Impact of Human Microbiome on Health

The human genome in the recent years, by the advent of technological advancements, has emerged as a major prolocutor for reciprocity between the human body and the food consumed. As known, microbiome comprises all the genetic materials within a microbiota and can thereby be also referred to as metagenome of the microbiota. Contemporary researches have revealed the influence of microbiome not only on human mind and health status, but also in wide range of disease switching, ranging from cardio-metabolic diseases, allergies and obesities to life-threatening diseases such as cancer. Though the complete mechanism of many diseases is yet unclear, research works have revealed that the metabolites, nutrients and microbes can be regarded as the key players for such physiological state. The major approach of this chapter is to enlighten the interrelationship of the microbiome on the human health either in a synergistic or in an antagonistic manner.


Introduction
In the last few decades, immense initiatives have been taken in understanding the role of microbiome on human health. In the present day, either in the field of therapeutic development or medical treatment, the impact of microbiome is especially apparent in the studies of different microbial communities and the human microbiome. In the recent times, 'omics' has provided a significant impetus on all the facets of biological research which has ushered the field to gain in momentum. The study, which is contemporarily popularised as study of 'human microbiome', is an outcome of the advancement in the field of genomics and other fields of microbiology, which has given the classical microbiology a new outlook and perspective. Thereby, the attention was driven and directed towards the genomics, which was the major objective of the Human Microbiome Project (HMP) (Turnbough and Wilson 2007). The HMP was used for the characterisation of all the microbial communities living in the human body, eventually switching the interest towards, not only, the type of microbes existing in the human body but also to the role and activity they perform both in the case of a healthy and diseased individual. Since 2003, after the publication of the first human genome (Chial 2008), the biomedical research on microbiome has obtained a significant scientific attention. There has been an immense leap from the culture-based surveys of various tissues or organs, for example, of gut and oral cavity, to molecular profiling of the microbial communities and their biochemical products like enzymes, proteins, and amino acids in all the different ecological niches of the human body (Eckburg et al. 2005;Gill et al. 2006;Costello et al. 2009) for this subject. This chapter attempts to put an insight into the distribution and diversification of human microbiome, the behaviour of human microbiome on the human health and microbiome as a paradigm for the future nutritional and medicinal strategies for human benefits.

Systemic Microbiome: Its Distribution and Diversification
Over 100 trillion microbes are estimated to be residing both inside and over the surface of humans, possessing genome which is approximately 150 times to that of the entire human being ). This includes microbes of different families such as bacteria, fungi, archaea and viruses, contributing about eight million unique protein-coding genes as compared to the human genome, which comprises only around 22,000 protein-coding genes (Tomayko et al. 2013). This variation and the nature of the organism, specific to the specific anatomic site of the body, is a consequence of their specific growth requirement. The other determinants for such growth include coevolution of microorganism, their extensive interaction amongst each other and with the human host, variation in the composition and function with respect to the population, human life span and inconsistency of the body sites, ecologic condition, difference in the oxygen tension, airway luminal temperature, mechanism of muco-ciliary clearance, sex, genetics and socio-economic status. Hence, there has been a development of the concept of interdependence, in variety of physiologic, immunologic and metabolic processes, which ultimately determines the microbiome community in a particular site of the human body system.

