Briefly, diabetes is a condition in which cells in your body are unable to utilize sugar you eat, the fuel of every cell in your body. This raises the blood glucose levels, leading to all the maladies associated with diabetes. Insulin dependent or type 1 diabetes is a condition which occurs early in life, caused by failure of beta cells in pancreas to produce insulin(the hormone that tells your cells to open their glucose transporters and take up that blood sugar). Type 2 diabetes or insulin independent diabetes occur later in life and is characterized by you cells going rouge and choosing not to respond to insulin. Later stages of type 2 diabetes is then followed by stress on beta-cells leading to their death and reduction in insulin production, as well. You might want to read the previous blog in the series for more details.

If you don't know what the hell the microbiome is, let me put it this way - "Not all microbes or bacteria are bad". As an embryo we develop in a sterile environment, but at the moment of birth as you are being pushed through the vaginal canal, you start picking up bacteria in that environment.

These bacteria forms an ecosystem in all your exposed surfaces that interact directly with environment. They are on your skin, in your respiratory tract, in your gut, in your rectum, and your genitals. And no, they are not bad, they live in peace with you(with exception of some oppurtunitic microbes that would take advantage of you if you were to become immune compromised for some reason). Now you may already know of lactobacillus, a bacteria that helps you digest sugar in the milk. But that is not the only benefit they provide. They do everything from shaping your immune system to also being am ally in avoiding the harmful pathogenic microbes around you.

Also, they are diverse, like we don't even know exactly how many different kinds are there in you, but they show a huge diversity in population. Also different communities of these bacteria are located at different positions in your body. In fact in terms of diversity every individual has unique signature of microbes they are carrying. The signature is so unique that that just like your genomic DNA, your microbes you leave on the mobile phone, your laptop, your dog and your bed can be used to identify you(yeah it has forensic applications).

Combined together the entire superset of microbes in your body, constitutes your microbiome. While on one hand there is uniqueness in microbiome, on the other it carry disease susceptibility signatures, as well. That is you can compare the relative abundance of different microbes in a person and predict with high accuracy if they are obese or lean(Turnbaugh et al., 2009)

In the previous blog, we did see that inflammation is mechanistic link between obesity and insulin resistance. And here I told you that you can sequence someone's gut microbiome and predict their risk of becoming obese or onset of diabetes. But predictions are based on correlations, and correlations don't tell you much about cause vs effect. So we need to dig in deeper. We need to look at the mechanistic link between your gut bacteria, obesity and insulin resistance.

Lets do this. Before we can know which bacteria in the gut does what to contribute to obesity and diabetes, let's ask what happens if there were no germs to begin with. So Bäckhed et al., in Gordon's lab did that. As you can see in this figure, that germ free mice accumulated less body fat as compared to those born with germs or those reconstituted with normal germs(Conv-R and Conv-D). And that is despite germ free mice eating more food, indictating that microbes do control how food you eat is processed, absorbed and even used by the body. They went ahead and confirmed this in 2007, showing the mechanism by which the microbes affect the the utilization of what we eat. Even interesting is the fact that you can make germ free mice and add bacteria from obese mice(Turnbaugh et al., 2006) and you will see that these mice gain weight like anything. Now, one of the biggest criticisms of using germ free animal models have been that any transplantation of gut microbiome in these animals, just causes an increase in them gaining fat mass. But there is an alternative to using germ free system. You can clean off the gut microbiome of adult mice using antibiotics. Post clearing you can put in the microbiome of your choice and see what happens. From some preliminary studies it does seem to atleast partly replicate what was observed in transferring microbes to germ free mice(Ellekilde et al., 2014)

Microbiome, Inflammation and Diabetes

So, one way to think about it is that altered gut microbiome causes obesity and obesity come in a package with chronic inflammation. This in turn causes insulin resistance. But, that is not the complete story. The microbes can promote the inflammation directly, as well. For example, low levels of Lipopolysaccharide(LPS, a bacterial toxin molecule which promotes inflammation) in blood, have been found to be associated with unhealthy microbiome(Musso and Gambino, 2010). The the bacterial toxins then make immune cells secrete inflammatory cytokines, such as - TNF-alpha, IL6 and INF-gamma which are known to cause insulin resistance.

It controls your mind

We saw in my previous post that LPS activates a receptor, TLR4 on macrophages which causes inflammation in hypothalamus among other places. This inflammation causes disregulatuon of appetite making you an obsessive binge eater. In fact, apart from regulating how food is absorbed and utilized, it also appears that gut microbes make the germ free mice, transplanted with microbes from obese mice, to compusively overeat(Mulder's et al., 2018)

Which should rather make us wonder that are these tiny beasts of few micrometers writing our menu or something? Aclock, Maley and Atipis may agree. They discuss how the different toxins can alter our mood and our cravings for food. In fact in line with this Soto et al., published this year in molecular psychiatry. They show that microbes present in diet induced obesity model has a differential affect on neurotransmitters signalling. This in fact can modulate eating behaviour of mice among other things.

