Metformin influences gut microbiome

A recent study at Sahlgrenska Academy and University of Girona indicates thatcontrol of blood glucose by metformin is achieved partly through modulation of the gut microbiota. Results of the study are published in journal Nature Medicine.

Fredrik Bäckhed’s research group at Sahlgrenska Academy has previously shown that the gut microbiota is altered in patients with type 2 diabetes and after bariatric surgery. By conducting a clinical study in patients with new onset diabetes, the group could clarify how the gut microbiomeis affected by metformin.

Sequencing of the microbiome of 22 patients before and after treatment compared with a placebo treated group of patients showed that the gut microbiome was altered dramatically within two months of treatment. Through experiments in the laboratory, the researchers demonstrated that metformin increases the growth of several bacterial species that are linked to improved metabolism.

Citation: Wu, Hao, Eduardo Esteve, Valentina Tremaroli, Muhammad Tanweer Khan, Robert Caesar, Louise Mannerås-Holm, Marcus Ståhlman, Lisa M. Olsson, Matteo Serino, Mercè Planas-Fèlix, Gemma Xifra, Josep M. Mercader, David Torrents, Rémy Burcelin, Wifredo Ricart, Rosie Perkins, José Manuel Fernàndez-Real, and Fredrik Bäckhed. “Metformin alters the gut microbiome of individuals with treatment-naive type 2 diabetes, contributing to the therapeutic effects of the drug.” Nature Medicine, 2017.
Adapted from press release by  the University of Gothenburg.

ResistoMap developed to track world wide microbial drug resistance

Scientists from the Federal Research and Clinical Center of Physical-Chemical Medicine, the Moscow Institute of Physics and Technology, and Data Laboratory have created the ResistoMap, an interactive visualization of gut resistome. Gut resistome is human gut microbiota potential to resist antibiotics and includes the set of all antibiotic resistance genes in the genomes of human gut microbes. Their ResistoMap will help identify national trends in antibiotic use and control antibiotic resistance on the global scale. This research is published in journal Bioinformatics.

Resistomap - interactive world map of human gut resistome
Resistomap –  an interactive world map of human gut microbiota potential to resist antibiotics.
Credit: Bioinformatics

Microbial drug resistance is caused by the extensive uncontrolled use of antibiotics in medicine and agriculture. It has been predicted that by 2050 around 10 million people will die annually due to reasons associated with drug resistance.

The ResistoMap has two main interactive work fields: a geographic map and a heat map. A user can choose the antibiotic group or country of interest to be displayed on the heat map and obtain a resistome cross section. The data can be filtered by the country of origin, gender, age, and diagnosis. The current version of the interactive map developed by the authors draws on a dataset that includes over 1600 individuals from 12 studies covering 15 countries. However, the dataset can be expanded by additional input from users reflecting the findings of new published studies in a unified format.

Using the ResistoMap, researchers fee that it is possible to estimate the global variation of the resistance to different groups of antibiotics and explore the associations between specific drugs and clinical factors or other metadata. For example, the Danish gut metagenomes tend to demonstrate the lowest resistome among the European groups, whereas the French samples have the highest levels, particularly of the fluoroquinolones, a group of broad-spectrum anti-bacterial drugs. This is in agreement with the fact that France has the highest total antibiotic use across Western Europe, while the use of antimicrobial drugs in Denmark and Germany is moderate, both in health care and agriculture. At the opposite end of the spectrum, Chinese and Russian populations appear to have increased levels of resistome, which is likely due to looser regulation policies, frequent prescription of broad-spectrum antibiotics, and their over-the-counter availability without prescription. The lowest levels of microbiota resistome are observed in the native population of Venezuela who have no documented contacts with populations of the developed countries. ResistoMap-informed analysis reveals certain novel trends that await further interpretation from the clinical standpoint.

Konstantin Yarygin, one of the creators of the visualization tool, says, “We anticipate that the exploratory analysis of global gut resistome enabled by the ResistoMap will provide new insights into how the use of antibiotics in medicine and agriculture could be optimized.”

Citation: Yarygin, Konstantin S., Boris A. Kovarsky, Tatyana S. Bibikova, Damir S. Melnikov, Alexander V. Tyakht, and Dmitry G. Alexeev. “ResistoMap—online visualization of human gut microbiota antibiotic resistome.” Bioinformatics, 2017.
Research funding: Russian Scientific Foundation.
Adapted from press release by the Moscow Institute of Physics and Technology.

Role of diet and gut microbiome in the major depressive disorder

An international group of researchers headed by André Carvalho has published in Psychotherapy and Psychosomatic a paper that provides new data and prospects for the links between the intestinal flora and several disorders, notably depression.

Persistent low-grade immune-inflammatory processes, oxidative and nitrosative stress and hypothalamic-pituitary-adrenal axis activation are integral to the pathophysiology of the major depressive disorder. The microbiome, intestinal compositional changes, and resultant bacterial translocation add a new element to the bidirectional interactions of the gut-brain axis. New evidence implicates these pathways in the onset of the major depressive disorder. In addition, abnormalities in the gut-brain axis are associated with several chronic non-communicable disorders, which frequently co-occur in individuals with depression, including but not limited to irritable bowel syndrome, chronic fatigue syndrome, obesity, and type 2 diabetes mellitus.

