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The gut microbiota and the human host: a new clinical frontier

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Introduction

Imagine the scenario: a scientist at a conference claims to have found a new organ in the human body. It is comparable to the immune system in as much as it is made up of a collection of cells, it contains a 100 times more genes than the host, is host-specific, contains heritable components, can be modified by diet, surgery or antibiotics, and in its absence nearly all aspects of host physiology are affected. While this may seem far-fetched, it is the current situation in which we find ourselves. We now realise that the human microbiota is an overlooked system that makes a significant contribution to human biology and development. Moreover, there is good evidence that humans co-evolved a requirement for their microbiota.1

In the past decade, partly because of high resolution observational studies using next-generation sequencing technologies and metabolite profiling (see glossary), the gut microbiota has become associated with promotion of health and the initiation or maintenance of different GI and non-GI diseases. As we enter the post metagenomic era, we need to move away from simple observations to determine what are merely correlations and what are causal links—and focus efforts and resources on the latter. This post metagenomic era is starting to provide new therapeutic targets based on a better understanding of how the microbiota interacts with the host’s physiology. Ultimately, we aim to integrate an individual’s microbiota into some form of personalised healthcare and, by better understanding its role, treat an individual’s diseases more efficiently and in a more targeted fashion. With a more complete understanding of the disease process, we will be able to more accurately stratify different disease states and determine whether or not the gut microbiota is a potential therapeutic target which we can modulate in order to treat specific diseases.

Current understanding of the gut microbiota

In the last decade, several large-scale projects, for example, the human microbiome project, have investigated the microbiota of a variety of bodily niches, including the skin as well as the oral, vaginal and nasal cavities.2 While some of these are relatively easy to access, the GI tract remains a challenging environment to sample, and to describe. Currently the majority of research is focused on the gut microbiota, since this is where the greatest density and numbers of bacteria are found, with most data being derived from faecal samples and, to a lesser extent, mucosal biopsies. While it is relatively easy to obtain fresh faecal samples, the information obtained from them does not represent the complete picture within the gut. From a number of limited studies, we know that the small intestine contains a very different abundance and composition of bacteria, with much more dynamic variation compared with the colon.3 The colonic microbiota is largely driven by the efficient degradation of complex indigestible carbohydrates but that of the small intestine is shaped by its capacity for the fast import and conversion of relatively small carbohydrates, and rapid adaptation to overall nutrient availability. While faeces are not an ideal proxy for the GI tract, they do give a snapshot of the diversity within the large intestine. Furthermore, the majority of the data comes from North American and European studies with very few studies in Asia, Africa or South America. Hence we have a somewhat biased view of the gut microbiota.

This rapid increase in interest in the microbiome has also been driven by the application of multi-‘omic’ technologies; we refer the reader to Lepage et al4 for more detailed explanation of these.

What do we know about the gut microbiota?

Bearing in mind the limitations above, the GI tract is often seen as a two phylum system (the Firmicutes and Bacteroidetes) although it should be noted that members of at least 10 different phyla can also have important functional contributions (see box 3). We are also very bacteria-centric when we look at the gut microbiota; only a handful of papers have looked at the viral component (or virome) and micro-eukaryotes (protozoa and fungi). When the gut microbiota of relatively large cohorts of individuals (eg, more than 100) is analysed, it can be seen that the ratio of the Firmicutes:Bacteroidetes is not the same in all individuals. Currently we do not know the significance of being at either end of this continuum, especially as a large shift in the relative abundance of a group of organisms translates to a modest change in bacterial numbers. Yet there is evidence that depletion of a single species, for example, Faecalibacterium prausnitzii, belonging to the Firmicutes phylum, has been associated with IBD.5 But in the scientific literature, we see counterarguments for any involvement of this species in IBD.6 This disparity highlights the current status of understanding. We know that the gut microbiota is essential to the proper function and development of the host but we are unsure which are keystone species and whether the microbiota’s function is more important than any individual member of the community. But this is too simplistic a view. In several cases, strain differences within a species can be the difference between being a pathogen/pathobiont and being a probiotic: for example, Escherichia coli is associated with IBD and colorectal cancer (CRC)7 ,8 yet an E. coli strain is used as a probiotic.

Dietary modulation of the gut microbiota

Metabolic activities of the gut microbiota

Carbohydrate fermentation is a core activity of the human gut microbiota, driving the energy and carbon economy of the colon. Dominant and prevalent species of gut bacteria, including SCFA-producers, appear to play a critical role in initial degradation of complex plant-derived polysaccharides,11 collaborating with species specialised in oligosaccharide fermentation (eg, bifidobacteria), to liberate SCFAs and gases which are also used as carbon and energy sources by other more specialised bacteria (eg, reductive acetogens, sulfate-reducing bacteria and methanogens).12 Efficient conversion of complex indigestible dietary carbohydrates into SCFA serves microbial cross-feeding communities and the host, with 10% of our daily energy requirements coming from colonic fermentation. Butyrate and propionate can regulate intestinal physiology and immune function, while acetate acts as a substrate for lipogenesis and gluconeogenesis.13 Recently, key roles for these metabolites have been identified in regulating immune function in the periphery, directing appropriate immune response, oral tolerance and resolution of inflammation, and also for regulating the inflammatory output of adipose tissue, a major inflammatory organ in obesity.14 In the colon, the majority of this carbohydrate fermentation occurs in the proximal colon, at least for people following a Western style diet. As carbohydrate becomes depleted as digesta moves distally, the gut microbiota switches to other substrates, notably protein or amino acids. Fermentation of amino acids, besides liberating beneficial SCFAs, produces a range of potentially harmful compounds. Some of these may play a role in gut diseases such as colon cancer or IBD. Studies in animal models and in vitro show that compounds like ammonia, phenols, p-cresol, certain amines and hydrogen sulfide, play important roles in the initiation or progression of a leaky gut, inflammation, DNA damage and cancer progression.15 On the contrary, dietary fibre or intake of plant-based foods appears to inhibit this, highlighting the importance of maintaining gut microbiome carbohydrate fermentation.16 Recognition of carbohydrate fermentation as a core activity of the gut microbiota provides the scientific basis for rational design of functional foods aimed at improving gut health and also for impacting on microbiota activities linked to systemic host physiology through newly recognised interkingdom axes of communication such as the gut:liver axis, the gut:brain axis and the gut:brain:skin axis.17

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