Disentangling type 2 diabetes and metformin treatment signatures in the human gut microbiota

Forslund, Kristoffer; Hildebrand, Falk; Nielsen, Trine; Falony, Gwen; Chatelier, Emmanuelle Le; Sunagawa, Shinichi; Prifti, Edi; Vieira-Silva, Sara; Guðmundsdóttir, Valborg; Pedersen, Helle; Arumugam, Manimozhiyan; Kristiansen, Karsten; Voigt, Anita Y.; Vestergaard, Henrik; Hercog, Rajna; Costea, Paul Igor; Kultima, Jens Roat; Li, Junhua; Jørgensen, Torben; Levenez, Florence; Doré, Joël; Nielsen, Henrik Bjørn; Brunak, Søren; Raes, Jeroen; Hansen, Torben; Wang, Jun; Ehrlich, S. Dusko; Bork, Peer; Pedersen, Oluf

doi:10.1038/nature15766

Cited by 1,629 publications

(1,486 citation statements)

References 48 publications

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“…There is convincing evidence [19,20] that metformin exposure induces significant changes in human intestinal microbiota (for example, decreases in abundance of Intestinibacter), and in the gut metabolome (for example, increased butyrate production). These observations stemmed from efforts to confirm and extend prior research (for examples, [21][22][23]) concerning relationships between microbiota composition, obesity and diabetes.…”

Section: Metformin and Gut Microbiotamentioning

confidence: 99%

The effects of metformin on gut microbiota and the immune system as research frontiers

Pollak

2017

Diabetologia

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Recent studies have revealed that metformin influences gut microbiota and the immune system although neither is a classic target of the drug. This research has revealed complexity not previously appreciated, and opened new research directions. The extent to which immunomodulatory effects and actions on the microbiota are related to each other and account for effects on host energy metabolism remains to be determined. These sites of action may be relevant not only to the efficacy of metformin for its established use in type 2 diabetes, but also to proposed novel indications in oncology and other diseases.

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Section: Metformin and Gut Microbiotamentioning

confidence: 99%

The effects of metformin on gut microbiota and the immune system as research frontiers

Pollak

2017

Diabetologia

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“…[6][7][8][9][10][11] As a consequence, these types of medication could have an effect on the risk of developing enteric infections or gut inflammation, and they may also have an effect on host metabolism. [12][13][14][15] Susceptibility to enteric infections A well-known example of reduced enteric infection resistance through alteration of the gut microbiota caused by medication is the increased risk of Clostridium difficile infections after (repeated) treatment with antibiotics.…”

Section: Consequences Of Gut Microbiota Changes Caused By Medicationmentioning

confidence: 99%

The influence of proton pump inhibitors and other commonly used medication on the gut microbiota

et al. 2017

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Proton pump inhibitors (PPIs), used to treat gastro-esophageal reflux and prevent gastric ulcers, are among the most widely used drugs in the world. The use of PPIs is associated with an increased risk of enteric infections. Since the gut microbiota can, depending on composition, increase or decrease the risk of enteric infections, we investigated the effect of PPI-use on the gut microbiota. We discovered profound differences in the gut microbiota of PPI users: 20% of their bacterial taxa were statistically significantly altered compared with those of non-users. Moreover, we found that it is not only PPIs, but also antibiotics, antidepressants, statins and other commonly used medication were associated with distinct gut microbiota signatures. As a consequence, commonly used medications could affect how the gut microbiota resist enteric infections, promote or ameliorate gut inflammation, or change the host's metabolism. More studies are clearly needed to understand the role of commonly used medication in altering the gut microbiota as well as the subsequent health consequences.KEYWORDS gut microbiota; medication; proton pump inhibitors Proton pump inhibitors affect the gut microbiotaProton pump inhibitors (PPIs), used to treat gastroesophageal reflux and to prevent gastric ulcers, are among the most commonly used drugs in the world.1,2 In the Netherlands, one PPI alone (omeprazole) was the fourth most prescribed drug in 2015. In observational studies, the use of PPIs has been associated with an increased risk of enteric infections caused by Clostridium difficile, Salmonella spp., Shigella spp and Campylobacter spp. [3][4][5] Since the gut microbiota can, depending on composition, increase or decrease the risk of enteric infections, we investigated the effect of PPI use on the gut microbiota. 6 Using the 16S rRNA sequences of stool samples from 1815 individuals spanning 3 independent cohorts, we observed profound changes in the gut microbiota of PPI users. In PPI users the relative abundance of 20% of the bacterial taxa, whereof 18 bacterial families, was statistically significantly different (either increased or decreased) compared with abundances in samples from non-users. 6 Concurrently with our research, other research groups were also investigating the influence of PPIs on the gut microbiota. A small intervention study was published a few months before ours and a similar observational study was published in the same issue of Gut. 7,8 In Table 1, the bacterial alterations associated with PPI use from all 3 studies are presented at the family level. There are many similarities between the results of all 3 studies and, when associations at different taxonomical levels are taken into account (e.g. the decrease of order Clostridiales and increases of class Gammaproteobacteria and order Actinomycetales), a consistent profile of alterations in gut microbiota associated with PPI use emerges. Other commonly used drugs and the gut microbiotaTo ensure that our observed alterations in gut microbiota associated wi...

