bacterial metabolites by intestine to liver.⁶³ These endotoxin metabolites received via toll-like receptors and cause damage to liver associated with higher levels of serum TNF-α, IL-6, and adipokines 2.⁶⁴ Moreover, bile acid dysregulation linked to dysbiosis, hepatic lipid accumulation increases insulin resistance, and inflammatory signaling.⁶⁵

When infection of Streptococcus pneumonia increase in liver, a protein that is reactive to the C-polysaccharide of bacteria called as C-reactive protein take part in antigen removal.^66,67 Concentration of CRP in blood directly proportional to inflammation in response to infection, trauma, and tissue infection, Hence, the CRP is monitor in various inflammatory conditions.⁶⁸ Higher faecal proportions of Bifidobacteria, enterobacteria and streptococci associated with alcoholic hepatitis.⁶⁹

Thus, intestinal microbiota is center for progression of alcoholic liver disease. Conversely, Proteobacteria, Bacteroidetes, and Enterobacteriaceae were found to be increased in NASH patient as compare to healthy controls, while Firmicutes declined.⁷⁰ Hence Bacterial translocation cause systemic infections in liver of Proteus and Enterobacter which have ability to bypass the intestinal barrier and associated with higher incidence of bacteremia. In liver cirrhosis, population of Bacteroidetes is significantly reduced, while Proteobacteria and Fusobacteria increased.⁷¹ Mixture of Bifidobacteria, Lactobacilli, and Streptococcus thermophiles probiotic was able to reduced high-fat diet (HFD)-induced steatosis, inflammation, and insulin resistance in a rodent model.⁷²

Obesity and Type 2 Diabetes Mellitus
Obesity and diabetes are the third most common disease in aged people after cardiovascular disease and cancer.^73,74 It’s a debate where obesity cause type 2 diabetes, high blood pressure and heart disease or because these illness person became obese.⁷⁵ Obese people are always on risk of developing type 2 diabetes. In obese persons, fat tissues cells have to process more nutrients than their regular capacity.⁷⁶

In metabolite study of plasma and stool samples 19 metabolites associated with BCAA (branched-chain and aromatic amino acids) linked to high BMI and obesity development.⁷⁷ Diet consisting saturated fat, associated with increased inflammation with abundant white adipose tissue (WAT) and metabolic disease, on the other hand polyunsaturated rich diet counteract inflammation and promote healthy lean phenotype due to changed metabolism.⁷⁸ Fat induced WAT accumulation occurred as a result of inflammation, mediated through gut microbial activation of TLR4 which serve as receptor for microbe-associated molecular pattern (MAMP) receptors, and further activate proinflammatory response through nuclear factor (NF)-kB pathway, producing antibacterial products, cytokines and chemokines.⁷⁹ Studies performed in different diabetic group shown lower intestinal Roseburia and Bacteroidetes. Abundant Faecalibacterium prausnitzii (both butyrate producing bacteria), and other strains Lactobacillus gasseri, Streptococcus mutans, Firmicutes and Clostridiales members also contributes to disease.⁸⁰

In a experiment where germ free mice inoculated with obese (ob/ob) or lean (+/+) microflora. Mice that received obese microbes extracted more calories from their food and increase in total body fat than in mice colonized with lean microbiota. In one study author insert the lean phenotype microbiota in obese phenotype, and find improve insulin sensitivity.⁸¹ Resistance of insulin reported as a increase in branched chain amino acid which are associated with gut microflora.⁸² Changes in metabolites related to obesity were directly linked to four different bacteria (Ruminococcus, Blautia, Dorea and in the Lachnospiraceae family, and SHA98.⁸³ Supplementation of A. muciniphila reduced inflammation reduces LPS level and improved glucose tolerance.^84,85 Fermented probiotic fiber has potential to protect against metabolic syndrome⁸⁶ consequence of reduced intestinal permeability.

