The bacteria in your gut affect blood insulin levels and may influence your chances of developing type 2 diabetes

Developing type 2 diabetes is for a large part influenced by your diet but also genes. However, a recent study has now shown that your gut microorganisms might also play an important role in the risk of developing type 2 diabetes (T2D). The article published in Nature Genetics entitled “Causal relationships among the gut microbiome, short-chain fatty acids (SCFA’s) and metabolic diseases”, claims evidence that bacterial metabolites such as SCFA’s are able to influence insulin levels and increase the risk of getting T2D.

Various studies have suggested that increased SCFA production benefits the host by exerting anti-obesity and antidiabetic effects, however, results of different studies are not always in agreement. Moreover, there is also evidence that increased production of SCFAs in the gut might be related to obesity, due to energy accumulation. Resolving these conflicting findings requires a detailed understanding of the causal relationships between the gut-microbiome and host energy metabolism, and the present study contributes to this.

The authors analyzed data from a large population study based in Groningen (The Netherlands), comprising 952 individuals with known genetic data, as well as information on parameters associated with metabolic traits such as BMI and insulin sensitivity. In addition, data were acquired for the type and the function of the bacteria which were present in the gut of the study participants. Combining this data, the authors tried to answer the question of whether changes in microbiome features causally affect metabolic traits or vice versa?

A technique called Mendelian randomization (MR) which is increasingly accepted to establish cause-effect relationships in the onset of diseases was applied. The primary outcome of the analysis was that host genes influence the production of the SCFA butyrate in the gut, which is associated with improved insulin response in the blood after an oral glucose tolerance test. In addition, abnormalities in the production or absorption of propionate, another SCFA, were causally related to an increased risk of T2D.

So far available data suggest that overweight humans or those with type 2 diabetes may have different microorganisms in their gut compared to healthy people. These microorganisms which are commonly found in healthy people are absent from the T2D patients. Whether the differences in the microbiota between healthy and T2D patients are an effect of the disease development or account for causality is challenging to be answered. With the data from the present study, authors are able to go one step further and demonstrate potential routes by which microorganisms are able to regulate our metabolic status underlying their importance for our wellbeing.

Collectively the present article suggests that production of bacterial SCFA’s play a pivotal role in the regulation of metabolic traits such as blood insulin levels and are associated with the onset of T2D.

Since the study was observational and did not include any T2D patients, confirmation of the results is essential. Follow up studies including T2D patients would be highly informative. With the rising prevalence of obesity in adults, which is reaching epidemic levels, the prevalence of T2D will also continue to rise. In the past years, scientists have mainly focused on the role of human gene data, but this has not led to major breakthroughs. Perhaps knowledge of the microbiome will elucidate molecular mechanisms which can be translated to novel effective treatments for metabolic disorders such as T2D.

REFERENCES
Sanna, S., van Zuydam, N. R., Mahajan, A., Kurilshikov, A., Vila, A. V., Võsa, U., . . . Oosting, M. (2019). Causal relationships among the gut microbiome, short-chain fatty acids and metabolic diseases. Nature genetics, 1.

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Real time measurements of intestinal
gases: a novel method to study how food is being digested

Researchers in Wageningen (The
Netherlands), have been able to identify for the first time, how gut microorganisms
process different types of carbohydrates by measuring in real time the intestinal
gases of mice. This is not only a novel method to understand how food is
digested but could also tell us more about the role of gut microorganisms in
gut health.

Intestinal gases

The intestinal microbiota is a diverse and
dynamic community of microorganisms which regulate our health status. The
advancement of biomolecular techniques and bioinformatics nowadays allows
researchers to explore the residents of our intestines, revealing what type of microorganisms
are there. However, studying only the microbial composition of an individual
provides limited insights on the mechanisms by which microorganisms can
interact with the rest of our body. For example, far less is understood about
the contribution of the gut microorganisms in the production of intestinal
gases such as hydrogen, methane and carbon dioxide through the breakdown of
food and how these gases affect the biochemical pathways of our bodies.