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“…Examples can be found in the literature in the context of energy-restricted diet in obesity, statins, metformin or digoxin [22,[65][66][67]. Here, specific components of gut microbiota are playing a fundamental role in drug metabolism, showing that they have to be taken into account in pharmacokinetics studies.…”

Section: Metagenomic Analysismentioning

confidence: 99%

The human gut microbiome as source of innovation for health: Which physiological and therapeutic outcomes could we expect?

2017

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Summary From the moment of birth, each human being builds a microbe-host symbiosis which is key for the preservation of its health and well-being. This personal symbiotic coexistence is the result of progressive enrichments in microorganism diversity through external supplies. This diversity is nowadays massively overthrown by drastic changes related to clinical practice in birth management, environmental exposure, nutrition and healthcare behaviors. The last two generations have been the frame of massive modifications in life and food habits, with people being more and more sedentary, overfed and permeated with drugs and pollutants. We are now able to measure the impact of these changes on the gut microbiota diversity. Concomitantly, these modifications of lifestyle were associated with a dramatic increase in incidence of immune-mediated diseases including metabolic, allergic and inflammatory diseases and most likely neurodegenerative and psychiatric disorders. Microbiota is becoming a hot topic in the scientific community and in the mainstream media. The number of scientific publications increased by up to a factor three over the last five years, with gastrointestinal and metabolic diseases being the most productive areas. In the intellectual property landscape, the patent families on microbiota have more than doubled in the meantime. In parallel, funding either from National Institutes (e.g. from NIH which funds research mainly in the field of allergies, infections, cancer and cardiovascular diseases, from the White House which launched the national microbiome initiative) or by pharmaceutical companies follow the same trend, showing a boost and a strong support in the research field on microbiota. All major health players are investing in microbiome research as shown by the number of deals signed and by funding during 2015. The Giens round table addressed how the medicine of tomorrow, considering human beings as a human-microbe symbiotic supraorganism, could leverage microbiome knowledge and tools. The rationale for our working group has been structured around four domains of innovation that could derive from ongoing efforts in deciphering the interactions between human cells and intestinal microbiome as a central component of human health, namely: (1) development of stratification and monitoring tools; (2) identification of new target and drug discovery, as a part of our supra-genome; (4) exploitation of microbiota as a therapeutic target that can be modulated; (4) and finally as a source of live biotherapeutics and adjuvants. These four streams will exemplify how microbiota has changed the way we consider a wide range of chronic and incurable diseases and the consequences of long-lasting dysbiosis. In-depth microbiota analysis is opening one of the broadest fields of investigation for improving human and animal health and will be a source of major therapeutic innovations for tackling today's medical unmet needs. We thus propose a range of recommendations for basic researchers, care givers as well as for hea...

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Disentangling type 2 diabetes and metformin treatment signatures in the human gut microbiota

Cited by 1,629 publications

References 48 publications

The effects of metformin on gut microbiota and the immune system as research frontiers

The effects of metformin on gut microbiota and the immune system as research frontiers

The influence of proton pump inhibitors and other commonly used medication on the gut microbiota

The human gut microbiome as source of innovation for health: Which physiological and therapeutic outcomes could we expect?

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