Human Gut Microbiome and Maintaining Good Health

Probiotics

Probiotics contain strains of live bacteria (and sometimes yeast) that are supposed to provide health benefits to the host via temporary colonisation of the gastrointestinal tract (1,4) They can often be found in fermented foods such as yoghurt and sauerkraut, and the power of probiotic foods was first acknowledged thousands of years ago, when the consumption of dairy products was linked to a higher life expectancy (38). The most commonly used strains of bacteria in commercial probiotics are Lactobacillus and Bifidobacteria, although there are hundreds of different types and combinations (1).

There are numerous ways in which probiotics are thought to confer health benefits, including increasing the production of SCFA, stimulating IgA secretion, reducing the production of pro-inflammatory cytokines, and activating regulatory T cells (1,39). The use of probiotics in clinical medicine is controversial, as many studies have been inconclusive. VSL#3 is a probiotic that contains various species of Lactobacillus, Streptococcus and Bifidobacterium, and has been shown to increase the rate of remission in humans with ulcerative colitis compared to placebo, but does not show a significant benefit in Crohn's disease (1,40).

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There is also strong evidence for the use of probiotics during antibiotic treatment. The administration of probiotics has been shown to reduce antibiotic-associated diarrhoea in children and adults, but it is not as effective in the elderly (39). There may also be adverse side-effects of probiotics when used in critically ill patients, especially newborns. It is possible that probiotic species can interfere with the indigenous gut microbes, and even promote infection (39).

Moreover, there is potential for the use of probiotics in metabolic disorders such as obesity and type 2 diabetes mellitus.

On administration of various Lactobacillus spp., both GF mice and normal mice showed a decrease in total body mass, glucose concentration and adipocyte size, as well as an increased expression of angiopoietin-like 4 protein, which is a lipoprotein lipase inhibitor (4). This suggests that probiotics could decrease the absorption of triglycerides, phospholipids and cholesterol in the obese, but evidence in humans is still lacking.

Prebiotics

Prebiotics are non-digestible fibres that are fermented to SCFA by the gut microbiota (1,4,41). This includes inulin, fructooligosaccharides (FOS), galactooligosaccharides (GOS), and disaccharides(1). Prebiotics can have a wide range of effects on the host, most of which are indirect. For example, there is evidence that they may be useful in reducing chronic low-grade inflammation often seen in diabetes mellitus and obesity (41). Inulin and FOS have been shown to stimulate the growth of Bifidobacteria, which helps maintain gut barrier function. This prevents endotoxins such as lipopolysaccharide (LPS) entering the bloodstream and activating the innate immune response, which can lead to inflammation (41). In rats, the administration of prebiotics was shown to increase GLP-1 and PYY secretion, which are important in regulating blood glucose and food intake, most likely due to the increase in SCFA output (1).

Prebiotics may also confer benefits to those with autoimmune diseases, as they can help regulate the immune system. It was shown that when mice were deprived of fibre, the gut microbiota began to degrade the mucosal layer of the intestine, which leaves the epithelium vulnerable to colonisation by pathogens (1). Other immunomodulatory effects of prebiotics include the activation of regulatory T cells, increasing mucus production, and inhibiting the adhesion of pathogens to the epithelium (42). Although prebiotics are thought to have many beneficial effects, there are very few studies in humans that support this (1,41).

Faecal microbiota transplantation (FMT)

FMT involves the transfer of stool from a healthy donor into the intestinal tract of a diseased patient (43). The history of FMT dates back to 4th century China, where faeces-derived products were used to remedy abdominal discomfort (44). Nowadays, it is used in cases of Clostridium difficile infection (CDI), which can often occur due to antibiotic use (43). There is evidence that FMT can resolve up to 90% of recurrent CDI cases, where the use of antibiotics such as vancomycin has previously failed (43). In a study of FMT in dogs with IBD, a reduction in symptoms was reported, and shortly after the treatment, the dogs' microbiomes had greater diversity and seemed to more closely resemble that of the donor than its own (1). The use of FMT in IBD has not been proven to be effective, apart from during flares when Clostridium. spp is implicated. There are some studies that reported an increased inflammatory in response to FMT treatment in patients with ulcerative colitis, and as such more research is needed before this treatment becomes standard (1). There is also evidence that FMT may be useful in treating irritable bowel syndrome (IBS), specifically in patients who suffer from constipation (43).

Research into the use of FMT in other conditions, such as metabolic and cardiovascular disorder, is ongoing (43,44). The current guidelines for FMT treatment restrict it to use in cases of CDI, as it has not been proven safe or efficient in other conditions (1).

Conclusion: future directions for research

The human gut microbiome plays an extremely important role in many physiological processes involved in immunity and metabolism. Elucidating the exact mechanisms by which the microbiota interact with the host and invading pathogens will advance the understanding of the pathogenesis of diseases with no known aetiology, such as IBD. As this field of research is relatively new, there is a lack of human data, which makes it difficult to provide evidence of a causal link between the dysbiosis of the gut microbiome and the onset of disease. Thus, there is a need for large-scale human studies in which the composition of the gut microbiome is monitored over a long period of time, possibly even from birth.

