Part 2: Microbial Management- A Gut Feeling About Obesity
by Hidaya Aliouche
You can catch up on the First blog here.
Part 2 takes a close look at the association between obesity and the gut microbiota. We hold a microscope to a selection of studies that have provided a compelling link between the microbial community and our expanding waistlines.
The discovery of a connection between the gut microbiome and obesity began in 2006. Jeffery Gordon and colleagues achieved this by studying mice. Mice are indispensable in the research world, they allow intervention at levels not achievable with humans. Therefore, in this context, they are excellent ways of determining how the microbiota affects metabolism. These mice were engineered to lack leptin, a hormone that acts on the brain, where it inhibits hunger signals and promotes feelings of fullness. As a result, these leptin-lacking mice overate and became obese. Comparison of the microbiota in these mice with lean control mice revealed that the leptin-lacking mice had half as many bacteria from a group of bacteria called Bacteroidetes and 1.5 times more from another group, Firmicutes (see Fig 1. A). This observation was mirrored in fat and lean humans. Interestingly, the proportions could be inverted in humans; when obese subjects lost weight through adoption of a low-fat diet, the amount of Firmicutes was found to decrease, whilst Bacteroidetes became more abundant.
Figure 1. Pictorial representation of the experimental set-up described in the text for Gordon et al., 2006.
The team then used another strange strain of mice, which completely lacked microbiota, to corroborate the link between microbiota and obesity. When subjected to an eight-week diet of 40% fat, these mice gained half as much weight as their normal counterparts, despite them consuming equivalent quantities of food (see Fig 1. B). When the microbiota-free mice received microbiota from the fat and lean mice via gut transplantation, recipients colonised by the microbiota from the fat donors gained more weight than recipient mice paired with lean donors (see Fig 1. C). To determine the cause of changing microbiota compositions on weight, the team analysed the gene profiles of the microbiotas in the fat and lean mice. This revealed that the microbiota of fat mice had expressed greater quantities of genes that enabled them to increase the energy harvested from their diet compared to their lean littermates. These experiments amongst others, have firmly established a link and putative cause, between the microbial composition and obesity. But we can’t assume that a microbiota capable of yielding high energy returns is just one way the microbiota cause us to pile on the pounds. There is a wealth of research available to demonstrate that their function opens multiple routes to weight-gain and ill-health.
Each function of the gut microbiome provides critical pieces of the puzzle. Together, the microbiota can be viewed as a huge working population with each constituent contributing a distinct service to us because of a set of individual skills. They use enzymes, which are catalytic converters of input molecules, called substrates. Each enzyme is highly specific and breaks down different food products into small components, or metabolites. The metabolic profile produced by the collective activities of the microbiota will vary between individuals as each person has a unique microbiota. Microbial metabolites may then nurture our own cells or another microbe, that can, in turn, benefit us. Their role extends further than simple provision of essential nutrients, however. Through their dissemination via circulation, these metabolites can also elicit physiological changes in the body ranging from development and regulation of the immune system to affecting our satiety. Non-digestible carbohydrates are the preferred nutrient and provide the primary energy source for most gut microbes. Among the by-products of their fermentation are short chain fatty acids (SCFAs). Principally, SCFAs are key sources of energy for both the gut tissue and microbes and promote cellular mechanisms that ensure tissue integrity. Systemically, SCFAs impact immune function, prevent inflammation and regulate our metabolism in a manner that promotes leanness. This is the reason why the interplay between diet, the microbiota and metabolic outcomes in the host appears to be linked so acutely to diet; the magnitude and diversity of the microbiota and their metabolites are greatly influenced by nutrient availability, which in turn, is governed by what we eat.
Most recently scientists at Lund University in Sweden have found that as many as 19 metabolites are linked to an individual’s Body Mass Index (BMI), the primary screening parameter for obesity through reporting weight as a function of height. Of them, metabolites called glutamate and amino acids showed the strongest correlation to obesity and to four different intestinal bacteria. Another case in point; the bilateral link between the gut microbiome and obesity can be firmly extended to the diet, illustrating that, in a manner of speaking, you are what we eat.