The Gut Microbiome
Amongst all the human systemic microbiome, the gut microbiome, composed of the genetic material of the microorganisms in the gut, occupies a very essential and special position. They play an important role in various physiological processes like metabolism, immunity development and nourishment supply. The genotype and the immune system of the host have been shown to contribute towards the development of gut microbiota (Thaiss et al. 2016). In response to environmental factors, such as diet, pathogens and xenobiotic substances, a crosstalk occurs between the human immune system and the microbiome. For instance, the myeloid cells, epithelial layer and the innate lymphoid cells, part of the immune system, crosstalks with the gut microbiota for which the microbiome composition, host physiology and disease susceptibility are the main consequences of such crosstalks and feedback loops between them. Along with the bacterial community, like Firmicutes and Bacteroidetes species (Table 20.1), these interactions are also contributed by the other microbiota like fungi (Pothoulakis 2009), archaea and viruses (Breitbart et al. 2003). Though the understanding of the immunological relationship between the fungi and archaea is limited currently, the trans-kingdom commensalism is expected to be formed from infancy (LaTuga et al. 2011).
The principal constituents are the bacteriome, virome and mycobiome, whose strong interdependence maintains the functionality of the gut microbiota, if imbalanced may also affect the other systems in various ways. Since the time of birth of an individual, when the sterile gut of the neonate gets exposed to the biota of mother's vagina during the vaginal delivery or hospital microbiota in case of caesarean section (which may even include the multidrug-resistant species), the microbes starts their colonisation with an eventual change by the age of 3-5 years, by when an individual starts resembling bacterial community to that of an adult both structurally and functionally (Bull and Plummer 2014). In adults, the composition of gut microbiota is uneven throughout the length of the gut. As compared to small intestine, which is rich in the species related to phylum Firmicutes, colon on the contrary exhibits the presence of members of phylum Bacteroidetes. The microbiome of lumen and that attached to the epithelial lining even show differences. The stool sample exhibited the presence of Bacteroides, Streptococcus, Ruminococcus, Lactobacillus, Enterococcus, Bifidobacterium and Clostridium which presented the lumen community while on the mucous layer detected the presence of Enterococcus, Lactobacillus and Clostridium (Swidsinski et al. 2005).

The Microbiome of the Lungs and the Airways
During the initiation of HMP, the airways and lungs were exempted from the study, believing these parts to be sterile in nature (Moffatt and Cookson 2017). This fact was always acceptable because of the negative results yielded by the various standard microbiological culture tests of the healthy individuals (Faner et al. 2017). Its study was also a challenge owing to the difficulty in assessing the lower tract without the invasive techniques such as bronchoscopy. Hence, there has been a delay in the systemic microbiome assay until the first study indicating the similarity of bacterial density of this part with the upper small bowel of human body was reported (Man et al. 2017). This has been made possible due to the advances in molecular techniques independent of culture practices (Faner et al. 2017). Human respiratory system is divided into upper respiratory tract (URT) and lower respiratory tract (LRT) with alveoli, present in the LRT, acquiring the surface area nearly 70 m 2 (Man et al. 2017). This complete tract is occupied by the niche-specific microbiota with higher density dwelling in URT. The development of microbiota has been thought to effect on the morphological genesis of this system (Man et al. 2017). During the first hours of a healthy neonate, non-specific microbes, presumed of maternal origin has been detected. Abundance of Staphylococcus spp. in the first week, in the URT due to niche specification, has also been detected, which is then occupied by the Corynebacterium spp., dominated by the Dolosigranulum spp. The Moraxella species has its dominance at the age of 4-6 months. The individuals with the possession of such microbiota have been found to possess stable microbiome community along with better airway health (Morris et al. 2013;Segal et al. 2013) This healthy development is prone to disturbance under certain conditions such as usage of antibiotics, oxygen tension, temperature and pH, presence of other siblings, seasonal variations, vaccinations, exposure to smoke and host genetics (Man et al. 2017). Attempt to observe the diversity of flora in URT and LRT is well observed (Table 20.1).

The Microbiome of the Cardiovascular System
Studies using species specific molecular techniques have declared that the diseasefree arteries and veins are microbe free in nature (Jin et al. 2019;Sobol 2014). Very few studies do report the presence of bacterial and viral genome in some vessels of healthy subjects. Amongst the microbes, Helicobacter pylori and herpes simplex virus are the most prevalent followed by Cytomegalovirus, Chlamydia pneumoniae, Mycoplasma pneumoniae and Epstein Barr virus and were also detected in healthy aorta, saphenous veins and internal mammary arteries (Clifford and Hoffman 2015).

The Microbiome of the Cardiovascular System
Studies using species-specific molecular techniques have declared that the diseasefree arteries and veins are microbe free in nature (Jin et al. 2019;Sobol 2014). Very few studies do report the presence of bacterial and viral genome in some vessels of healthy subjects. Amongst the microbes, Helicobacter pylori and herpes simplex virus are the most prevalent followed by Cytomegalovirus, Chlamydia pneumoniae, Mycoplasma pneumoniae and Epstein Barr virus and were also detected in healthy aorta, saphenous veins and internal mammary arteries (Clifford and Hoffman 2015).