Research such as this would help us to understand how the gut microbiome changes over time, and how this may be related to the progression of disease. Most studies largely focus on the bacterial species in the gastrointestinal tract, as they are by far the most abundant, but I believe it is important to shift the focus to include viruses, fungi and parasites as well, as these may also have important interactions with the host. Therapeutic manipulation of the gut microbiome may be very promising, especially in common metabolic disorders (obesity, diabetes, etc) which affect millions of people. However, evidence surrounding the use of prebiotics, probiotics and FMT is controversial. Besides, these therapies aim to restore the balance of the microbiota, but this works on the assumption that dysbiosis causes the disease, which again has not been proven.

Overall, it is clear that the gut microbiome is a potential controller of wellness, and therapies that target the gut microbiome could provide treatments for a wide variety of disorders. Research must now aim to identify the exact mechanisms by which the microbiome influences host health and the specific roles of different microbial species. Only then, in my opinion, can we begin to develop potentially revolutionary therapies.5 The role of the gut microbiome in disease5.1 Inflammatory bowel disease (IBD)IBD is an idiopathic disorder characterised by episodes of inflammation in the intestine, leading to fever, abdominal pain and diarrhoea (2,28). Crohn's disease (CD) and ulcerative colitis (UC) are the most common forms, and the incidence of IBD is rising worldwide (28). Dysbiosis (decrease in diversity) of the gut microbiota has been consistently associated with IBD, but there is not enough evidence to support a causal relationship. However, studies into the composition of the gut microbiome in IBD have shown the increased presence of specific pathobionts, such as members of the Enterobacteriaceae family and Clostridium spp. (29), which could induce inflammation via TLR-4 signalling and the activation of effector T cells (2).

Studies also show the reduced abundance of species such as Faecalibacterium prausnitzii (of the Firmicutes phylum), which are known to both upregulate anti-inflammatory cytokine production and suppress pro-inflammatory cytokines (2,30), as well as produce butyrate, which is important in colonic barrier function (2). There is also a correlation between the repeated use of antibiotics in childhood and the incidence of CD (31), as antibiotics are known to reduce bacterial diversity in the gut. The gut virome is also an important aspect of IBD. Analysis of the stool of patients with CD demonstrates an increased presence of viral bacteriophages such as Caudovirales compared with that of healthy patients, which may contribute to microbial dysbiosis (28). Moreover, increased fungal diversity is thought to contribute to IBD pathogenesis, as analysis of inflamed areas of the colon showed greater expansion of fungal species compared to uninflamed areas (29). The resulting intestinal dysbiosis may lead to greater production of pro-inflammatory cytokines, and fewer anti-inflammatory cytokines, as well as reduced SCFA production, which may lead to a loss of integrity of the gut epithelial barrier (30).

Infusions of SCFA, specifically butyrate, in patients with UC has been shown to reduce inflammation (19), which suggests that SCFAs play an important role in the development of IBD. There is potential for the development of treatments for IBD that target the gut microbiome, although these are still in their preliminary stages (29,30) (see section 6.).5.2 Obesity and Type 2 Diabetes Mellitus There are estimated to be 600 million obese people worldwide, which earns obesity the title of a global epidemic, and it is also a risk factor for type 2 diabetes. There are many factors that have been linked to weight gain and insulin resistance, such as diet, environment, genetics, and, more recently, the gut microbiome. Many studies into the microbiome of obese people have found that the ratio of Firmicutes to Bacteroidetes (the two most abundant phyla in the microbiome) was increased compared to lean subjects (32).

Firmicutes predominantly produce butyrate, and Bacteroidetes produce acetate and propionate, all of which are SCFAs important in energy metabolism and blood glucose regulation(21). Therefore, a change in the ratio of these phyla may increase energy absorption from food, which could contribute to increased adiposity and decreased insulin secretion, but the exact mechanisms remain unknown (33). Some studies, however, did not find a change in the ratio of Firmicutes to Bacteroidetes, which suggests that it may be necessary to focus more on the species than the phyla and that a simple imbalance in bacteria cannot be the sole contribution to an obese phenotype (34). Experimental evidence for the link between obesity and the gut microbiome is extensive. When GF mice are colonised with microbiota from obese mice, they exhibited rapid weight-gain, whereas GF mice that were colonised with microbiota from lean mice did not (35).

Furthermore, obese people who underwent Roux-en-Y gastric bypass surgery showed a greater-than-expected weight loss, which suggests that the surgery may have an effect on the gut microbiome (36). This was demonstrated experimentally when the microbiota from obese mice that underwent RYGB was transplanted into obese mice who underwent sham' surgery. The latter exhibited weight loss and decreased fat mass(37). Chronic low-grade inflammation is often seen in obesity and type 2 diabetes (4,19). This has been linked to the gut microbiota by the endotoxin lipopolysaccharide (LPS), which is found on the outer membrane of gram-negative bacteria (4). Dysbiosis of the microbiota can impair the gut barrier function, which allows more LPS to enter the plasma, leading to the recruitment of pro-inflammatory cytokines (19). Although the link between obesity, type 2 diabetes and the gut microbiome is undeniable, the development of these conditions is highly complex, and more research is needed to fully understand the role played by the microbiota.