Atherosclerosis
Atherosclerosis is the deposition of fat molecule on artery wall, Plaque of fat and other minerals reduce the diameter of artery for the flow of oxygenated blood. There are some factor like high LDL, obesity, smoking and consumption of unhealthy diet results of this condition along with family history. Western diet comprises diet reach in choline and carnitine have increased risk of cardiovascular disease.^87,88 Gut microflora convert these compound into trimethylamine (TMA), which is further interconvert into trimethylamine- N-oxide in the liver and trigger heart problems.^89-91 This conversion of TMA catalyzed by microbial TMA lyase. Atherosclerosis development triggered by TMA through up regulation of the CD36 of macrophages and promotes uptake of cholesterol and formation of foam cells.^92,93 Reduced expression of cytochrome P450 7A1 and 27A1 which metabolize drug and other molecule in liver, and promotes vascular inflammation by activating nucleic acid factor-κB signaling pathway, monocytes through mitogen-activated kinase.^94-96 Inhibits cholesterol reverse transcription.^97,98

Gut microbiome composition in atherosclerotic patients observed to be more inflammatory.⁹⁹ Elevated Escherichia coli, Klebsiella spp., Enterobacter aerogenes, Streptococcus spp., Lactobacillus salivarius, Solobacterium moorei, and Atopobium parvulum. Depleted abundance of gut species such of Bacteroides spp., Prevotella copri, and Alistipes shahi^100,101 has been recorded in patient. Administrative study of Lactobacillus plantarum as probiotic reduce blood cholesterol and therefore restrain the formulation of atherosclerotic plaques in hyper-cholesterol patients.¹⁰² When A. muciniphila supplemented in atherosclerosis prone mice, it protected atherosclerosis development while mice were feed on Western diet.¹⁰³ Indeed, mice harboring high choline-metabolizing bacteria are susceptible to diet-induced metabolic disease.¹⁰⁴ Secondary metabolite of polyphenol class like Gallic Acid a-Asarone, Equol, Urolithins and Quercetin-3-glucuronide function in protection of cardiovascular system.^105,106

Microbial metabolism modulation through diet intervention or direct supplementation provides effective strategy for prevention of cardiovascular diseases.

Ageing
Aging is a consistent decline in vital activities that is associated with inflammation. Age dependent changes are associated with oxidative/ genotoxic stress and change in gut microbiota composition by the time.^107,108 Bifidobacteria by the span of life decline, whereas Clostridium perfringens, Lactobacilli, and Enterococci increase with age.¹⁰⁹ Composition change of gut microbiota directly correlated with intestinal inflammatory state.¹¹⁰ Current studies on microbiome and aging associated changes evidenced the role of certain population which regulates pro-inflammatory and anti-inflammatory networks in the gut microbiota.^111,112 Inflammatory markers such as LPS-binding proteins increase in aged healthy person.^113,114 Hence low grade inflammatory status facilitates by LPS.¹¹⁵

Malaria
Malaria is a mosquito transmitted disease affect 219 million population yearly, Plasmodium species is causative agent. Different mice studies showed that mice devoid of commensals bacteria are more susceptible to Shigella flexneri, Bacillus anthracis, and Leishmania infection.^116,117 Moreover, gut microbiota can diminish intestinal immunity and increase susceptibility toward enteric pathogens such as Citrobacter rodentium and Campylobacter jejuni.^118,119 Providing the importance of the microbiota in regulating immune system function homeostasis.

Mice study Demonstrated E. coli expressing a-galactosyl, host were protected from effective Plasmodium liver-stage infection.¹²⁰ Influence of the microbiota on the progression of malaria clinical outcome infections has only now started to emerge.

Absorption of Vitamin B12
Vitamin B-12 or cyanocobalamin is essential co-factor for iron metabolism as well as nucleotide synthesis and neuronal system function. Deficiency could introduce tiredness, anemia, constipation, weight loss, memory problems, and neurological issues.¹²¹ Major problem arise either deficiency in food or malabsorption due to lack of bacterial population helps in interconversion in intestine.¹²² Cobalamin deficiency cause less cell division, neuropathy, nervous system disease, and pernicious anemia.¹²³ B12 deficiency is prevalent in vegetarian diet people as plants are not a source. Concentrations of cobalamin can be detected in fermented food.¹²⁴ An intrinsic glycoprotein factor secreted by gastric mucosa serves as important absorption factor. Cobalamin deficient patient’s microbiota showed dramatical changes after cyanocobalamin and methylcobalamin supplementation.¹²⁵ Methylcobalamin alleviate butyrate producing bacteria which may alleviate intestinal inflammation. Previous studies confirmed that vitamin B12 deficiency is also contributes to inflammatory bowel disease.¹²⁶

