**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 [20–22]. 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 [23]. But advanced researches have revealed that microbiota are also vertically transmitted to the infants from their mothers [24]. 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 [29]. 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 [30].

#### **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 [31]. 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 [32]. 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) [35]. 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 [4]. The presence of conjugate transposons in gut microbiome is another important source of horizontal gene transfer in bacteria [36]. 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 *Salmonella enterica* [37] such as the secretory system type III pathogenicity islands encoded by SPI-I and SPI-II (virulence genes are present in pathogenicity islands, and play a key role in the pathogenesis of *Salmonella* infections through invasion in host cell. Currently, 12 *Salmonella* pathogenicity islands have been investigated with common motifs) [38].

Novel strategies in drug discovery are being pursued by targeting horizontal gene transfer involved in the resistance to antibiotic [39] as well as virulence [40]. Targeting virulence factors with Salmonellosis inhibitors causes less damage to indigenous microbes compared to traditional antibiotic therapy, less selective pressure

**179**

*Gut Microbiome: A New Organ System in Body DOI: http://dx.doi.org/10.5772/intechopen.89634*

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

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 [42] comprising solute carriers (SLC) and ATP binding cassettes (ABC)

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 [44]. 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) [45]. The hPepT1 is also found in microbes like *Escherichia coli* residing the gut [46, 47] to uptake amino acids and on the microbial outer membrane channels (OmpC and OmpF) present in *E coli* [48] *S. typhi* [49] and *H. influenza* to uptake small and hydrophilic nutrients pos-

Passive diffusion and secondary transport mechanisms in bacteria may involve uptake of drug into bacterial cytoplasm [52, 53]. In the inner membrane of *E. coli,* four protein transporters (PTR) namely YdgR or permease A (DtpA), YjdL, YhiP, and YbgH have been characterized as family members belonging to POT. Among these peptide transporters, the DtpA mediates the transport of dipeptides and tripeptides, thereby exhibiting peptide selectivity very similar to the human oligopeptide transporter (hPepT1) in gut enterocytes [54, 55]. These findings emphasize the potential of modifications of the human physiological state by indirectly modifying

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 [57]. 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

resistance factors by targeted pathogenesis during the therapy [41].

transporters involved in the transport of a broad range of substrates [43].

*2.5.1 Co-evolution of drug transporters in host and microbes*

sessing a molecular weight lower than 600 kDa [50, 51].

the microbiome through drugs [56].

**3. Microbiome association with diseases**

#### *Gut Microbiome: A New Organ System in Body DOI: http://dx.doi.org/10.5772/intechopen.89634*

*Parasitology and Microbiology Research*

**in exploring new drug targets**

**2.4 Relationship of environment in shaping the microbiome**

models that use only host genetic and environmental factors [30].

**2.5 Co-evolution and co-differentiation of host microbe interaction** 

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 [31]. 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 [32]. 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) [35]. 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 [4]. The presence of conjugate transposons in gut microbiome is another important source of horizontal gene transfer in bacteria [36]. 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 *Salmonella enterica* [37] such as the secretory system type III pathogenicity islands encoded by SPI-I and SPI-II (virulence genes are present in pathogenicity islands, and play a key role in the pathogenesis of *Salmonella* infections through invasion in host cell. Currently, 12 *Salmonella* pathogenicity islands have been investigated with

Novel strategies in drug discovery are being pursued by targeting horizontal gene transfer involved in the resistance to antibiotic [39] as well as virulence [40]. Targeting virulence factors with Salmonellosis inhibitors causes less damage to indigenous microbes compared to traditional antibiotic therapy, less selective pressure

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 [29]. 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

**178**

common motifs) [38].

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 [41].

## *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 [42] comprising solute carriers (SLC) and ATP binding cassettes (ABC) transporters involved in the transport of a broad range of substrates [43].

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 [44]. 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) [45]. The hPepT1 is also found in microbes like *Escherichia coli* residing the gut [46, 47] to uptake amino acids and on the microbial outer membrane channels (OmpC and OmpF) present in *E coli* [48] *S. typhi* [49] and *H. influenza* to uptake small and hydrophilic nutrients possessing a molecular weight lower than 600 kDa [50, 51].

Passive diffusion and secondary transport mechanisms in bacteria may involve uptake of drug into bacterial cytoplasm [52, 53]. In the inner membrane of *E. coli,* four protein transporters (PTR) namely YdgR or permease A (DtpA), YjdL, YhiP, and YbgH have been characterized as family members belonging to POT. Among these peptide transporters, the DtpA mediates the transport of dipeptides and tripeptides, thereby exhibiting peptide selectivity very similar to the human oligopeptide transporter (hPepT1) in gut enterocytes [54, 55]. These findings emphasize the potential of modifications of the human physiological state by indirectly modifying the microbiome through drugs [56].