The virtues of fibre in the diet are universally extolled, being implicated in improved digestion, protection against heart disease, stroke, type II diabetes and bowel cancer. Two recent studies have expanded this list of health benefits, with researchers demonstrating that fibre contributes to bowel health and diet-induced obesity. Both focussed on the role of a soluble fibre called inulin, which is amenable to microbial digestion (or fermentation) and its role in inflammation. In addition, both studies highlight the increasingly prevalent opinion that obesity is a chronic inflammatory disease in which altered reduced microbial diversity and composition damage the integrity of the gut, allowing inflammation to take hold. Clearly gut integrity is a crucial stipulation for healthy host-microbiota relationships. This integrity is afforded by a barrier comprised of a tight monolayer of cells overlaid by a protective layer of mucus (Fig. 2A). The microbiota is sequestered in the mucus and lumen, where food traverses during digestion, to prevent interaction with the immune cells which circulate in the connective tissue underlying the epithelium. Contact of the microbiota with immune cells provokes an immune response. Consequently, a damaged barrier results in a barrier breach which culminates in inflammation (Fig. 2B).
Figure 2. A) View of the gut barrier in mice on a HFD lacking fermentable fibre (inulin): there is a reduced diversity and abundance of microbiota, gut barrier erosion, and concurrent microbiota encroachment. This triggers activation of immune cells in the underlying connective tissue, resulting in an inflammatory response as shown. The same changes were mirrored in the Hanson et al., study B) View of the gut barrier in mice on a HFD supplemented with inulin: shown is an expansion in the number of epithelial cells, restored barrier integrity and increased microbial diversity. This was also found in the Hansonn et al. study, where additional supplementation with Bifidobacterium longum also prevented mucosal erosion.
In the first study, Gewirtz and colleagues examined the role of dietary fibre as a cultivator of a healthy host-microbe relationship. Mice were fed a standard diet or a high-fat diet (HFD, comprised of foods linked to development of obesity) which were both supplemented with a fermentable fibre, inulin. Supplementation with fibre in the mice fed a HFD protected the mice against diet-induced obesity. The process underlying this effect was examined by determining the effect on the gut barrier which showed an expansion of mucus-producing epithelial cells, which correlated with reduced barrier erosion and subsequent protection against obesity. Inulin supplementation also restored low microbial diversity of the HFD fed mice (the HFD had reduced the microbial load by a factor of 10), with an increased Firmicutes/Bacteroidetes ratio observed, demonstrating that inulin bolsters both the diversity and abundance of the microbiota. Interestingly the mediator of these effects was not SCFAs, which are known nurturers of the gut barrier; instead by the microbiota themselves interacting with the immune system to produce chemical messenger that directly fortifies the intestine to prevent encroachment of microbiota.
In the second study, Hansson et al. investigated the potential role of fibre in protection against barrier degradation mediated by the microbiota. Mice were fed a Western style diet, which resulted in an altered microbiota composition that paralleled an increased penetrability and impaired growth of the barrier. This effect could be remedied when microbiota from ‘standard diet fed’ mice were transplanted into the mice. The effect was exacerbated by administration of a specific species of bacteria, Bifidobacterium longum, as well as supplementation with inulin.
There are two points of considerable weight that are raised. The first is that soluble fibre, exemplified by inulin, can prevent obesity. Inulin is additionally categorised as a prebiotic, a form of soluble fibre that can promote the growth of beneficial bacteria. The second is the effect of B. longum; a probiotic, a microorganism that promotes the growth of beneficial bacteria that benefit the host health. Prebiotics are therefore promoters of probiotics. This finding adds to the knowledge that the prebiotic fibre is important, suggesting that probiotic cultures are an additional factor in the protection against obesity. The understanding of altered gut microbiota in combination with dietary habits has thus far provided a cursory insight into how the microbiota affect weight gain. In turn, the notion that the gut microbiome can be exploited as a therapeutic target to combat the prolific phenomenon of piling pounds has not escaped the attention of the commercial sector. We explore this in our final installment.
You can now read the third instalment here.
I am a postgraduate student at the University of Manchester. Having completed a degree in Biochemistry I am now pursuing a career in the field of science and medical communications. In my spare time you can find me sweating it out outdoors, crocheting in a corner and baking up a storm (not necessarily in that order…or at the same time).