The Role of Gut Microbiota in The Health of The Host

Introduction

Recent studies have allowed us to come to the conclusion that we are super organisms in which microbial symbionts play essential physiological functions. The human microbiome has emerged as the crucial moderator in interactions between food and our body and can change our mind and health status or play a pivotal role in a wide range of diseases. There are 52 currently recognised bacterial phyla on Earth, 5 to 7 of which reside in the gastrointestinal tract which houses over 100 trillion bacteria. Firmicutes, Bacteroidetes and Actinobacteria are the 3 major phyla which most of the gastrointestinal microbiota belong to. In my self study essay I will be talking about the importance of gut microbiota and the role they play in the health of the host as well as the potential links they have with certain diseases. Firstly ill speak about the multi functions microbiota play in immune and nervous systems as well as their role in metabolism, homeostasis and protection against overgrowth of pathobionts. I’ll then go on to mention the potential link they can have to the following diseases, Obesity, Colorectal cancer, Clostridium Difficile Infection and Inflammatory Bowel disease. I will conclude with my own personal opinion on the topic and possible future perspectives and research that needs to be carried out.

Functions of Gut Microbiota

Gut microbiota have a massive role to play in, immune, neuroendocrine and metabolic interactions which stabilise and regulate their symbiotic relationship with the host.

1) Immunity and the Nervous system: The gut barrier shields the host internal environment from the outside environment and consists of the epithelial and mucous layers. Disruption of its function increases gut permeability to commensal microbes and their products and leads to aberrant immune-inflammatory responses such as inflammation and allergy and autoimmune disorder, controlled by dysregulated T-cell response and molecular mimicry. Gut microbiota cross-regulate physical and immunological functions of the gut barrier.

Tight regulation of gastrointestinal T-lymphocytes balance such as Treg/TH17 balance is vital in maintaining intestinal homeostasis and preventing aberrant immune- inflammatory response. Recent studies have shown gut microbiota have a role to play in host immune response regulation and immunity at both local and systemic levels. Studies on germ free mice indicated gut microbiota facilitate maturation of lymphocytopoiesis and haematopoiesis, adaptive and innate immunity. Host microbiota and their SCFAs (short-chain fatty acids), also regulate maturation and functionality of microglia, which are the tissue macrophage of the central nervous system (CNS) [ 8 ], they also have a massive role in maintaining microglia homeostasis which is crucial for CNS health maintenance.

Gut microbiota also have a modulatory role in the enteric nervous system (ENS), which communicates bidirectionally with the CNS to form the gut-brain axis by autonomously regulating the physiology and function of the gastrointestinal tract. Major component of ENS are the enteric glial cells (EGC) which form the enteric glial network and regulate auctions such as gut motility, immune-inflammatory reactions, blood flow and endocrine/exocrine reactions. Various gastrointestinal disorders such as IBD, infection-induced gut inflammation, neurodegenerative disorders and motility disorders have all been linked to dysfunctions in ENS and EGC.

Recent studies have shown the close proximity of gut microbiota and ENS throughout the gastrointestinal tract allows them to modulate the function and development of ENS. Studies on germ free mice have shown a notable decrease in gut motility compared to specific-pathogen free and altered Schaedler flora counterparts and highlights the importance gut microbiota play in ENS postnatal development in the mid-to-distal intestine.

Finally toll like receptors (TLRs) serve a critical role in maintaining intestinal homeostasis and the symbiotic relationship between the host and gut microbiota. Expression of TLR4 possibly confers ENS the ability to instantly react to stimuli derived from gut microbiota, which suggests TLRs might be the link between intestinal microbiota and ENS development. All the above points highlight gut microbiota have a vast number of roles to play throughout the immune and nervous systems.

2) Metabolism: Gut microbiota facilitate host energy harvesting and metabolic efficiency through the enrichment of metabolism of amino acids, polysaccharides, micronutrients and xenobiotics as revealed from human faecal samples using metagenomic sequencing techniques and 16 S ribosomal RNA. Fermentation of unabsorbed starch and soluble dietary fibre is another important role of gut microbiota, with the end product in the form of SCFAs which act as one of the energy substrates for the host, and contribute to an extra 10% daily dietary energy for other metabolic processes. SCFAs regulate energy homeostasis by stimulating GPR41-mediated leptin production. Studies on mice have shown a link between interactive host-microbe signalling and gut-brain axis immune-inflammatory crosstalk as leptin exhibits pleiotropic effects on physiological functions such as appetite and energy metabolism along with immune response and sympathetic nerve activity.