Urogenital Microbiome
The human urinary tract along with urine was earlier considered to be 'sterile', until the modern-day research, which has confirmed the presence of microbes in this system, significantly in healthy individuals. The advances in techniques such as 16 s rRNA sequencing have considerably helped in revealing the normal microbiota of the human body system. After analysis of the urine, the most common genera reported are Lactobacillus (more in women) and Streptococcus (more in men), both of which, along with few other groups, deliver a protective role in this system against different pathogens. Various bacterial taxa, as illustrated (Table 20.1), had been recognised in healthy adults, but some specific genera such as Saccharofermentans, Proteiniphilum, Parvimonas and Jonquetella were found in persons with age more than 70 years. The variation of urinary microbiome related to age and sex may be due to differences in voiding habits, hygiene, urinary metabolites, anatomic structures, hormonal variation and histology. Even the vaginal microbiome at premenstrual phase, reproductive age and post-menopausal phase exhibits variation (Aragón et al. 2018).

The Microbiome of the Nervous System
Central nervous system is considered to be one of the most immune privileged systems because of its closed compartmentalisation. It is isolated by physical barriers like blood-brain barriers and blood-cerebrospinal fluid barriers, from the circulatory system (Obermeier et al. 2013;Ransohoff and Engelhardt 2012). Thus, lack of lymphatic drainage, expression of major histocompatibility complex by the parenchymal cells and anti-inflammatory environment of the central nervous system accounts for such privileged status of seclusion from the microbiota (Berer and Krishnamoorthy 2014). Though, in our body, there exists a bidirectional communication system, involving hormonal, immunological and neural signalling pathways, between the brain and the gut, accessed by the microbial flora of the intestine and certain metabolites, also known as the gut-brain axis. It is estimated that nearly 90% of serotonin (5-HT), a neurotransmitter, is produced in the intestine under the influence of gut microbiota, and the activation of its receptors in the enteric nervous system is responsible for the neuroprotection and adult neurogenesis in the mouse model (De Vadder et al. 2018).

The Microbiome of the Skin
The largest organ forming the external interface of the human body to the environment is the skin. Nearly 1.5-2.0 m 2 of the skin covers an average human with 2-3 mm depth. Three tissue layers are found in the skin: epidermis, dermis and hypodermis. Epidermis is colonised by millions of the microbes such as bacteria, fungi, arthropods and even viruses. It acts as the physical, anatomical and immunological barrier to various pathogens extending protection of the body, unless this barrier is broken or there is an imbalance between commensal and pathogenic organisms resulting to cutaneous or systemic diseases. Their acidic pH, continuous shedding of epidermal cells, hydrophobic nature, salinity and association with the antimicrobial compounds make them an efficient barrier (Ross et al. 2017). Though microbes do exist on them in spite of the above characteristics, the number of microbes inhabiting the skin ranges from one million to about one billion in each cm 2 . Although, human skin is inhabited by quite diverse microflora, but most commonly found bacterial phyla includes Proteobacteria, Corynebacteria, Propionibacteria, Bacteroidetes, Firmicutes and Staphylococcus spp. Amongst fungi, Malassezia spp., Cryptococcus spp., Epiciccum spp., Aspergillus spp. and Rhodotorula spp. are most commonly found. The factors that affect the prevalence and dominance of community on the skin include biological sex, skin depth, skin location (skin thickness, folds, density of hairs), age, health, geographical location, ethnicity, use of lotions, soaps, cosmetics, and antibiotics and hygiene practices.

Influence of Microbiome on Human Health
As humans are known to have a constant symbiosis with microorganisms, the human microbial community, inhabiting the various system exhibits their influence on them. There are nearly 100 trillion symbiotic microorganisms that exist on and within the human body and have shown to play very important roles both in human health and disease causation. The influence of this microbiome on various systems is as follows:

Influence of Microbiome on Maintenance of Human-Gut Environment
Amongst all the systems, the highest and heterogeneous microbial density resides in colon and is mostly codependent in nature and present along both longitudinal (proximal to distal) and axial (mucosal to lumen) gradients of the gastrointestinal (GI) tract. The microbiome has been reported to aid in food digestion, vitamin biosynthesis, bile acid biotransformation, building of innate immunity, maintenance of intestinal barrier (Valdes et al. 2018), etc. Thus, gut is an "essential organ", carrying approximately 150 times more genes than are found in the entire human genome ) (Fig. 20.1).

