Type 2 Diabetes - The gut feeling that you might be a bacteria

in #steemstem6 years ago (edited)

March 2017, I was attending a lecture by Rob Knight(the God of microbiome), at Keystone fibrosis symposia, Snowbird, Utah. And he just stardled me with a random fact in his talk. He said, and I quote(not in identical words, but the point he made) -

If you just take an entire human and extract all the DNA, 99% of that DNA content will be of bacteria! So you are just 1% human and 99% bacteria. You can also count the number of human cells and number of bacteria. They outnumber us by 10 bacterial cell for every human cell in the body.

So it is kind of hard to imagine that cells that out number the human cells in our body, have no role in keeping us alive and kicking(or even making us sick for that matter). Well they do have a role in many aspects of life, but for purpose of this article I will dig into its role in onset of Type 2 diabetes.

image

They are all around us, they are on us, maybe they are us!
Source | Created by Nogas1974
[CC BY-SA 4.0](CC BY-SA 4.0)


Recap


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.


The story of Microbiome


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)


Altered microbiome - Altered metabolism


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.

image

The microbiome interacts with the known risk factors of type 2 diabetes.
Created by @scienceblocks


The Obesity axis

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.


Health Tips and future therapies for type 2 diabetes.


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.


Steembasicincome giveaway


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.


Bonus video


Rob Knight's Talk


Type 2 diabetes series


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

References


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  3. Turnbaugh PJ, Hamady M, Yatsunenko T, Cantarel BL, Duncan A, Ley RE, Sogin ML, Jones WJ, Roe BA, Affourtit JP, Egholm M, Henrissat B, Heath AC, Knight R, Gordon JI. A core gut microbiome in obese and lean twins. Nature. 2009 Jan 22;457(7228):480-4. doi: 10.1038/nature07540. Epub 2008 Nov 30. PubMed PMID:19043404; PubMed Central PMCID:PMC2677729.

  4. Bäckhed F, Ding H, Wang T, Hooper LV, Koh GY, Nagy A, Semenkovich CF, Gordon JI. The gut microbiota as an environmental factor that regulates fat storage. Proc Natl Acad Sci U S A. 2004 Nov 2;101(44):15718-23. Epub 2004 Oct 25. PubMed PMID: 15505215; PubMed Central PMCID:PMC524219.

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  6. Turnbaugh PJ, Ley RE, Mahowald MA, Magrini V, Mardis ER, Gordon JI. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature. 2006 Dec 21;444(7122):1027-31. PubMed PMID: 17183312.

  7. Ellekilde M, Selfjord E, Larsen CS, Jakesevic M, Rune I, Tranberg B, Vogensen FK, Nielsen DS, Bahl MI, Licht TR, Hansen AK, Hansen CH. Transfer of gut microbiota from lean and obese mice to antibiotic-treated mice. Sci Rep. 2014 Aug 1;4:5922. doi: 10.1038/srep05922. PubMed PMID: 25082483; PubMed Central PMCID: PMC4118149.

  8. Musso G, Gambino R, Cassader M. Obesity, Diabetes, and Gut Microbiota: The hygiene hypothesis expanded? Diabetes Care. 2010;33(10):2277-2284. doi:10.2337/dc10-0556.

  9. Mulders RJ, de Git KCG, Schéle E, Dickson SL, Sanz Y, Adan RAH. Microbiota in obesity: interactions with enteroendocrine, immune and central nervous systems. Obes Rev. 2018 Apr;19(4):435-451. doi:10.1111/obr.12661. Epub 2018 Jan 23. Review. PubMed PMID: 29363272.

  10. Alcock J, Maley CC, Aktipis CA. Is eating behavior manipulated by the
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    Review. PubMed PMID: 25103109; PubMed Central PMCID: PMC4270213.

  11. Soto M, Herzog C, Pacheco JA, Fujisaka S, Bullock K, Clish CB, Kahn CR. Gut microbiota modulate neurobehavior through changes in brain insulin sensitivity and metabolism. Mol Psychiatry. 2018 Jun 18. doi: 10.1038/s41380-018-0086-5. PubMed PMID: 29910467.

  12. Dąbrowska K, Witkiewicz W. Correlations of Host Genetics and Gut Microbiome Composition. Front Microbiol. 2016 Aug 30;7:1357. doi: 10.3389/fmicb.2016.01357. eCollection 2016. Review. PubMed PMID: 27625642; PubMed Central PMCID: PMC5003823..

  13. Rachel Fellows et al. Microbiota derived short chain fatty acids promote histone crotonylation in the colon through histone deacetylases, Nature Communications (2018). DOI: 10.1038/s41467-017-02651-5

  14. Nagpal R, Mainali R, Ahmadi S, Wang S, Singh R, Kavanagh K, Kitzman DW, Kushugulova A, Marotta F, Yadav H. Gut microbiome and aging: Physiological and mechanistic insights. Nutr Healthy Aging. 2018 Jun 15;4(4):267-285. doi: 10.3233/NHA-170030. Review. PubMed PMID: 29951588; PubMed Central PMCID: PMC6004897.