Neurological Disorders
Gut is also called second brain of human, so disorder in neurological system state the gut health disturbance that is consequence of microbe ecosystem misbalance.¹²⁷ Neurological complication aroused due to failure of gut membrane function that allow other microbes and their metabolites to blood stream as a loss of permeability,¹²⁸ Which may disrupt the synthesis of SCFA (short chain fatty acid) served as vitamin and hormone cofactors,^129-131 and generate molecules that reduce inflammation,¹³² and play a function to boost immune activities. Medium chain fatty acid, alpha lipoic acid which is the activator of the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) which response in antioxidant element signaling pathway.^133,134 Increased inflammation of gut linked to neurodegenerative diseases.^135-137 Gut microbiota alteration have been directly linked with mental comorbidities like depression, multiple sclerosis and Parkinson disease. Structural, biochemical or electrical abnormalities in the brain, spinal cord cause physical impairment such as neuromyelitis optica spectrum disorders, multiple sclerosis, Parkinson disease, Alzheimer disease, Huntington disease, and amyotrophic lateral sclerosis.^138-142 Enrichment of Archaea (genus Methanobrevibacter) was relative to controls as well as depletion of members from the Firmicutes (eg, Clostridium genera) and Bacteroidetes phyla reported. Consumption of antioxidant throughout life can also impede neurological symptoms along with enhancement of immune system. Neurological diseases are mainly can be cured through cleaning of colon. Certain Ayurveda remedies also showed very tremendous result after a panchkarma procedure of “Basti” (rejuvenation of large intestine).¹⁴³

Depression and Anxiety
Role of gut microbiome has been implicated in various disorders, with particularly strong evidence for its role in depression and neuropsychiatric disorder.¹⁴⁴ Post gut microbiota transfer of depression patient healthy mice showed elevated level of tumor necrosis factor alpha (TNF-α).

Interleukin-6 (IL-6), interleukin-8 (IL-8), along with C-reactive protein (CRP) and higher kynurenine/tryptophan ratio. Total blood cortisol was also increased which is reflecting stress environment in body. Patient data showed

Profound difference in Prevotellaceae family and Prevotella genus. Short chain fatty acid, plasma lipopolysaccharide binding protein did not directly correlate. Although, Alistipes, Faecalibacterium, and Ruminococcus were correlated with a detectable level of isovaleric acid.¹⁴⁵ Response of gut microbes is gender biased; Lactobacillus rhamnosus did not improve stress in male.¹⁴⁶ Protiobic species Lactobacillus helveticus and B. longum are able to reduce depression in patients with major depressive disorder (MDD).¹⁴⁷ These results are contradictory with negligible effect on clinically depressed patients.¹⁴⁸ Although, animal model able to produce the human relevant data, but investigation of human samples to establish a proper relationship investigating mechanism behind it is needed. Encouraging results of probiotics.

Cancer
Cancer is a leading cause of death worldwide. In 2018, cancer accounted for 9.6 million deaths.¹⁴⁹ Role of numerous gut populating bacteria, have been recognized as protectant against the tumors genesis.¹⁵⁰ Lactobacillus rhamnosus GG (LGG).

Is the most studied probiotic for cancer intervention studies.¹⁵¹ In colon cancer patient, change in bacterial community has been reported with abundance of pathogenic bacteria.¹⁵² Lactobacillus and Bifidobacteria prevent tumor development by MyD88 suppression, which play essential role in developing carcinomas.^153,154 Lactobacillus johnsonii modulate immune system in colorectal patient by Enterobacters modulation.¹⁵⁵ In an experiment with colonized Helicobacter hepaticus mice exhibit colonic Th17 inflammatory molecule also have a beneficial role in human ovarian cancer.^156,157 murine melanoma, pancreatic and colon cancer.^158,159 Helicobacter pylori is known for alter stomach pH and acid reflux, which could protect against Barrett’s esophagus and esophageal cancer.^160,161

