Researchers from Groningen University, The Netherlands discovered that bacteria from our gut can metabolize and block the action of the main drug used to treat Parkinson’s disease [1].

Parkinson’s disease is related to low levels of dopamine in the brain and the main treatment for the patients is levodopa (L-dopa), a precursor of dopamine. The drug is absorbed in the small intestine and through the bloodstream is transported to the brain, where it is converted into dopamine.

Prior studies showed that only part of the drug reaches the brain. This is because the human enzyme tyrosine decarboxylase (TDC) converts L-dopa to dopamine before it can get to the brain. Dopamine is too big to cross the strict barrier between the blood and the brain (while L-dopa can cross this barrier), so when this happens the drug can’t reach the brain regions that it needs to reach to treat Parkinson’s disease.

To avoid this early conversion of L-dopa to dopamine, patients receive L-dopa in combination with another drug, Carbidopa, which inhibits the activity of the human TDC enzyme. However, even with the combined treatment, L-dopa efficacy varies greatly between patients, meaning that for some patients the drug works well but for others, it doesn’t.

Since it was known that some bacteria have also TDC enzymes, researchers from Groningen University tried to answer whether these enzymes are present also in the gut bacterial communities and if yes, what is their implication with L-dopa treatment. For the first time, researcher El Aidy and her team discovered that some bacteria from the small intestine of the rats had TDC enzymes and were able to convert L-Dopa into dopamine similarly to the human TDC [1].

Furthermore, rats that had a lot of bacterial TDC in the small intestines also had less L-dopa and more dopamine in the bloodstream. This suggests that bacterial TDC is converting L-dopa to dopamine in the gut before it reaches the brain.

The next step was to test the effect of drugs, known to be effective against human TDC such as Carbidopa, against bacterial TDC. Carbidopa was highly effective in blocking the action of the human TDC (as we already knew), but it had minimal effect on the bacterial enzymes. This can explain why the effect of the drug differs between patients, even when they are given Carbidopa. It all depends on how much bacterial TDC a person has in his or her intestines.

To confirm these findings, researchers used also human fecal samples from patients with Parkinson’s disease. Indeed, results were in accordance with the animal studies: patients with high bacterial TDC in their gut were the ones who required higher dosages of L-dopa.

The human gut is colonized by a wide diversity of micro-organisms, and the more we learn about these bacteria, the more it becomes clear that it is very important to our overall health. However, even though our knowledge the gut bacteria increased rapidly the past decade, little still is known about their effect on drug metabolism. This seminal study, for the first time, describes how gut bacteria affect drug availability in patients with Parkinson’s disease and explains why some people require a higher dosage of L-dopa for the treatment to be effective. The next step is to find a way to also limit the effect of bacterial TDC on L-dopa and allow the drug to work as intended.

REFERENCES:
[1] van Kessel, Sebastiaan P., et al. “Gut bacterial tyrosine decarboxylases restrict levels of levodopa in the treatment of Parkinson’s disease.” Nature communications 10.1 (2019): 1-11.

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Can the gut microbiome help us treat autism?

Can the gut bacteria help us to fight autism? According to a recently published study, introducing bacteria from healthy individuals into the gut of the children diagnosed with autism spectrum disorders (ASD) can markedly improve not only gut function but also the severity of ASD symptoms.

ASD affect social interactions and communication, characterized by restricted, repetitive patterns of behavior, and activities. Currently, no cure exists for ASD treatment, but some medicines are available and can help with symptoms like depression, seizures, and insomnia. Due to the limited treatment options, scientists are looking for novel ways to treat autism and recently the role of the bacteria which live in our gut, is under evaluation as a new target for treatment. Children with ASD often suffer from gastrointestinal  disorders, suggesting that the gut-brain axis is regulating ASD. In fact, there is some evidence in the literature where the severity of such disorders was linked with ASD severity.

Among the first observations supporting a role for the gut bacteria, stem from germ-free mice (mice born without being exposed to bacteria) which showed depressive-like behavior. Several studies showed that this abnormality can be corrected through colonization with gut bacteria.  In humans, several previous studies have reported differences in the composition of the gut bacteria when comparing children with and without ASD. Hence, the question which arises is can we change these bacteria in a way to change also disease activity?  

In 2017 a study called “Microbiota Transfer Therapy alters the gut ecosystem and improves gastrointestinal and autism symptoms: an open-label study,” published in Microbiome journal, showed evidence that gut bacteria can potentially be used in autism treatment. During this study, researchers used the microbes which were present in the feces of healthy individuals without ASD and transplanted them to children with ASD. This treatment not only reduced gut problems but also improved autism symptoms.

The rationale behind this treatment is that beneficial bacteria from healthy individuals will be introduced in the gut of the children with ASD, correcting microbial disbalances and improving their gut function. However, the question in studies that target microbiota is whether the improvements are transient or have a long-lasting effect.

Two years after the first publication of the microbiota transfer therapy, the authors published the follow-up results from the same group of children and demonstrate that the beneficial effects from fecal transplantation, in both gut problems and ASD symptoms were persistent. In addition, both parents and a professional evaluator reported a slow but steady reduction of core ASD symptoms (language, social interaction, and behavior)  during treatment and over the next two years.

These findings are highly promising for microbiota transplantation as a non-pharmacological treatment for children with ASD with gastrointestinal problems. However, as authors write in their article the cure is not there yet and “We recommend future research including double-blind, placebo-controlled randomized trials with a larger cohort.” Emphasizing the necessity to understand better the mechanism first of the fecal microbiota transfer before it can be applied it as a treatment.

 

Further reading:

Dae-Wook Kang et al. 2019. “Long-term benefit of Microbiota Transfer Therapy on autism symptoms and gut microbiota”, Scientific Reports, 9. https://www.nature.com/articles/s41598-019-42183-0

Dae-Wook Kang et al. 2017. “Microbiota Transfer Therapy alters gut ecosystem and improves gastrointestinal and autism symptoms: an open-label study”. Microbiome, 5. https://microbiomejournal.biomedcentral.com/articles/10.1186/s40168-016-0225-7

 

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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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This project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 728018

New Brain Nutrition is a project and brand of Eat2BeNice, a consortium of 18 European University Hospitals throughout the continent.

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