The composition of the gut microbiota is influenced by several genetic and environmental factors (e.g. diet). Several lines of evidence indicate that gut-microbiota-diet interactions play a significant pathophysiological role in depression and related medical comorbidities. Gut dysbiosis and the leaky gut may influence several pathways implicated in the biology of major depressive disorder, including but not limited to immune activation, oxidative and nitrosative stress, and neuroplasticity cascades. However, methodological inconsistencies and limitations limit comparisons across studies.

Authors conclude that intestinal dysbiosis and the leaky gut may constitute a key pathophysiological link between depression and its medical comorbidities. This emerging literature opens relevant preventative and therapeutic perspectives.

Citation: Slyepchenko, Anastasiya, Michael Maes, Felice N. Jacka, Cristiano A. Köhler, Tatiana Barichello, Roger S. Mcintyre, Michael Berk, Iria Grande, Jane A. Foster, Eduard Vieta, and André F. Carvalho. “Gut Microbiota, Bacterial Translocation, and Interactions with Diet: Pathophysiological Links between Major Depressive Disorder and Non-Communicable Medical Comorbidities.” Psychotherapy and Psychosomatics 86, no. 1 (2016): 31-46. doi:10.1159/000448957.
Adapted from press release by Karger medical and scientific publishers.

Sleep loss and change in gut microbiota

Results from a new clinical study conducted at Uppsala University suggest that curtailing sleep alters the abundance of bacterial gut species that have previously been linked to compromised human metabolic health. The new article is published in the journal Molecular Metabolism.

Changes in the composition and diversity of the gut microbiota have been associated with diseases such as obesity and type-2 diabetes in humans. These diseases have also been linked with chronic sleep loss. However, it is not known whether sleep loss alters the gut microbiota in humans. With this in mind, Christian Benedict, associate professor of neuroscience, and Jonathan Cedernaes, M.D., Ph.D, both from Uppsala University, collaborated with researchers from the German Institute of Human Nutrition Potsdam-Rehbruecke. In their study, the researchers sought to investigate in nine healthy normal-weight male participants whether restricting sleep to about four hours per night for two consecutive days as compared with conditions of normal sleep (about 8 hours of sleep opportunity) may alter the gut microbiota in humans.

“Overall we did not find evidence that suggests that the diversity of the gut microbiota was altered by sleep restriction. This was somewhat expected given the short-term nature of the intervention and the relatively small sample size. In more specific analyses of groups of bacteria, we did however observe microbiota changes that parallel some of the microbiota changes observed when for instance obese subjects have been compared with normal-weight subjects in other studies, such as an increased ratio of Firmicutes to Bacteroidetes. Longer and larger clinical sleep interventions will be needed to investigate to what extent alterations of the gut microbiota may mediate negative health consequences attributed to sleep loss, such as weight gain and insulin resistance,” says senior author Jonathan Cedernaes.

“We also found that participants were over 20 percent less sensitive to the effects of the hormone insulin following sleep loss. Insulin is a pancreatic hormone needed to bring down blood glucose levels. This decreased insulin sensitivity was however unrelated to alterations in gut microbiota following sleep loss. This suggests that changes in microbiota may not, at least in the short-term, represent a central mechanism through which one or several nights of curtailed sleep reduce insulin sensitivity in humans,” says first author Christian Benedict.

Citation: Gut Microbiota and Glucometabolic Alterations in Response to Recurrent Partial Sleep Deprivation in Normal-weight Young Individuals.
Authors: Christian Benedict, et., al.
Journal: Molecular Metabolism
Adapted from press release by Uppsala University

Gut bacteria boost chemotherapy drugs in a research trial

Two bacterial species that inhabit the human gut activate immune cells to boost the effectiveness of a commonly prescribed anticancer drug, researchers report in Immunity.The study identifies a new role for Enterococcus hirae and Barnesiella intestinihominis in activating cancer-fighting T cell immune responses, thereby enhancing the effects of the chemotherapy drug cyclophosphamide.

“The anti-cancer drug’s efficacy relies on a complex interplay between the microbiome of cancer patients and their ability to mount an efficient immune memory response against some bacteria of the gut microbiota,” says co-senior study author Mathias Chamaillard, Inserm research director of the Center for Infection and Immunity of Lille.

In a few cases, the antitumor effects of intestinal bacteria can also contribute to the effectiveness of chemotherapy drugs.It has not been clear which specific bacterial species activate antitumor immune responses in response to chemotherapy, and exactly how they do so.

In the new study, Chamaillard and senior study author Laurence Zitvogel of the Institut de Cancérologie Gustave Roussy Cancer Campus showed that two intestinal bacteria, E. hirae and B. intestinihominis, both act to orchestrate the anticancer therapeutic effects of cyclophosphamide-an immunosuppressive chemotherapy drug used to treat a wide range of cancers.

Using mouse models, the researchers showed that oral treatment with E. hirae activated antitumor T cell responses in the spleen in parallel with the direct toxic effects of cisplatin on the tumor, thereby curbing tumor growth. On the other hand, oral treatment with B. intestinihominis achieved a similar effect by promoting the infiltration of T cells in various mouse tumors.

Press release: How gut microbes help chemotherapy drugs