Metabolism
Microbial inhabitants within the host often contribute to metabolism such as: • Bile salt metabolism • Synthesis of essential and non-essential amino acids • Replication of virulence factors in enteric pathogen • Pro-drug transformation into active drugs and • Metabolism of xenobiotic compounds • Antibiotics by chemical transformation (Sarkar et al. 2018) Gut microbiota and host interaction result in the secretion of a series of metabolites including trimethylamine-N-oxide (TMAO); short-chain fatty acid (SCFA) such as acetate and butyrate; secondary bile acid; and indoxyl sulphates that activate numerous signalling pathways affecting host physiological processes (Jin et al. 2019).

Contribution Towards the Host Immune System
When a child is born, the immune system at birth is under a relative state of immaturity. The developing immune system is characterised by a skewed T-and B-cell development and a blunted inflammatory cytokine production with respect to the regulatory responses. The consequence of such an underdeveloped immune system is high susceptibility to infections. Thereby, the regulatory environment ensures the establishment of the microbiota which ultimately helps in immune regulation and limits the mucosal inflammation following their colonisation (Elahi et al. 2013).
Many intestinal bacteria also prevent the colonisation of pathogen by producing antimicrobial substances such as bacteriocin (inhibit pathogen growth), by competing for nutrition and attachment sites. This act is termed as barrier/competitive-   (Collado et al. 2010). Exposure to intestinal bacteria has also been found to prevent certain allergic responses in the hosts.
Thereby, the commensals, specifically the bacterial species and the products or metabolites derived from them, are considered as an intrinsic regulator of all the immune responses for the upliftment and restoration of human meta-organism's health (Belkaid and Hand 2014).

Gut Microbiota and Associated Diseases
Gut bacteria are intrinsically linked with the health of our entire body. However, a change in gut microbiota composition, termed as dysbiosis, can result in enhanced susceptibility of the host towards pathology. Dysbiosis can cause various diseases such as inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS), chronic kidney disease (CKD), cardiovascular disease (CVD), atherosclerosis, obesity, autism, allergy, asthma, hypertension, coronary artery disease, and heart failure (Tang and Hazen 2017;Backhed, et al., 2012).

Irritable Bowel Syndrome (IBS) and Inflammatory Bowel Disease
(IBD) IBS and IBD are related to bowel disorder with signs and symptoms of abdominal cramping, pain and bloating associated with features of disordered defecation in IBS and ongoing inflammation of all part of GI tract in IBD. Although IBS is a multifactorial disease (Soares 2014), intestinal dysbiosis has also been found associated with this disease by facilitating adhesion of enteric pathogens. IBD includes Crohn's disease (CD) and ulcerative colitis (UC). Gut microbiota has been implicated to have roles in IBD pathogenesis, and the usage of antibiotics may help in reducing inflammation or prevented the same in murine models of disease and in patients.

Chronic Kidney Disease (CKD)
Intestinal dysbiosis is most often accompanied by defective intestinal barrier function, which promotes the production of bacterial by-products that are rapidly absorbed and retains in intestinal lumen. When increased absorption is coupled with reduced clearance of these substances by the kidneys, levels of gut derived toxins rise in circulation and may potentiate vascular calcification, atherosclerosis and adverse cardiovascular functioning, which are the clinical conditions in the later stage of CKD. Numerous epidemiologic studies have shown a relationship between gut-derived vascular toxins and cardiovascular events in patient with CKD (Valdes et al. 2018).

