1.8.1 Composition

The GI tract has evolved to become a functional organ comprising anatomically distinct areas. The digestive process starts in the oral cavity, then moves through the stomach, small and large intestine and finally the rectum. This passage allows the presence of several microbial niches due to different environmental conditions, such as acidity in the stomach, varying retention times and different nutrient availabilities (Table 1.8.1). Physicochemical variables are contributing factors to the diverse community of micro-organisms residing in the GI tract (see Table 1.8.1). Within the intestinal tract, genomic analysis has shown the number of micro-organisms to be approximately 10¹³ to 10¹⁴ in total [5], with the overall microbiome (the combined genome of all the micro-organisms) approximately 100 times greater than the human genome [4]. Within the large intestine, there is also variation in diversity of species within specific compartments, such as the mucosa, lumen and epithelium [6]. The small intestinal sites, duodenum, jejunum and ileum, also comprise differing numbers and species.

Micro organisms residing within the GI tract carry out many necessary roles, for example in metabolism, immune defence and GI physiology [7]. Some are associated with health benefits whereas others are known to be potentially pathogenic. Lactobacilli and bifidobacteria are associated with many positive effects and have been used in various health food products as probiotics. A possible reason for this could be their ability to prevent commensal and potentially pathogenic microbial population levels from increasing through various inhibitory mechanisms [8–11]. Potential pathogens include Clostridium difficile, Escherichia coli and Helicobacter pylori which have been connected with antibiotic-associated diarrhoea, vomiting and stomach ulcers respectively [12,13].

Although each individual has a distinctive microbiome, the majority of key players remain the same but in varying quantities.

1.8.2 Functions of the human gastrointestinal tract

A main function of the GI microbiota is modulation of the immune system. Germ-free mice have been extensively used in studies investigating the involvement of the microbiota in immune response development [14]. The microbiota can form a protective barrier which decreases the chance of pathogen invasion by possibly occupying receptor sites in the GI tract [14]. The micro organisms compete by several different mechanisms, such as nutrient scavenging, receptor occupation and the production of antimicrobial substances, which can elicit a specific or non-specific effect such as the modulation of pH. Antimicrobial substances produced in the GI tract include acids, antimicrobial peptides (AMPs), defensins, cathelicidins and C type lectins, all of which are capable of targeting bacterial cell walls, thus controlling population levels of commensal organisms or aiding protection against pathogens [15,16].

Competition plays a vital role in immune defence, helping to prevent potential pathogen invasion. Specialised GI tract lymphoid tissues produce secretory immunoglobin A (IgA) [17] which neutralises receptors on target bacteria, allowing some control over the GI microbiota [18]. Activation of IgA is due to localised GI dendritic cells, which sample the luminal micro organisms; therefore antibodies against GI microbiota have already been developed.

A number of features aid in the control of GI population levels, for example IgA and AMPs. Dendritic cells (DCs) are specialised white blood cells which act as antigen-presenting cells (APCs); they sample the intestinal lumen, and therefore GI microbiota, and are able to secrete antibodies to neutralise any potential growing threat [18]. Distinguishing between threats involves Toll-like receptors which are expressed on eukaryotic cells; these have a unique function of recognising conserved regions within bacterial membranes [19]. Due to this ability, signalling molecules such as cytokines can elicit an inflammatory response [20]. Antimicrobial peptides have the ability to work across the GI tract; they are localised towards the intestinal mucosa, preventing the expansion of microbes throughout the lumen and minimising contact with host GI tract epithelium [21]. Lactic acid bacteria produce lactate and acetate, which can be detrimental to other microbes, through their ability to disrupt bacterial outer membranes [22].

The GI tract must also be able to tolerate microbes and not always elicit an immune response. This can be achieved in three different ways: a physical barrier between host cells and bacterial cells, antigen modification on bacterial cells or modifying immune responsive cells in the GI tract [14]. DC’s are specialised in the GI tract to induce and stimulate T-cell differentiation into T-helper cells and T-regulatory cells, an alternative to cytotoxic T-cells which can damage the GI tract epithethial lining [23]. Another potential problem is lipopolysaccharide (LPS) on the gram-negative bacterium’s outer membrane; host recognition of LPS can lead to septic shock or low-grade chronic inflammation [24]. To overcome this, LPS toxicity can be reduced by phosphorylation [25]. In mice, it has been shown that GI epithelial cells inherit a tolerance to LPS endotoxin [26].

Bacterial metabolism is a key part of the microbiota. They are able to breakdown non-digestible food products into short-chain fatty acids (SCFA). Such substrates include non-starch polysaccharides (NSP), starch, oligosaccharides, proteins and amino acids [27]. These organic acids can be used for growth and energy, not only for themselves but as a secondary source for the host [28]. Acetate, propionate and butyrate are the main SCFAs produced and have various impacts on human metabolism and the immune system [28,29]. Butyrate is involved in cytokine development as an essential signalling molecule and provides structural aid in the intestinal epithelium; it also stimulates apoptosis and therefore is an important growth regulator for colonocytes [30,31]. Acetate can aid intestinal inflammation during an immune response, allowing for more immune cells to translocate to the infected site via G-protein-coupled receptors. Acetate is also metabolised in muscle and other systemic tissues [32]. Propionate has been shown to lower cholesterol concentration [33]. SCFAs also have abilities in AMP generation, aiding in immune system defence [5].

Studies have shown that microbial GI composition plays a role in human brain development and behaviour, with germ-free mice displaying higher anxiety issues and less motor control than conventionally raised animals [34]. Bifidobacterium infantis has been shown to regulate the metabolism of tryptophan, an amino acid involved in the production of serotonin showing a potential link between GI micro-organisms and neurotransmitter concentrations [35]. As such, the GI microbiota may have an additional impact on host psychology. The microbiota have also been shown to interfere with the hypothalamic-pituitary-adrenal axis – interactions between the hypothalamus, pituitary and adrenal glands [36]. The GI microbiota have been associated with the control of different signalling molecules such as neurotransmitters. These connections suggest that the GI microbiota have an impact on host response to stress as well as mood/psychological disorders [37,38].

1.8.3 Factors influencing composition of the microbiota

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