The gut microbiome is comprised of various types of bacteria, fungi, protozoa, and viruses naturally occurring in humans and animals as normal microflora. Gut microorganisms are typically host specific, and their number and type vary according to different host species and environment. Gut microbes contribute directly and/or indirectly to various physiological processes including immune modulation, regulation of various neurotransmitter, and hormones, as well as production of many antioxidants and metabolites. They also play a role as antibiotic, anti-inflammatory, anti-diabetic, and anti-carcinogenic agents. Moreover, the ability of gut microbes to attenuate various systemic diseases like coronary heart disease, irritable bowel syndrome, metabolic diseases like diabetes mellitus, and infectious diseases like diarrhea has recently been reported. Current research findings have enough evidence to suggest that gut microbiome is a new organ system mainly due to the microorganisms’ specific biochemical interaction with their hosts and their systemic integration into the host biology. Investigations into the potential ability of gut microbiome to influence metabolism inside their host via biochemical interaction with antibiotics and other drugs has recently been initiated. This chapter specifically focuses on the importance of gut microorganisms as a new organ system.
- gut microbiota
- metabolic disorders
- gut health
- drug metabolism
Certain microorganisms have the unique ability to populate the human gastrointestinal tract and thus generally referred as gut microbiota. Gut microbiota is always non-pathological, and hence, the immune system is not triggered because of their presence. Humans co-evolved with a huge number of intestinal microbial species that offer to the host certain benefits by playing an important role in preventing them from pathogenic activities . In addition to metabolic benefits, symbiotic bacteria benefit the host with various functions like boosting the immune homeostasis and inhibiting the colonization by other pathogenic microorganisms. The ability of symbiotic bacteria to inhibit pathogen colonization particularly in the gut is mediated via several mechanisms including direct killing of pathogen, competition for limited nutrients, and enhancement of immune responses . The intestinal microorganisms also co-evolved and have strong affiliations and association towards each other. In this evolutionary process, the persistent and enduring members of this microflora become more competent during unsettling influences and thereby become essential for human health . Definite composition of human microbiome varies between individuals  particularly among lean and obese people. The microbiome is also affected by the dietary modifications adapted for the weight loss . Examination of metabolic profiles of human infant microbiota revealed that ingestion, storage and digestion of dietary lipids were explicitly regulated by the microbiome [6, 7].
The human gut microbial communities are a mixture of microorganisms. The classes of microbes that constitute the gut microbiome communities differ between hosts. The difference is attributed to factors such as, inability of a microorganism to migrate between different hosts, intense environmental conditions inside and outside host’s gut and host inconsistency in terms of genotype, diet, and colonization history . The co-evolution of humans and their symbiotic microorganism has created bilateral interactions which are important for the health of humans, and any genetic or ecological change in this bilateral interaction can result in pathological conditions like infection . Gut microbial communities are important for diverse host functions, including metabolism, fertility, development, immunity, and even antioxidant activities which promote health and fitness of the host [9, 10, 11, 12]. The gut microbiome has a much larger genetic variety compared to the genome of the host, e.g., human genome is comprised of 20-25,000 genes whereas microbiome inhabiting the body is estimated to be in trillions. Almost 1010 microorganisms enter the human body daily and with the progress of co-evolution of gut microbes in humans, the capability of microbes to exchange their genes and associated functions with the environment are some of the main factors leading to host adaptation. Therefore, the “hologenome” model appraises the host and its microbes genomes as one unit under assortment [13, 14]. It is acknowledged that host-symbiont co-evolution is accountable for basic biological aspects. In this chapter we aim to discuss the importance of gut microbiomes as a new organ system because of its association with the genetics and its role in the disease and health condition of the host. Moreover, the involvement of these microbiomes in shaping the overall health and constructing a symbiotic relationship with their host species is discussed as well as the co-evolution of gut microbes with the human body.
2. Inheritance of microbiome
A microbiome is the community of microbes dwelling collectively in a selected habitat. Humans, animals, vegetation, soils, oceans or even buildings have their own specific microbiome .
