The intestinal microbiota is confined most to the colon where some 1.5 kg of microbes or 1014 microorganisms reside. There are more genes in the human microbial than in the human genome. In the gut associated lymphoid tissue (GALT) enterocytes or intestinal epithelial cells represent the first barrier against invading organisms by secreting either mucin or defensins or sensing pathogens via TLRs. DCs also act as APCs. In aged GALT, a marked impairment of the immune response has been reported. Microbial components account for the production of short chain fatty acids (SCFA) such as butyrate, acetate and propionate. SCFA have antiinflammatory and anti-neoplasmic activities which exert a protective function. (Magrone, Immunity & Ageing 2013, 10: 31).

Bacteria living in the gut are being studies not only because they play a role in gastroinestinal disorders like inflammatory bowel disease, Crohn’s disease and colorectal cancer, but also because they can influence diverse and distal organs such as the brain. The gut-brain-axis begins with the enteric nervous system (ENS), a network of neruons that runs through the gastrointestinal tract. From there, the gut communicates with the brain via the vagus nerve, which connects the ENS to the central nervous system. 

Protection of Mucosal Surfaces

Protection of mucosal surfaces against conolinization and invasion by microbes is provided by a combination of constitutive, non-specific substances (e.g., mucus, lysozyme, lactoferrin and definsins) and also by specific immune recognition that relies on secretory IgA (SIgA). In the GI tract, microbe sensing and processing occurs in the Peyr’s patch tissue consisting of mucosal epithelium and associated lymphoid tissue. Microbes are sabled and ingestedc by the M Cell which passes them to APCs. (Corthesy, “Recombinant immunoglobulin A:powerful tools for fundamental and applied research” Trends in Biotechnology, 20(2), 2002, 65-71

Consequences of Disturbing Gut Microflora

Antibiotic-assocaited diarrhaea (AAD): Diarrhae is a frequent adverse effect of antiboiotic treatment and a common condition in hospitalised patients. The mechasmis by which antibiotics lead to AAD are multifaceted and include alteration of the normal intestinal microflora, often accompanied by overgrowth of patheogenic micro organisms. Nosocomial diarrhaea (NCD) is an entity defined as diarrhaea eveloped within 72 hf of hospitalisation (the 3 day rule). (Gorkiewicz, International J Antimicrobial Agents, 33(S1), 2009, S37-S41).

Synthetic Biotics:

Snthetic biotics invovles use of genetic engineering to create new biological parts. Synlogic for example first looks at underlying mechnisms or metabolic dysfunctions that cause a diase. This involves a review of the existing literature to identify and validate potential molecular targets. For example, it assed GI component and role of diet restriction when evaluating for example PKU and HCU as potential target indications. PKU is a rare genetic disease caused by the inability to metabolize or break down phenylalanine (Phe), an amino acid found in many foods, including vegetables, breads and creals. Over time, the toxic building of Phe can lead to severe neurological disorders and developmental delays in patients. HCU is caused by the loss of functional of the enzyme cystathione beta-synthase, which results in the toxic building of homocysteine and its metabolites in human blood and urine. Syptoms include life-threatening strokes caused by thromboembolism, lens dislocation, skeletal abnormalities and intellectual disability. Similar to that for PKI, HUC disease management involves adopting a highly restrictive diet (low in methionine, a precursor to homocysteine). Using molecular biology techniques it next tests prototypes that can carry out specific functions such as consuming toxins, regulating cellular funciton and targetting drivers of disease. Then standard molecular techniques to construct bacterial strains with key elements for devleopment such as the generation of auxotrophs, which are unable to synthesize one or more essential growth factors. The synthetic biotics are grown under controlling manufacturing conditions, lyophilized and formulated into a stable powder that can be adminsitered orally. These syntehtic biotics are desigend to be nonreplicating, noncolonizing and reversible by rapid GI clearance. Synlogic has made progress in development of the investigational synthetic biotics SYNB1618 and SYNB1934, which are engineered strains of E. coli Nissle encoding phenylaanine ammonial lyase (PAS), an enzyme that breaks down Phe. They are designed to metabolize Phe in the GI tract and convert it into a harmless metabolite. Synlogic is also developing the SYN81353 synthetic bioc for the potential treatment of HCU. It is an engineered strain of E. coli Nissie that consumes methionine in the GI tract ot prevent the accumulation of hemocysteine. That strain was developed as part of a research collaboration with Ginkgo Bioworks.