Kidney Disease
Various combination of different type of disorders like high blood pressure, diabetes, urinary tract obstruction, kidney stone, enlarged prostate are also part of pyelonephritis. In kidney disease lower intestinal microflora has been found to be altered mostly associated with decreased Prevotellaceae and Lactobacillaceae families.¹⁶² Analysis of fecal microbiota showed overgrowth of aerobic bacteria, such as Enterococci and Enterobacteria species, was 100 times greater in hemodialysis patients along with Lower numbers of Bifidobacteria and higher Clostridium perfringens.¹⁶³ In Chronic Kidney Disease urea secrete into the gastrointestinal tract where hydrolysis of urea takes place by urease which is expressed by some gut microbes. Ammonia produced in gut which can affect the growth of commensal bacteria.¹⁶⁴ Mild consumption of fiber diet, use of antibiotic, intestinal wall edema, and oral iron intake, metabolic acidosis also cause dysbiosis.¹⁶⁵ Nephroprotective metabolite such as vitamin K and butyrate lowered due to microbes producing (e.g., short chain fatty acids), such as Lactobacillus.¹⁶⁶ Gut bacteria Clostridium and Bacteroides generate some toxin and metabolite (phenol, indole) which later absorbed in blood and filter by kidney. Plasma metabolites of hemodialysis patients confirms the Colonic origin of indoxyl sulfate and p-cresol which is fermented product of phenylalanine and tyrosine.¹⁶⁷

Factor that influence gut microbiota
Several intrinsic and extrinsic factors can influence gut microflora composition, some extrinsic factors like Diet/lifestyle, Drugs/Antibiotic, Age, Host immunity, and intrinsic factor involved genetic factors.¹⁶⁸ There is some most studied factor that has been proven to alter gut microbiota.

Diet
In our routine life diet that we consume daily affect the microbe health in our gut. Reports showed that changing of fooding habits alter the microbe makeup in gut. Previously a mice study showed decline in gut microbial diversity after having high fat diet (60%). In diabetic patient A. muciniphila decreases, treatment with A. muciniphila reduces fat content. Among different kind of diets fiber rich diet is proven to be beneficial and associated with gut microbiota modulation.¹⁶⁸ Composition of gut microbe varies to the consumed diet; Bacteroides composition is associated with protein and high animal fat diet. On the other hand Prevotella is more common to carbohydrate diet. Hence diet is associated with enterotype partitioning. The high-fat diet contributes to dysbiosis which ultimately caused disease.¹⁶⁹ Strong health benefits evidence of fermented foods and beverages are reported in several diseases with their significance on the gut microbiota balance.¹⁷⁰ Incorporation of fermented foods diet (e.g., kimchi, kefir, etc.) may counter the proinflammatory effects of gut dysbiosis.¹⁷¹

Infections
Some pathogenic microbe’s secreted metabolites can inhibit gut microbes growth. In a study where researcher showed Citrobacter rodentium enteropathogenic effect on the mice microbiota, reduced abundance of lactobacillus. Clostridium Difficile presence cause severe dysbiosis in gut microflora. In human infected patients microbiota studies in mice data showed transplantation results in high microbial richness and diversity. It is clearly proven by previous results that shift in the host microbiota have potential to clear infections and pathogenesis as well.

Medications
When people have any symptom and disease complication various medicines recommended in response to cure illness but some of them cure the disease but affecting the gut bacterial diversity. Antibiotics are the most commonly used class of drug prescribed for any type of infection and illness but showed a profound effect also, which could be persistent. Antibiotic consumption in neonate cause symbiosis, which may be an inclining factor to inflammatory bowel disease and obesity.¹⁷²

Genetics
Host, microbiota and environment contribute or affect the genetic makeup of species. Presence of gut bacteria is influenced by genetic makeup affecting host metabolism and causing disease.¹⁷³ As like common genetic makeup sibling or parent also showed similar microbiota communities than unrelated individuals. In monozygotic twins, gut microbiota is reported to be similar to dizygotic twins as genotyping and metagenome analysis showed.¹⁷⁴