2.2 Host genetics and gut microbiome
The human gut environment is extremely complex with a unique ecology which comprises of trillion of microbiota with approximately 1.5 kg in mass. By using genetic techniques like 16S sequencing, 1000 microorganisms have been identified within the gut, with approx. 200 (0.5%) defining the core of the intestine microbiome . These bacteria protect the gut epithelial cells against external pathogens. They also help the breakdown of indigestible dietary polysaccharides in the gut and thus supply a quick chain of fatty acids, including acetate, butyrate, and propionate, which serve as vital metabolites for direct energy source of intestinal epithelial cells, prevention of insulin resistance and modulators of insulin secretion  (Figure 1).
The genetic makeup of humans is virtually identical, yet the small differences in DNA give rise to remarkable phenotypic assortment across the human population. The trillions of microbes inhabit our bodies and create complex, body-habitat-specific, adaptive ecosystems that are finely tuned to frequently changing host physiology . A healthy “functional core” is actually a complement of metabolic and other molecular functions that are performed by the microbiome within a particular habitat but are not necessarily provided by the same organisms in different people .
2.3 Inherited microbiomes
The gastrointestinal tract (GIT) of humans is colonized by a vast variety of microbial population that can be understood as a complex and polygenetic trait which has been interacting and co-evolved with their host genetic environment [20, 21, 22]. It was previously considered that fetus lives in a germ free environment in the mother womb and the gut microbiota are transferred to the baby from mother’s birth canal and body via horizontal transmission only . But advanced researches have revealed that microbiota are also vertically transmitted to the infants from their mothers . Presence of microbes in the meconium of the babies born by cesarean section clearly demonstrates that the gut microbes are not only derived after the birth [25, 26]. Moreover, presence of many microbes in the umbilical cord blood of the preterm babies and in the amniotic fluid substantiate the findings that the fetus in the mother womb is not totally sterile [27, 28]. Many gut bacterial genera are shared among the mammal species. The microbiomes of mice show strong fidelity throughout the generations and reiterate the intrinsic significance of these microorganisms in health.
2.4 Relationship of environment in shaping the microbiome
As mentioned above human intestinal microbiome composition is shaped by multiple factors like genetics, diet, environment and lifestyle. Several studies point towards stronger contribution by the environmental factors in shaping the gut microbial composition compared to the genetic factor . It has also been speculated that gut microbial diversity affects the prediction accuracy for certain human traits including glucose and obesity problems, as compared to different animal models that use only host genetic and environmental factors .
2.5 Co-evolution and co-differentiation of host microbe interaction in exploring new drug targets
Horizontal gene transfer (HGT), genomic and metagenomics are possible approaches to identify drug targets that may also be considered as an evidence of co-evolution of hosts and their symbionts. Symbionts have the capacity to perform many metabolic activities including fermentation of dietary carbohydrates, drug metabolism, antimicrobial protection and immunomodulation, which is primarily due to the presence of genes in their genome which are missing in mammalian genomes. Therefore, horizontal gene transfer mechanisms are potential targets for drug discovery that become more evident with the use of gnotobiotics (germ free animal) in experimental trial to unveil the microbial function in the complex GIT microenvironment, and to investigate how orally administered drugs impact the gut microbial ecology in long term. HGT has gained immense interest in medical field as it contributes to the spreading of antibiotic resistance genes as well as it may cause closely related microbial strains to differ drastically in terms of clinical parameters . Genetic variation in intestinal microbes may trigger the production of metabolites, but it may also generate changes in host’s genome that may increase metabolite uptake or prevent their further synthesis. Co-evolution may lead to co-differentiation since permanent association of host and symbiont lineage can result in diversification . The co-differentiation correlate resemblances in the microbial symbiont and the host [33, 34] which can be extended to an entire microbial community that passes vertically from host to offspring. Over the course of speciation, the microbial communities differentiate as a mirror to host phylogeny (such situation would be expected in hosts where parents immunize their offspring with microbial clique, e.g., Koala bear mother inoculate “pap” with dropping to shift young one from milk to eucalyptus leaves diet) . Fecal microbiome from healthy humans is a mirror of distal gut microbiome which is highly rich in genes involved in the vitamin synthesis, breakdown of nutrients, and metabolism of xenobiotics as compared to already sequenced human genome and microbes genome . The presence of conjugate transposons in gut microbiome is another important source of horizontal gene transfer in bacteria . The HGT is involved not only in spreading antibiotic resistance genes, but also as a source of clinical response of closely related microbial strains of
Novel strategies in drug discovery are being pursued by targeting horizontal gene transfer involved in the resistance to antibiotic  as well as virulence . Targeting virulence factors with Salmonellosis inhibitors causes less damage to indigenous microbes compared to traditional antibiotic therapy, less selective pressure for evolution and transfer of resistance and may be more effective against divergent organisms that have acquired a particular virulence factor by HGT. Genomic islands which are a good source of genes and gene transfer systems are also being targeted with small molecule inhibitors that are co-administered with antibiotics to prevent resistance factors by targeted pathogenesis during the therapy .