Gut Microbiome-Associated Cardiovascular Disease (CVD)
Metabolic origin of traditional CVD risk factors such as obesity, dyslipidaemia and insulin resistance indicates close linkage between the gut microbiome and CVD. Recent studies have implicated that atherosclerosis has generated the largest amount of data in association with gut microbiome. According to a hypothesis, gut microbiota metabolites elicit inflammatory cascade by translocating into bloodstream and promote atherosclerosis. Oral bacteria causing oral cavities have also been found in atherosclerosis plaque (Clifford and Hoffman 2015). In many CVDs, heart failure is considered as end stage with a higher rate of morbidity and mortality (Jin et al. 2019). Low intestinal perfusion and disruption of intestinal barrier have been reported as reasons for reduced cardiac output and blood redistribution. The translocation of microbiota and endotoxins into blood circulation leads to an aggravated systemic inflammation that further can lead to increased chances of heart failure (Peng et al. 2018).
Various studies suggested the direct and indirect link between gut microbiota and the development of hypertension (Jin et al. 2019). It is a complex clinical condition and can be influenced by number of factors. It is considered as modifiable risk factor for CVD. In some studies, Prevotella, Faecalibacterium, Klebsiella, Clostridium and Streptococcus are found in abundance in hypertensive patients, indicating a close association of host microflora to such a clinical condition. Other studies demonstrated that reduction in gut microbial diversity, short-chain fatty acid (SCFA)-producing bacteria and increase in sympathetic drive to the gut and lactic acid producing bacteria, respectively, have direct role in blood pressure regulation. Thus, it can be concluded that blood pressure is closely linked to diversity, richness and evenness of microbiome living in the gut and the improved gut microbiota may be a target for future therapies for hypertension (Peng et al. 2018).

Human Nervous System Association with Gut Microbiota
The gut-brain axis plays a major role in central nervous system (CNS) and intestinal and immune system functioning, as mentioned earlier. Gut-brain axis is the bidirectional biochemical signalling between GI and CNS activities, integrating efferent and afferent neural, endocrine, nutrient and immunological signals, providing gut microbiota and its derived metabolites a route to access the brain (Bull and Plummer 2014; Joscelyn and Kasper 2014). Wang and Kasper illustrated that this bidirectional communication system enables brain to command GI functions such as metabolism, peristalsis, mucin production and other immunological functions.
Gut microbiota is also found to have impact on hypothalamic-pituitary-adrenal (HPA) axis, thus playing a role in body's stress response Teitelbaum et al. 2008). The gut microbiota has also been shown to synthesise neurotransmitters and neuromodulators. Various neurotransmitters produced by bacterial species are presented in Table 20.2. Those released neurotransmitter then stimulates epithelial cells to synthesise modulators within the enteric nervous system (ENS) or directly acting on primary afferent axons (McVey Neufeld et al. 2013). Moreover, it has been shown that ENS plays a major role in fundamental gastrointestinal physiological functions such as motility, fluid secretions and blood flow. Furthermore, numerous studies have revealed the correlation between microbiome, microbiota derived products, antibiotics, prebiotics and probiotics and CNS (Wang and Kasper 2014).
Anxiety and stress, characteristic mood disorders, associated with nervous, endocrinal and immunological system have also been shown to have an association with the gut microbiota. Stressors such as chemical, biological or any environmental stimuli can act as an active component to trigger the anxiety and stress response which ultimately activates the hypothalamic pituitary adrenal (HPA) axis. Intestinal dysbiosis and gut pathogens have thereby been shown to cause stress and anxiety. Animal models have represented to ameliorate these disorders by using probiotic formulations (Messaoudi et al. 2011). Various output and input of role of gut microbiota is depicted in Fig. 20.2.

Microbiome as a Paradigm for Future Nutritional and Medicinal Strategies
The analysis of microbiome of human body shows both the pathogenic as well as beneficial microbial network (Ozturk et al. 2017). Customizable medicine based on an individual's microbiome is an excellent approach for therapeutic choices based either on exercises or/and medications which considers the genetic makeup of an individual, their health condition and quality of life (Hasani-Ranjbar and Larijani 2017). Human genomes are about 99.9% indistinguishable to one another; the generally steady human gene pool does not completely clarify all the phenotypic varieties amongst people. On the other hand, the bacterial biological system, living in each human body, that contributes multiple times larger number of qualities than the human genome, could be significantly unique in relation to an individual. Therefore, the human microbiome can be regarded as the true cause of numerous responses that can influence the structure and plenitude of microorganism (Hasani-Ranjbar and Larijani 2017) in the human body.
Recently various studies have shown that intestinal microbiota is fundamentally associated with various therapeutics as in cardiovascular diseases, cancer, etc. These include narrow spectrum antibiotics along with probiotics, prebiotics and synbiotics, faecal microbiota transplantation, nutritional modulators, immune modulators and phage therapy.