Diet alters microbiome

Also, not only they can affect what we eat but even your diet can mould the abundance of which microbiota you harbour. For instance the typical western diet bias the Firmicutes/Bacteriodetes ratio towards Firmicutes(these are two out of many classes of bacteria in your gut). This pattern is generally associated with obesity and type 2 diabetes development as well(Musso and Gambino, 2010). But then we all have that one friend that just won't gain weight or get metabolic disease no matter how much s/he eats? What up with this guy, like seriously?

Your Genes can pick you microbial friends.

Well one probable reason might be that this friend of yours just harbour the gut microbes that keep them fit. But if diet could change the gut microbes why isn't it changing in these people? Well, it appears that not only these microbes can affect our biology, but our biology upto some extent can select which microbes we favor. At least this is what it looks like from twin studies, where monozygotic twins are more similar in terms of microbiome than dizygotic twins. (Dąbrowska and Witkiewicz). Mostly genes implicated in immune system development, metabolism and gut epithelium can mould this. Though exact mechanism needs further research, and I think it's a research worth pursuing. Nevertheless you need to keep in mind that not only our genes select what microbes we carry around but the microbes themselves can affect the expression of genes via epigenetic(regulation of expression of genes) pathways(Fellows et al., 2018)

Aging - That senile bacteria!

Anyway, diet, obesity, inflammation and genetics seem to fit together in picture with microbiome in onset of type 2 diabetes. Nonetheless, I mentioned in my previous article as well that not every aged person is obese, but diabetes incidence increase with age. This should make you ask - what the hell is up with aging and microbiome, if anything. Now the cause effect relationship in age and microbiome changes is not really clear, but the microbiome does seem to be altered with age. In fact it might be in a two way relationship for all we know.(Nagpal et al., 2018). I think both accumulating senescence in gut epithelium and the weak and senile immune system may contribute to this. One possibility is that weak immune system in elderly may not be able to inhibit residency of bad microbes as much as that of young would.

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Health Tips and future therapies for type 2 diabetes.

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What does all this research mean for humans? How can this information help us take better decisions in life? What therapeutic value does it hold, if any? Well, now that we have established that gut microbiome does have a contribution in development of type 2 diabetes, rather than just being a predictor of it, it becomes obvious to find ways to target it.

The unwanted curse of C-section, the wrong bacteria!

For instance, take an example of babies born via conventional vaginal birth vs C-section. It has been observed that C-section babies are full of skin microbiota rather than usual vaginal microbes. This might contribute to high prevelence of obesity and other maladies correlated with C-section births(Martinez et al., 2017). Now C-section is an important medical procedure which has contributed to decreased infant mortality rate and is really necessary at times. But in order to intervene and find a way around it, Rob Knight populated his new born C section baby with vaginal microbiome(see bonus video below).

Don't abuse Antibiotics, just don't

Apart, from this I would be careful in using antibiotics. At least try to avoid abusing them. The use of antibiotics in kids, the shift in microbiome composition, and obesity have been correlated(Turta and Rautava, 2016). Nevertheless, antibiotics are sometimes really crucial in fighting many infections. If you have to take it, don't forget to pop some probiotics along with it, which I hope your doctor prescribed you anyway. Infact the probiotics and prebiotics have yielded interesting results in improving insulin sensitivity in animal studies. And, soon clinical trials may follow for checking their efficiency in prevention of type 2 diabetes progression.(Kim et al., 2018)

Feed the good guys

Your dietary habits can keep your microbiome healthy. You should in fact personalize your diet regime, because it appears that how one responds to certain nutrient in food is very personal to an individual(Zeevi et al., 2015). Now this can result from your genetics, epigenetics and gut microbiome. Nevertheless, unless you know what is best for you I would suggest that avoiding a combination of High fat and high sugar diet would be best idea. Moreover, if you are a foodie like me including a high fibre meal in your diet every now and seems to be a good idea to maintain a healthy microbiome.(Desai et al., 2016).

Finally, this made me wonder that if gut microbiome is contributing to type 2 diabetes, what about just replacing unhealthy microbiome with healthy one? Yes I mean fecal transplant if you were wondering. It so happens that clinical trial for this has already been performed upto phase 3. So if you take microbes from gut of lean person and transfer it to patients with type 2 diabetes, you can improve insulin sensitivity. The effect was transient but it seemed effective in these patients. However the catch was that efficacy of intervention also depended on preexisting microbiota population in these people(Koottee et al., 2017). Which means not everyone was able to benefit from it. However, further optimisation of the intervention(maybe getting rid of all pre-existing microbes and repopulating the gut) would make it beneficial for everyone. Modifying the gut microbiome composition by use of drugs and diet is also on the table.

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Steembasicincome giveaway

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Now, I did intentionally leave out the connection of gut microbiome, phychological health(stress, depression, anxiety) inflammation and type 2 diabetes. I think that kind of deserves an article of its own. Also I had another selfish motive for doing so. I want to pick people for sponsoring @steembasicincome shares. So how do you think microbes can cause type 2 diabetes via psychological conditions or how psychological conditions can cause type 2 diabetes via microbiome path. Connect the dots in the comments. I will reward one logical and interesting hypothesis with 2 shares of steembasicincome.

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Bonus video

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Rob Knight's Talk

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Type 2 diabetes series

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1. Type 2 Diabetes - from the eyes of immune cells.

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References

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