2.5.1 Co-evolution of drug transporters in host and microbes
It has been established that the majority of molecules possessing physiological or pharmacological features are either transported into and or out of the cells by transporting proteins rather than by a passive transport mechanism where drug molecules cross cell membranes through solute transporters that are already involved in the movement of different metabolic intermediary molecules through channels. More than 1000 different types of transporting proteins (transporters) are present in humans  comprising solute carriers (SLC) and ATP binding cassettes (ABC) transporters involved in the transport of a broad range of substrates .
Human intestinal peptide transporter 1 (hPepT1) belonging to the proton-coupled oligopeptide transporter (POT) family which is also known as solute carrier 15A (SLC15A) is present in the enterocytes, the PepT2 (oligopeptide transporter 2, SLC15A2) in kidney, the PHT1 (peptide histidine transporter 1, SLC15A4) in brain and the PHT2 (peptide histidine transporter 2, SLC15A3) located in spleen, lungs and thymus. Both hPepT1 and PepT2 mediate the transport of di−/tri-peptides and a broad range of peptidomimetics in the organisms, whereas PHT1 and PHT2 mediate the translocation of histidine and with a few selected di- and tri-peptides . The hPepT1, an oligopeptide transporter 1 located in the enterocystes of the small intestine, has low affinity and high capacity transporter protein to transport 400–800 different dipeptides and tripeptides and drugs like ACE’1 (Enalapril) and antiviral (acyclovir) . The hPepT1 is also found in microbes like
Passive diffusion and secondary transport mechanisms in bacteria may involve uptake of drug into bacterial cytoplasm [52, 53]. In the inner membrane of
3. Microbiome association with diseases
As described above microorganisms present in the gut of the living organisms contribute to health or cause disease of these organisms by interplay with their immune system. Microbiome is developed at birth according to host interaction but later it is evolved and modified by surrounding factors like environmental and diet. The variation in genetic expression of different individuals is thought to be linked with different microbial composition . Genotype of the host affects the composition of gut microbes. Even mutation of a single gene can cause modification in the structure of gut microbiota. The exact mechanism of association between the gut microbes and the genotype of host is still unknown. Bifidobacteria are highly prevalent beneficial bacteria in gut microbiome and are associated with lactase non-persistent genotype. This genotype is responsible for the synthesis of lactase enzyme which helps to digest the lactose, present in the milk. Absence of this enzyme leads to lactose intolerance in different organisms. So it is important to investigate susceptibility of different underlying pathological conditions by studying microbiomes association with genotype and environmental factors that vary among different human populations .
Different studies showed that metabolic disorders are largely congenital and are associated with different microbiomes. For example, gut microbiomes have been linked to metabolic disorders and obesity .
3.1 Gut microbes and gastrointestinal tract (GIT) diseases
In gut microbiome, dysbiosis (imbalance of microbial flora) can be induced by host factors and/or external factors such as the intake of antibiotics, mental and physical stress, and nutrients in the diet. Dysbiosis is likely to impair the regular gut microbiota and the appearance of pathobionts and the production of metabolites which may be dangerous to the host or may deregulate beneficial microbial-derived metabolites. The microbial symbiosis has a significant role in the development of many diseases  such as the gastrointestinal diseases [61, 62], infections , metabolic disorders, liver diseases , autoimmune diseases , mental or psychological diseases  and respiratory diseases .
