Bug Therapy to treat Diabetes and obesity in future?

The long held notion of ‘junk DNA’ has been found to be incorrect (ENCODE project), similarly, characterizing the gut microbiota as bystanders in the intestinal tract is now being widely challenged (Osborn O, Olefsky JM (2012), Nature Med 18(3):363-374).

A recent paper in Proceedings of National Academy of Sciences (PNAS) adds muscle to the fact that a single species of bacteria (Akkermansia muciniphila) can modulate diet induced obesity in mice. A. muciniphila is a Gram-negative bacteria that constitutes 3–5% of the gut microbial community. The paper also highlights the various mechanisms by which this bacterium might exert its effect (Everard A et al. (2013), PNAS)

The study shows dramatic decrease in gut A.muciniphila in diet induced obese mice. On restoring the abundance of this strain in obese and diabetic mice it was found that viable A. muciniphila controls gut barrier function, fat mass storage, and glucose homeostasis via several mechanisms. This study identified an association of obesity with a decrease in mucus thickness that is characteristic of obesity and associated disorders. Interestingly, the authors found that A. muciniphila restored this mucus layer. Strikingly, viable A. muciniphila induces these effects, whereas heat-killed A. muciniphila did not protect the mice from diet-induced obesity and associated disorders. One of the other key findings was that treatment with this bacteria led to increase in acylglycerol levels more specifically 2-OG and 2-AG. Incidentally, 2-OG is known to stimulate intestinal L cells which lead to secretion of GLP-1 (Hansen KB, et al. (2011), J Clin Endocrinol Metab 96(9):E1409–E1417). GLP-1 is known to increase insulin secretion. Also, A. muciniphila treatment completely reversed diet-induced fasting hyperglycemia via a mechanism that was associated with a 40% reduction in hepatic glucose-6-phosphatase expression thereby suggesting a reduction in gluconeogenesis. Hence this association might point to how A. muciniphila exerts its effects on glucose homeostasis. 

Many bacteria (Lactobacilus spp, Bifidobacterium spp etc.) have been shown to have effect on fat mass development during diet induced obesity (Fåk F, Bäckhed F (2012), PLoS ONE 7(10):e46837). However, in this study the emphasis was to study the bacterial strain that is affected during obesity and type 2 diabetes in humans and rodents. It would be interesting to see how this development would enthuse the world of gut microbiome research and interest the pharmaceutical/biotech companies to invest in this field which would then pave the way for not only treatment but prevention of inflammatory, lifestyle and even mental diseases in the near future.

Gut Microbiome – Type 2 diabetes association; outcome and possibilities

The phrase ‘my gut feeling’ has got another scientific validation with some new metagenomics studies published recently. After all, it seems that the gut can dictate the potential well being of an individual. A case in point is the latest paper in Nature journal in which the researchers conducted a gut metagenomic study on Chinese patients suffering from type 2 diabetes (http://www.nature.com/nature/journal/vaop/ncurrent/full/nature11450.html). Gut microbiome has been in the forefront of research especially after the advent of the Next Generation Sequencing technology. Today, the advancement in the field of development of sequencers and sequencing technology is even challenging the Moore’s law.

Gut microbiome also being called as the “other genome” or human’s “second genome” is implicated in many of the chronic diseases/disorders like obesity, inflammatory bowel disease and even depression so it is natural that with the latest technology in hand the scientists would focus on this in a much more refined manner. The present study finds some interesting facts about the commensals in the gut of Chinese patients suffering from type 2 diabetes. Functional characterization showed that there was a decrease in the level of bacterial chemotaxis, flagellar assembly, butyrate biosynthesis and metabolism of cofactors and vitamins in the gut bacteria of these patients. The researchers also found markers that indicated that the gut environment of a T2Dpatient is one that stimulates bacterial defence mechanisms against oxidative stress. This might be interesting as previous studies have implicated high oxidative stress levels to pre-disposition to type 2 diabetes. Strikingly, the researchers found orthologue markers that suggest that these diabetic patients might have a hostile gut environment. The researchers also found that there is moderate gut bacteria dysbiosis and an increase in several opportunistic pathogens.

The above mentioned salient outcomes of the study raise many exciting questions and possibilities. Does the change in gut microbiome composition a cause or an effect of the disease? Scientists would be addressing this part next with some studies in animals. Can in the future the gut microbiome sequencing be used as a predictive tool? Can modulating the gut microbiome cure such diseases? Can effective research in pro-biotics now fill in the space and fulfill what modern medicines could not achieve so far?

This is a perfect example of how a 21^st century technology has ignited a fresh look at the association of the microbiome with the human health

Inflammasome – Gut microflora link to Metabolic syndrome; A case for metagenomics

Metabolic syndrome so far is attributed to the deregulation of the metabolic processes leading to increase triglycerides, fat, insulin resistance etc. and thereby leading to diabetes mellitus, coronary heart disease and hypertension. Inflammation is also one of the key factors that can cause an onset of metabolic syndrome.

Recently, a new article in Cell Research (a Nature publication) puts a new perspective on the role of gut micro biota as a causative effect in the process of inflammatory response in the liver (http://www.nature.com/cr/journal/vaop/ncurrent/full/cr201255a.html)

The article highlights certain interesting points and hypothesizes that defective inflammasome signaling in the gastro-intestinal tract allows colitogenic microbes to prosper in the colon, and subsequently trigger harmful inflammatory signaling pathways in systemic organs when the gastro-intestinal barrier is breached. The fact that defective inflammasome signalling can skew the gut micro biota towards colitogenic species of the Prevotellaceae family and the candidate phylum TM7 is not only interesting but opens a new dimension on the role of intestinal “niche” environment in regulating the microbiota species and thereby controlling different aspects of well being of humans (though the research highlighted above is in mice).

Role of gut microbes in maintaining robust immune system or even mental health have been reported earlier. In this era of genomics, it is therefore imperative that we use metagenomics to study gut microflora to understand the intestinal “niche” microenvironment. This would help in designing better targeted antibiotics for therapeutical intervention and thereby possible prevention of many of today’s lifestyle diseases!