Effects of Antibiotic Abuse on Microbiota
In the USA and Europe, jointly, in the year 2015, because of the onset of antibiotic resistance amongst pathogens, around 50,000 deaths were witnessed, which was projected to increase to a score of around ten million deaths per year worldwide by 2050 (Langdon et al. 2016).
In addition to the development of resistance, the usage of antibiotics has been reported to disrupt the ecology of the human microbiome. Whereby, a dysbiotic microbiome loses the capability to perform vital functions such as nutrient supply, production of vitamin, and defence against the pathogens; thereby it leads to an eventual impairment of the metabolic, immunological and developmental system of the host. For an instance, drug-induced modification of the gut microflora can influence a group of Foxp3 + Treg cells that control demyelination in exploratory autoimmune encephalomyelitis (EAE) (Ochoa-Repáraz et al. 2010). Another study reflects the antigens produced by Bacteroides fragilis (capsule polysaccharide) can protect against EAE (CNS demyelination) and further in human multiple sclerosis (Ochoa-Repáraz et al. 2011). Similarly, the effects of common antimicrobial treatments on the gut microbiota have been illustrated in Table 20.3.

Probiotics
Probiotics are characterised as live microorganisms which are not part of the human host microbiome yet give a medical advantage to the host when administered or directed in sufficient quantity. Probiotics have been extensively studied in recent years as it imparts various health benefits by the metabolites it produces in the relief from certain intestinal disorders as well as controlling EAE. Clinical trials have been able to demonstrate that certain cardio metabolic disorders (CMD), such as type 2 diabetes mellitus (T2D), dyslipidaemia and arterial hypertension, as well as chronic kidney diseases (CKD) can be managed by the ingestion of probiotics (Neto et al. 2018). Saccharomyces boulardii has been shown to exert antiinflammatory effect which helps to control inflammation related to the dysbiosis in lumen (Rodríguez-Nogales et al. 2018). Various metabolites produced by microorganisms present in the host and its associated health benefits are discussed in Table 20.4.

Prebiotics and Synbiotics
Prebiotics are those food components that cannot be digested by human body but can be selectively digested by the members of probiotics, and thereby serves as a food fibre for probiotics. Recent studies have demonstrated that the use of prebiotics can result in enhancing the ecological performance of the gut microbiota, thus promoting a much more beneficial community (Vandeputte et al. 2017). This conceptualizes that the human microbiota can be enhanced, stabilised and shifted by feeding with certain specific prebiotics such as carbohydrates. However, characterisation of the relationship between the prebiotic and probiotic is still a challenge. The point when the idea of synbiotic was first presented, two setups were proposed: first, where the prebiotic and probiotic segments were independent, each being in charge of a  Kamal et al. (2019) specific impact or medical advantage, and second, a symbiotic segment, where the probiotic was explicitly structured with a prebiotic substrate that would synergistically support the intensity, survival or metabolic movement of a related probiotic strain in the ecology of gastrointestinal system (Krumbeck et al. 2016).
As of late, two novel methodologies have been proposed for creating such synergistic synbiotics, both being dependent on their ecological function and wellness. First, the in vivo strategy which depends upon the determination and isolation of probiotic strain that would increase in number when a certain population of participants are administered with the specific prebiotic component (Krumbeck et al. 2015). Second, called as a multi-taxon insertion, depending on sequencing, based on the identification of genes, would examine the fitness of probiotic strain in relation to the type of prebiotic administered by the usage of libraries of transposon mutants . A list of prebiotics with their probiotic components are given in Table 20.5.