Intestinal gases consist mostly of
nitrogen, and carbon dioxide, which originate primarily from inhaled air. Hydrogen
and methane though, are produced as by-products of carbohydrate fermentation
(break down), by intestinal microorganisms. However, not all carbohydrates are
digested in the same way. For instance, food with simple sugars can be rapidly absorbed
in the small intestine unlike complex carbohydrates such as fibers, which reach
the colon where they are digested by the colonic microbiota.

Lower_digestive_system

Measuring hydrogen in mouse intestines

To study these interactions and gain
knowledge on how microorganisms process carbohydrates, the research team led by Evert van
Schothorst from the Human and Animal Physiology Group of Wageningen University
(WU) in collaboration with the WU-Laboratory of Microbiology fed mice two
different diets with the same nutritional values but with different types of carbohydrates
(1). The first diet contained amylopectin,
a carbohydrate which can be digested readily in the small intestine while the
second diet contained amylose, a slowly digestible carbohydrate that is
digested by intestinal microorganisms in the colon.

Animals fed the easily digestible carbohydrates
showed minimal production of hydrogen whereas the group fed with the complex
carbohydrates presented high levels of hydrogen. Moreover, the two groups were
characterized not only by distinct microbial composition (different types of
bacteria present) but also distinct metabolic profiles (short chain fatty acids),
suggesting that the type of carbohydrate strongly affects microbial composition
and function.

The importance of
hydrogen

Hydrogen consumption is essential in any anoxic
(without oxygen) microbial environment to maintain fermentative processes. In
the intestine it can be utilised through three major pathways for the
production of acetate, methane and hydrogen sulphide. These molecules are
critical mediators of gut homeostasis, as acetate is the most predominant short
chain fatty acid produced in mammals with evidence suggesting a role in inflammation and obesity (2). Methane, which is produced by a specific type of microorganisms,
called archaea, has been associated with constipation related diseases, such as
irritable bowel syndrome(3) and also recently with athletes’ performance (4)! Finally hydrogen sulphide
is considered to be a toxic gas, although recent findings support the notion
that it also has neuroprotective effects in neurodegenerative disorders such as
Parkinson and Alzheimer diseases (5).

To the best of our knowledge, this is the first time that food-microbiota interactions have been studied continuously, non-invasively and in real time in a mouse model. Hydrogen is a critical molecule for intestinal health and understanding its dynamics can provide valuable information about intestinal function, and deviations in conditions such as Crohn’s disease or irritable bowel syndrome (IBS).

Further reading

1. Fernández-Calleja, J.M., et al., Non-invasive continuous real-time in vivo analysis of microbial
hydrogen production shows adaptation to fermentable carbohydrates in mice.

Scientific reports, 2018. 8(1): p.
15351.

https://www.nature.com/articles/s41598-018-33619-0

2.
Perry, R.J., et al., Acetate mediates a
microbiome–brain–β-cell axis to promote metabolic syndrome.
Nature, 2016. 534(7606): p. 213

3. Triantafyllou, K., C. Chang, and M. Pimentel,
Methanogens, methane and gastrointestinal
motility.
Journal of neurogastroenterology and motility, 2014. 20(1): p. 31.

4. Petersen, L.M., et al., Community characteristics of the gut microbiomes of competitive
cyclists.
Microbiome, 2017. 5(1):
p. 98.

5. Cakmak,
Y.O., Provotella‐derived hydrogen sulfide, constipation,
and neuroprotection in Parkinson’s disease. Movement Disorders, 2015. 30(8): p.
1151-1151.

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Recently, the idea that gastrointestinal microbiota are able to affect host behaviour is gaining momentum and it is based on studies conducted with animal models but also in humans with neurological disorders. However, the mechanisms that underlay this complex interplay between gut, brain and microbiota are not completely understood. Here we discuss recent findings on how microbial products could potentially affect the gut-brain axis.