3.1.1 Inflammatory bowel disease
The inflammatory bowel disease (IBD), which includes Crohn’s disease (CD) and ulcerative colitis (UC), has for quite some time been suspected to be a host reaction to its gut microbiota. CD represents the chronic inflammation of the GIT (involving any part from mouth to anus) with idiopathic etiology while UC is the chronic inflammation of the large bowel of the GIT with no known cause. Numerous aspects of the microbiota’s association in IBD have been inspected in recent years. About 10–20% of adults and adolescents worldwide are affected by IBD . The precise cause of IBD is unidentified, but it is believed to be a multifactorial disease. Inflammation, infection, visceral hypersensitivity, immunity, genetic factors, motor dysfunction of the GIT as well as psychopathological factors are suspected to play a role in its development . Moreover, abnormal gut microbiota has been noticed in the IBD patients and in animals with intestinal inflammatory disease [70, 71, 72, 73]. Some of the metabolically active anaerobic bacteria in the colon and terminal part of ileum interact with the immune system of epithelium and mucosal layer of the host intestine. Continuous stimulation of these microbial antigens promote pathogenic immune responses and may cause defects in the barrier functions of mucous layer by killing some beneficial bacteria or by immune dysregulation, consequently resulting in UC and CD. Moreover, disrupted microbiota structure and function in inflammatory bowel disease intensify the immune response of the host causing dysfunction of epithelium and increased permeability of the mucous layer of the intestine .
It is difficult to identify a single factor responsible of IBD; however, several observations have demonstrated a change in the gut microbial composition in IBD patients, both CD and UC . Even though the gut microbiota has been recognized as responsible for the IBD establishment in non-predisposed hosts, numerous researches have revealed a high rate of pathogenic
3.1.2 Gastric cancer
For gastric cancer,
3.1.3 Colorectal cancer
Worldwide, the colorectal cancer (CRC) is the fourth most common cause of death associated with cancer . Like other cancers, the CRC is a complex disease related to environmental and genetic factors. Ongoing research has proposed that gut microbiota assumes a role in the convergence of these factors, likely through forming a tumor-advancing environment.
In certain studies, by using a germ-free mice model of adenomatous polyposis coli (APC), a markedly reduced incidence of colonic tumor and a lower tumor load was revealed when compared to normally raised mice. Further other distinct CRC phenotypes such as bleeding from rectum and iron deficiency has also been shown with an invasion of inflammatory cells emerging from an intestinal epithelial barrier dysfunction. Therefore, it seems that the microbiome and host factors (for example, age and genetic predisposition) are important to the CRC growth and progression .
3.2 Role of gut microbiota in cardiovascular diseases
Cardiovascular and metabolic disorders are collectively known as cardiometabolic diseases and are associated with high morbidity and mortality along with significant health care expenditures . The gut-derived and endogenously produced endotoxins including indoxyl sulfate,
3.3 Microbiota and integumentary system
The gastrointestinal (GI) system and skin are highly vascularized and densely innervated organs with crucial neuroendocrine and immune roles which are uniquely related to the normal function of skin . Evidence of bidirectional and intimate connection between the gut and skin health as well as a close link between GI health to skin allostasis and homeostasis has been established . GI disturbances resulted often in cutaneous manifestations and the GI system, especially the gut microbiota, appears to participate in the pathophysiology of many inflammatory diseases, i.e., acne, atopic dermatitis and psoriasis [92, 93].