Gut microbic also synthesise vitamins which are micronutrients that exhibit beneficial value for both microbial and host metabolisms. Vitamin K producing gut bacteria, (e. g. Bacteroides fragilis), anaerobically synthesise Vitamin K2 which contributes to lower risk of cardiovascular disorders such as coronary heart disease, by decreasing vascular calcification, lowering cholesterol levels and elevating HDL. Gut microbiota also exclusively synthesise Vitamins B5 and B12 which act as coenzymes for the production of cortisol and acetylcholine which are vital for the nervous system to function properly. Neuropsychological and hermatogical disorders as well as insomnia and gastrointestinal discomfort have all been linked to Vitamin B5 and B12 deficiencies. Gut microbiota also play an important role in the co-metabolism of bile acids, which aid digestion, cholesterol and lipid metabolisms. In humans 95% of bile acids are reabsorbed at the distal ileum. The 5% of unabsorbed primary bile acids become secondary bile acids through bioconversion or deconjugation by bile salt acids secreted by colonic microbiota. After this they are partly reabsorbed in the colon and then transported back to the liver for conjugation. Unabsorbed secondary bile acids are excreted by the host. Primary and secondary bile acids are ale to regulate bile acid production, glucose metabolism and maybe even hepatic autophagy, by activating host FXR signalling. Secondary bile acids may even protect the host from an array of infectious pathogens and contribute in shaping gut microbiota composition by using antimicrobial properties which alter microbial cell membrane integrity to cause spillage of intracellular contents and inhibit the growth of bile acid-intolerant microbes.

3) Protection from Pathobionts: Human microbiota protect the host from overgrowth of pathogenic microbiota (pathobionts) using 2 mechanisms of action. Competition with the pathogens for shared niches and nutrients, and suppressing the pathogen by enhancing host defence machinery. Dominant non-pathogenic gut microbiota members occupy the niche and suppress the growth and colonisation of pathogens. A decrease in dominant microbiota members during gut microbiome perturbation allows opportunistic pathogenic strains to colonise empty niches and leads to infection.

Dysbiosis and Diseases

Dysbiosis is an imbalance in the taxonomic composition of gut microbiota and can be caused by both external and host factors. External factors can include antibiotic consumption, diet and stress. Dysbiosis prevents gut microbiota from maintaining host wellness and can lead to an increase in pathobionts which leads to unregulated production of microbial-derived products or metabolites that can be harmful to the host and cause a range of diseases on local, systemic or remote organs. In short dysbiosis is the possible link between gut microbiome and disease manifestation.

1) Obesity: Obesity is a global health hazard and affects more than 600 million people worldwide. Obesity can be caused by a number of factors such as genetics, behaviour and environmental factors and is linked to the gut microbiome through its function in host metabolism regulation. Elevated energy intake and decreased energy expenditure are classic signs of obesity and are linked to metabolic syndrome, causing excessive fat accumulation and posing a greater risk of developing obesity associated disorders, e. g. type 2 diabetes and premature mortality. Gut microbiota contribute to obesity development by facilitating augmentation in food digestion causing higher energy harvest and increased fat deposition, through suppressing lipoprotein lipase-inhibitors to store triacyl glycerides in adipocytes and promoting hepatic DNL through the expression of hepatic fatty acids- synthesising enzymes. Furthermore an increase in endotoxic LPS of Gram-negative gut bacteria can lead to obesity-associated metabolic syndrome, obesity-associated insulin resistance and low-grade inflammation. As seen in animal models, prebiotic or probiotics may be used through dietary intervention to selectively modulate microbial composition as a possible therapeutic approach to obesity-related metabolic disorder because of its association with gut microbiota dysbiosis.

These are promising treatments for the future but more clinical trials and supportive data from human models are required in order to prove the their success.

2) Clostridium Difficile Infection (CDI): Clostridium difficile is a Gram-positive toxin and spore-producing anaerobe and is a Firmicutes member in gut microbiota. CDI is a severe disease with 453, 000 cases resulting in deaths in America in 2011 alone. Diarrhoea, pseudomembranous colitis, sepsis and mortality in severe cases are some of the symptoms associated with CDI. Administering antibiotics can be a major risk factor for CDI, 5 to 35% of people develop diarrhoea as a side effect. CDI has used multiple horizontal gene transfer modes within strains and possibly commensal microbes in order to acquire resistant genes toward a number of antibiotics including clindamycin, erythromycin, chloramphenicol and linezolid.