  15. Martinez KA 2nd, Devlin JC, Lacher CR, Yin Y, Cai Y, Wang J, Dominguez-Bello MG. Increased weight gain by C-section: Functional significance of the primordial microbiome. Sci Adv. 2017 Oct 11;3(10):eaao1874. doi: 10.1126/sciadv.aao1874. eCollection 2017 Oct. PubMed PMID: 29026883; PubMed Central PMCID: PMC5636202.

  16. Turta O, Rautava S. Antibiotics, obesity and the link to microbes - what are we doing to our children? BMC Med. 2016 Apr 19;14:57. doi: 10.1186/s12916-016-0605-7. PubMed PMID: 27090219; PubMed Central PMCID: PMC4836077

  17. Kim YA, Keogh JB, Clifton PM. Probiotics, prebiotics, synbiotics and insulin sensitivity. Nutr Res Rev. 2018 Jun;31(1):35-51. doi: 10.1017/S095442241700018X. Epub 2017 Oct 17. PubMed PMID: 29037268.

  18. Zeevi D, Korem T, Zmora N, Israeli D, Rothschild D, Weinberger A, Ben-Yacov O, Lador D, Avnit-Sagi T, Lotan-Pompan M, Suez J, Mahdi JA, Matot E, Malka G, Kosower N, Rein M, Zilberman-Schapira G, Dohnalová L, Pevsner-Fischer M, Bikovsky R, Halpern Z, Elinav E, Segal E. Personalized Nutrition by Prediction of Glycemic Responses. Cell. 2015 Nov 19;163(5):1079-1094. doi: 10.1016/j.cell.2015.11.001. PubMed PMID: 26590418.

  19. Desai MS, Seekatz AM, Koropatkin NM, Kamada N, Hickey CA, Wolter M, Pudlo NA, Kitamoto S, Terrapon N, Muller A, Young VB, Henrissat B, Wilmes P, Stappenbeck TS, Núñez G, Martens EC. A Dietary Fiber-Deprived Gut Microbiota Degrades the Colonic Mucus Barrier and Enhances Pathogen Susceptibility. Cell. 2016 Nov 17;167(5):1339-1353.e21. doi: 10.1016/j.cell.2016.10.043. PubMed PMID:27863247; PubMed Central PMCID: PMC5131798.

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Signing off
@scienceblocks

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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

Well when I am stressed I get chocolate or ice-cream cravings. So, according to your post, if I am stressed for a long period of time and follow my cravings then it might alter my microbiome which in the long run might lead to a higher risk of diabetes D:

That does make sense. So 2 sbi coming your way.

Thankies

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My guess is that it may have to do with your bodies response to stress. I know stress has a hormonal response and we'll have more cortisol in our system or some other hormone. I think our bodies would have a similar thing going on like it did with the chronic inflammatory response.

And It controls your brain. so if we're binge eating food with no nutrient density then it makes thing 100x's worse if we have poor habits.

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This is a fascinating post @scienceblocks!

Over the years I have become increasingly more interested in reading materials like this because of the amount of studies that have been associating; for example, gut microbiome and mental disorders (e.g depression and anxiety). And, here you are talking about how microbes may cause compulsive eating!

Oh, before I go:

...can be used to identify you(yeah it has forensic applications.

Wow! 😳

All the best to you and thank you for sharing this work! :)

Wow, I have been a fan of your blog. Feels good to see a comment from you. And I know right, it is pretty amazing that these microbes can affect our mental health by modulating the neurotransmitter signalling. Actually there was a study about how the microbes intervene with vagus nerve signalling as well. But I avoided talking about it in order to keep it all simple.

I am planning on hitting the psychology metabolism axis in my next blog. I hope you like that as well. And thanks for reading and your time.

Oh, great! I am looking forward to reading your next blog already, then :)
Ps: Thank you very much for your kind words!

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Informative post @scienceblocks ,getting new knowledge is always good.Always post informative posts like this.good

Post is no doubt very good but very time consuming to read. Make it short or you may divide it in 2-3 parts.



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I've read your post. There are many scientific information in this post. For which I upvoted for you.

I also have a scientific post, it's link:- https://steemit.com/science/@arsadulislam/einstein-s-theory-of-relativity-is-proven

If you like my post, then give a vote
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Hey Scienceblocks,

thank you very much for this interesting article again.

Recently I came across another interesting research article concerning the microbiome. In an article published in nature they found that even non-antiobiotic drugs such as antidepressants and PPIs can change your microbiome tremendously.

So guys, don't take every bitter pill the doctor offers you, check the article above first.

Best

Chapper

It is not surprising that it does. Since I am out right now, I can't get access the full text. Do they comment on how does anti depressant change the microbiome. Like is the change more similar to microbiome of obese, lean, depressed, happy individuals?

Yes, I have no idea what you gonna about this ;-)