3.3.1 Role of the gut microbiota in skin homeostasis
The mechanism by which GI flora exert their effect on skin homeostasis is still unknown; however it is postulated that probably such effect may be related to the modulatory influence of gut commensals on the systemic immunity . Certain gut microbiota and their metabolites, i.e., polysaccharide A, retinoic acid from
In cases of disturbance in intestinal barriers, it was found that intestinal bacteria and their metabolites may have the propensity to accumulate in the skin and have also access to the bloodstream which ultimately disrupts skin homeostasis. In fact, DNA of intestinal microbes has been separated from the plasma of psoriatic patients, thus showing a direct connection between the gut microbiota and skin homeostasis . The short chain fatty acids (SCFAs), i.e., acetate, butyrate and propionate resulting from the fermentation of the fibers in GIT are believed to play an important role in the maintenance of certain skin microbiota which consequently affect cutaneous immune defense system. For example, propionic acid has an antimicrobial effect against the most common community-acquired methicillin-resistant
3.3.2 Dyshomeostasis due to dysbiosis
Intestinal dysbiosis may have the negative potential to affect the skin function since gut microbial flora has a huge potential to produce molecules, both harmful and beneficial, that could then reach the circulation and influence skin. Metabolic products of aromatic amino acids, i.e.,
3.4 Gut microbiome and pulmonary health
Infectious diseases of the respiratory tract including pneumonia and influenza result in deaths of approximately 3.25 million people annually . The majority of the therapies being used currently are suboptimal because the problems of efficiency, toxicity and antibiotic resistance are difficult to overcome . Most of the respiratory tract infections represent failure of host’s immune defense. Recently, it was suggested that gut microbiota plays a crucial role in the initiation and adaptation of the immune response in other distal mucosal sites including lungs. Therefore, it is of interest to understand the underlying mechanisms that regulate the interplay between lung defense and gastrointestinal tract and how this interaction aids in achieving optimal lung health.
3.4.1 Asthma and allergies
An abnormal T-helper type 2 (Th2) cell responses is often associated with asthma and allergies. The Th2 cells are recognized by their ability to synthesize inflammatory cytokines including IL-13, IL-9, IL-5 and IL-4  Evidence suggests that the development of allergic diseases in lung is directly affected by alteration in gut immune response . In fact, a single oral dose of
3.4.2 Viral and bacterial respiratory infections
Gut microbiota also plays a critical role in the immune response to respiratory tract viral infections like influenza. In infected mice, the CD8 and CD4 T cell subpopulations are directly influenced by the intestinal microbiota . It has also been suggested that an intact intestinal microbiota is necessary for the expression of pro-inflammatory cytokines including pro-IL-18 and pro-IL-1β, which are essential for clearance of influenza . This indicates that microbial signals are provided by gut microbiota which are crucial for the shaping and priming the immune response to viral pneumonia.
Similar findings regarding the role of gut microbiome in immune response to respiratory bacterial infections have also been observed in germ-free mice. These mice were found to be more susceptible to pulmonary infection caused by bacterial pathogen
3.5 Gut microbiome and pregnancy
All systems of the body including maternal microbiome are affected by pregnancy. Changes in gut and vaginal microbiome during gestation are of particular significance because during vaginal delivery there is vertical transmission of microbes to the newborn [106, 107, 108]. During pregnancy the vaginal microbiota composition changes throughout the gestation period. In addition to vaginal microbiome, the maternal intestinal microbiome also undergoes change during pregnancy. It has been reported that bacterial diversity decreases in women as the pregnancy progresses . Particularly, the ratio of pro-inflammatory
The consequences of changes in maternal vaginal and gut microbiota on mother health are not clear; however, the gestational changes in fecal and vaginal microbiota are considered to be important for the adaptive response necessary for protection as well as to promote the fetus health. These changes also help in providing a particular microbial inoculum to the newborn at birth before its exposure to other environmental microbes. Also the microbial communities’ composition in maternal vagina and gut are not independent of each other. In fact, in pregnant women of 35–37 weeks of gestation most of bacteria, including species of
Some research studies reported that shift in gut microbiota of mother during pregnancy may be an adaptive response for the mother and newborn health. In mice, an increase in the gut bacteria associated with gestational age, promotes body weight gain indicating a co-evolution of these microbes with their hosts during pregnancy . Moreover, during vaginal delivery, the vertical transmission of these maternal gut microbiomes to the neonate may help the newborn to get an immediate access to microbiota at birth [107, 111].
4. Role of gut-microbiome in brain physiology
Both extrinsic and intrinsic factors play an important role to regulate the development and maturation of the central nervous system (CNS) in humans. In germ-free and antibiotic-treated animals the physiology of the CNS can be affected by neurochemistry as well as by specific microbiota . Evidences for interaction between neuropsychiatric and gastrointestinal pathology in humans have been reported in different psychiatric conditions including autism, depression and anxiety .