Faecal Microbiota Transplantation
Sometimes the mere usage of antibiotics is insufficient to treat few diseases and rather requires urgent alternatives to manage the severity of the clinical condition. This has led to the introduction of transplantation of the faecal microbiota. The process involves the separation and delivery of the faecal microbiota from stool of healthy donor to the gastrointestinal tract of the receiver patient, thereby enabling an efficient cure by normalising the microbiota composition. Recent investigations have explained the mechanism behind the faecal microbiota transplantation (FMT), which has been used to treat Clostridium difficile infection (CDI) for the restoration of the gut microbiome to gain the ability to inhibit Clostridium difficile indirectly by competing for nutrients. The faecal microbiota also prevents the colonisation by unwanted microorganism by the activation of immune system as well as by direct release of certain antimicrobial components and other metabolites that helps in the inhibition of vegetative and as well as the sporulated disease-causing organism (Khoruts and Sadowsky 2016). Table 20.6 shows the list of diseases and infections which can be treated by using FMT.

Nutritional Modulators
Intake of dietary medications for a long period of time impacts the structure and function of microbiome of the human body. The change in the availability of nutritional content of the diet causes corresponding alteration of the human microbiome. Recent findings have suggested that depending upon the intake of dietary, the microbiome richness diversifies. The lower is the genetic richness of microbiome; the lower will be the immune status of the person, relating to abnormal metabolic function and poor anti-inflammatory activity (Cotillard et al. 2013;Le Chatelier et al. 2013). The diet patterns may even contribute in managing different diseases (Table 20.7) by way of microbiome.

Immune Modulators
Microbiome-based approaches involving antibiotics, probiotics, prebiotics and synbiotics, faecal microbiota transplantation and nutritional modulators correlate directly with the alteration of immune status of an individual focusing on the innate immunity. Thereby, the human microbiome is being affected for benefits with the change in immune status. Until now, there are inadequate information in this method; however, treatment of inflammatory diseases using steroids is in abundance.
Intestinal innate and acquired immunity as well as systemic acquired immunity involves various mechanisms for the control of gut microbiome. Some of them include change in barrier function, expression of leptin, molecule β, human leukocyte antigen (HLA) class I and class II loci, activation of toll-like receptors, natural killer cells, CD4+ cells and Foxp3+ as well as the production of antimicrobial Competition for nutrients; direct suppression by antimicrobial peptides; bile-acid-mediated inhibition of spore germination and vegetative growth; activation of immune-mediated colonisation resistance Khoruts and Sadowsky (2016) Ulcerative colitis (UC) Increasing the production of short-chain fatty acids, (butyrate); inhibitingTh1 differentiation, activity of T cells, leukocyte adhesion; production of inflammatory factors Shen et al. (2018) Irritable Bowel Syndrome (IBS) Visceral hypersensitivity; altered barrier function, gastrointestinal motility and the gut-brain axis Grover et al. (2014) Obesity Decrease adiposity; Alter metabolic phenotype by increased bacterial diversity Marotz and Zarrinpar (2016)  Obesity Henning et al. (2018) peptides and α-defensins (Ticinesi et al. 2019) for the proper functioning of the gut microbiome.

Phage Therapy
Phage therapy involves the introduction of explicit bacteriophages that targets a microorganism which in turn has the ability to generate a beneficial microbiome shift. However, a limitation to this strategy is the simultaneous resistance offered by the microorganism in play which is yet to be proven. Till date, none of the phage therapy approaches have been established as an FDA-approved drug. Recently, scientists are working hard to perform phage based killing of microbes, but it is much more complicated. CRISPR (clustered regularly interspaced short palindromic repeats) is one of the approaches to advance the limitations (LeMieux 2019). It is a tool derived from prokaryotic immune system empowered to study and modify organisms with ease and efficiency. The system helps to modify the gut genome of gut microorganisms and bacteriophages. This engineered CRISPR-Cas system ultimately can control gene expression and modulate production of metabolite and protein presenting a new approach for the development of drugs that can target the microbiome (Table 20.8).

Conclusion
Although these interventions are used as medicinal and nutritional strategies and have been clinically experimented for a successful result, more focus and deliberate attempts are being made for the establishment of such casualty in order to define the functional metabolic change. These therapies are yet not so widely utilised due to the requirement of huge amount of money and time. Hence, advancement in this field targeting the relation of human microbiome with health and diseases, identification of the composition and activity of microbiome as well as linking it, and most importantly using technical resources such as bioinformatics to incorporate and fill up the loopholes ascertaining to the models is quite difficult. Future research based on these directions is a key to solve the problems and hence enlightening with knowledge about the human microbiome and their influence on the human health.