Intestinal microbiota grow through the fermentation of undigested carbohydrates that end up in the large intestine. It was shown that absence of microbes or disruption of the microbiota, led to increased populations of impaired microglia cells in mice. Microglia cells are the primary effector cells for immune signalling to the central nervous system. The presence of a complex microbiota community, was shown to be essential for proper microglia maturation and function [1].

The main products of microbial fermentation in the gut are; acetate, propionate and butyrate, collectively known as short chain fatty acids(SCFA’s). Their beneficial role in human physiology have been well described, and recently evidence suggests that these molecules are able to cross blood brain barrier [2]. Moreover, gut microbiota have been associated with the brain barrier integrity. Mice raised in absence of bacteria are reported to have reduced brain barrier integrity. Once colonized with either a butyrate or an acetate/propionate producing bacteria, significant improvements were reported in the barrier [3]. Notably the integrity of the blood-brain barrier from the germ free mice was able to be restored through the oral administration of butyrate.

Gut_Microbes and Mental HealthSCFA’s are among the molecules having the privilege to cross the blood brain barrier and access the brain directly, their role should be studied in detail.

Recent studies also demonstrate that gut microbes regulate levels of intestinal neurotransmitters. The enteric nervous system interacts with a plethora of neurotransmitters (more than 30 have been identified so far.) Actually, the bulk of serotonin production ~90%, a neurotransmitter associated with mood and appetite is located in the gut. Specialized cells known as enterochromaffin cells are the main serotonin producers in the gut. In the absence of intestinal microbiota gastrointestinal serotonin levels are depleted. However, they can be restored by the addition of a specific spore forming consortium of intestinal bacteria. Specific bacterial metabolites have been reported to mediate this effect [4].

Other intestinal microbiota have been reported also to regulate the levels of the GABA neurotransmitter. Reduced levels of GABA have been associated with anxiety, panic disorder and depression. Bacterial GABA producers have been known to exist for years but it was not until 2016 that a gut bacteria was identified as GABA consumer [5]. For example, decreased levels of bacterial GABA producers were identified in a human cohort of depressed individuals. Studies in mice reinforce these findings. Intervention with the lactic acid bacteria Lactobacillus rhamnosus (JB-1) in healthy mice reduced anxiety related symptoms (accompanied by a reduction in the mRNA expression of GABA receptors in the Central Nervous System.) Lactic acid producing bacteria have also been reported to produce GABA in several food products such as kimchi, fermented fish and cheese [6].

Collectively, our gut microbiota encodes for ~100 times more genes than the human genome. The potential for some of these microbial genes to produce compounds able to interact with the nervous system and regulate critical pathways implicated in the gut brain axis is realistic and worth being explored.

Authors Prokopis Konstanti, MSc and Clara Belzer, PhD are working in the Department of Molecular Ecology, Laboratory of Microbiology, Wageningen University, Netherlands.

Footnotes

  1. Erny, D., et al., Host microbiota constantly control maturation and function of microglia in the CNS. Nature neuroscience, 2015. 18(7): p. 965-977.
  2. Joseph, J., et al., Modified Mediterranean Diet for Enrichment of Short Chain Fatty Acids: Potential Adjunctive Therapeutic to Target Immune and Metabolic Dysfunction in Schizophrenia? Frontiers in Neuroscience, 2017. 11(155).
  3. Braniste, V., et al., The gut microbiota influences blood-brain barrier permeability in mice. Science translational medicine, 2014. 6(263): p. 263ra158-263ra158.
  4. Yano, J.M., et al., Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis. Cell, 2015. 161(2): p. 264-276.
  5. P. Strandwitz, K.K., D. Dietrich, D. McDonald, T. Ramadhar, E. J. Stewart, R. Knight, J. Clardy, K. Lewis; , Gaba Modulating Bacteria of the Human Gut Microbiome. 2016.
  6. Dhakal, R., V.K. Bajpai, and K.-H. Baek, Production of gaba (γ – Aminobutyric acid) by microorganisms: a review. Brazilian Journal of Microbiology, 2012. 43(4): p. 1230-1241.

 

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