The role of gut-brain interaction in the nervous system development is also recognized. Gut-brain axis actually establishes a relationship between gut-microbiota and their interaction with brain leading to changes in the status of the CNS. The dysbiosis in microbial species of the gut may lead to induce imbalance in host homeostasis, atypical immune signaling and ultimately progression of CNS diseases .
The permeable blood brain barrier (BBB) and functional lymphatic vessels residing in dura meningeal membrane may serve as a gateway for transmission of signals . The exposure to several environmental factors can affect the generation of neurons during the development of the CNS . It has been suggested that maternal-fetal interface permeability permits regulatory factors from the gut microbiota to stimulate Toll-like receptor 2 (TLR2) that helps to promote neural development of fetus and also impart its effects on cognitive function during adulthood .
The combination of microbial strains (especially the probiotic) can actively counteract the deficient neurogenesis which further strengthen the developmental link of microbiome to the hippocampal neuronal generation . The brain-blood barrier (BBB) is a highly selective and semipermeable barricade that permits the passage of neutral, low molecular weight and lipidic soluble molecules . In the development of the structural components and growth of vasculature, BBB requires arachidonic acid (AA) and decohexaenoic acid (DHA) which are provided as polyunsaturated fatty acids (PUFA) by gut microbiome . It has been demonstrated that the restoration of BBB is possible in germ-free mice by colonization of
5. Impact of different environmental conditions on gut microbiome
The most important environmental factors that may lead to dysbiosis include (i) Physical or psychological stress, (ii) use of antibiotics, and (iii) diet (Figure 2).
5.1 Physical or psychological stress
Stress is usually defined as homeostasis disruption due to physical, psychological or environmental stimuli known as stressors leading to adaptive behavioral and physiological response in order to restore homeostasis . The effect of both psychological and physical stress on gut microbiome is widely recognized and has been observed in both humans as well as animals . Some research conducted in mice has shown that the microbial composition in the cecum was altered in response to the exposure of a social stressor by placing an aggressive male mouse into the cages of non-aggressive mice. Furthermore, the plasma concentration of stress hormones such as adrenocorticotropic hormone (ACTH) and corticosterone was found to be significantly higher in germ-free mice as compared to specific pathogen-free mice. In addition, several stressors including acoustic stress, self-control conditions and food deprivation have a negative impact on the gut microbiome resulting in the impairment of the immune system [123, 124].
5.2 Use of antibiotics
It has been observed in both humans and animals that the treatment with antibiotics can result in a decreased population of beneficial bacteria including
5.3 Diet and obesity
Food is metabolized by the gut microbial species to extract nutrients, but some microbial species are more efficient in extracting nutrients from food as compared to other species. As different individuals have slightly different microbial populations, it is probable that more nutrients are harvested by some people’s gut microbes making them perhaps more prone to become overweight. A high percentage of
The human body is a super-organism consisting of 10 times more microbial cells than our own body cells. The body’s assortment of microorganisms is mainly in gastrointestinal tract, collectively called the gut microbiota. It can be comparable to an organ in because it performs functions necessary for our survival by contributing directly and/or indirectly in various physiological processes. For the past decade, human gut microbiota has been extensively studied as many scientists believe that human health mainly depends on microbes that are living on or in our body apart from our own genome. Recently, research findings have suggested that gut microbiome is evolving as a new organ system mainly due to its specific biochemical interaction with its host which affirm its systemic integration into the host physiology as gut bacteria are not only critical for regulating gut metabolism, but also important for other systems of host including immune system. The focus of this chapter was to highlight the importance of gut microorganisms as a new organ system and their possible involvement with host systems as well as the metabolism of different drugs and nutrients in the gut by these microbes. So, in this chapter, we have reviewed opinions of different researchers about the role of gut microbiota in maintaining health as well as its contributory role in different ailments. However, literature revealed that the involvement of gut microbiota in altering host genetics effecting disease progression needs further investigations.
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