The exact mechanism of antibiotic-associated diarrhoea remains unknown but its correlation with CDI requires research on the link between C. difficile and the gut microbiome in a healthy state. It’s currently thought that dominant gut microbiota protect the host from C. difficile overgrowth in the normal microbiome by using colonisation resistance mechanisms. While researchers propose that primary bile acids serve as germinant for C. difficile spores and secondary bile acids inhibit C. difficile vegetative growth. Administration of antibiotics reduce diversity in secondary bile acids by perturbing gut microbial communities. This makes the host more susceptible to CDI because there is a reduction in the bioconversion of primary to antimicrobial secondary bile acids and this leads to C. difficile outgrowth. Greater amount of vegetative C. difficile leads to diarrhoea as toxin secretion damages the intestinal barrier and stimulates severe inflammatory response and impairs ion absorption. New therapeutic treatments have been developed involving restoration of gut microbiota thanks to a better understanding of CDI and the role antibiotic-induced microbiome dysbiosis has to play in its pathogenesis. An example of such treatments is FMT, where gut microbiota from healthy donor faeces are used to restore gut homeostasis and patients who received it showed long lasting elevation of faecal microbial diversity and a high recovery rate 90% compared to vancomycin 60%.

While studies showed patients who received FMT had a 94% healing rate of CDI with no recurrence of the disease observed over a 16 month follow up. After receiving FMT patients showed signs of an increase of beneficial bacteria and elevation in plasma level of antimicrobial peptide LL-37 along with a reduction of pro-inflammatory cytokines. Studies using FMT indicate a strong association between the gut microbiome and development of CDI. Although more advanced studies need to be carried out in order to discover the exact beneficial strains and underlying mechanisms of FMT, it holds a lot of potential for the future and highlights the widespread use of microbiota displacement therapy in combatting CDI.

4) Inflammatory Bowel Disease (IBD): IBD is a group of idiopathic, multifactorial, persistent and recurring gastrointestinal inflammations in two forms, CD and UC. In CD inflammation can occur anywhere along the whole gastrointestinal tract whereas UC is restricted to the large intestine. IBD effects 1. 4 million people in Europe and 2. 2 million in Americ and common symptoms associated are abdominal pain, fever and relapsing diarrhoea. The mechanism of disease pathogenesis for IBD is lacking however we know it combines environmental and host factors and there is a potential link between gut microbiota and IBD development. Dysbiosis in the gastrointestinal microbiome may be a secondary consequence of gastrointestinal inflammation, through development of antibodies against commensal microbial antigens and auto antigens leading to loss of microbiota that might be responsible for maintaining the gut mucus barrier integrity which leads to severe gut inflammation. It is suggested in studies on mice that gut dysbiosis potentially might contribute to IBD pathogenesis and serve as a secondary consequence of gut inflammation, indicating a bidirectional relationship between IBD and gut dysbiosis. Current IBD treatment targets the aberrant pro-inflammatory immune response at intestinal mucosa but it tends to reoccur long term and chronic treatments with immune suppressive agents will develop neurotoxic side effects. There is a great need to develop future curative treatments that are effective for all, as the etiology of IBD in each patient can differ individually and a lot of patients relapse after treatment is complete.

Conclusions: Based on the research I’ve carried out for my self study essay on the human gut microbiome Ive come to the conclusion the symbiotic relationship between the gut microbiota and the host is an extremely important one. Based on their function in the immune and nervous systems, as well as the roles they play in metabolism and homeostasis, its evident that the gut microbiome has a highly import role in human health. The role they play in obesity, CRC, CDI and IBD also highlights the possible role they play in diseases however their exact link is debatable because there is no direct link and their exact mechanisms remain for the most part unknown. This largely comes down to the fact our understanding of the gut microbiome is still at a very preliminary stage. We need to understand which point of disease do microbiota interact as well as what role they take in disease manifestation and in order to achieve this experimental design needs to be revised. However the future is bright as applications of microbiome-based disease diagnosis as well as treatments hold the potential to revolutionise disease management. Large scale microbiome-based projects such as MetaHIT and The Human Microbiome Project Consortium are helping to advance our current knowledge on the human microbiome and hopefully help achieve the points mentioned above in the not so distant future.