Effects of Gut Microbiota Manipulation by Antibiotics on Host Metabolism in Obese Humans: A Randomized Double-Blind Placebo-Controlled Trial

Reijnders, Dorien; Goossens, Gijs H.; Hermes, Gerben D. A.; Neis, Evelien P. J. G.; Beek, Christina M. van der; Most, Jasper; Holst, Jens J.; Lenaerts, Kaatje; Kootte, Ruud S.; Nieuwdorp, Max; Groen, Albert K.; Damink, S.W.M. Olde; Boekschoten, Mark V.; Smidt, Hauke; Zoetendal, Erwin G.; Dejong, Cornelis H. C.; Blaak, Ellen E.

doi:10.1016/j.cmet.2016.07.008

Cited by 106 publications

(162 citation statements)

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“…Although 1-week treatment with vancomycin of 57 obese, prediabetic men did lead to significant microbial differences (reduction in diversity and Firmicutes and increase in potentially pathogenic Proteobacteria) [100,101], no beneficial effects on insulin sensitivity, inflammation or gut permeability were demonstrated (101). Vrieze et al [100] even found a negative effect on insulin sensitivity.…”

Section: Pre- Pro- and Antibioticsmentioning

confidence: 99%

The intestinal microbiota, energy balance, and malnutrition: emphasis on the role of short-chain fatty acids

Fluitman

Clercq

Keijser

et al. 2017

Expert Review of Endocrinology & Metabolism

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Introduction: Malnutrition refers to both over-and undernutrition and results from a disruption in energy balance. It affects one in three people worldwide and is associated with increased morbidity and mortality. The intestinal microbiota represents a newly identified factor that might contribute to the development of malnutrition, as it harbors traits that complement the human metabolic and endocrine capabilities, thereby influencing energy balance. Areas covered: In the current review, we aim to give a comprehensive overview on the microbiota, its development and its possible influence on energy balance, with emphasis the role of short-chain fatty acids. We also consider microbial characteristics associated with obesity and undernutrition and evaluate microbial manipulating strategies. The PubMed database was searched using the terms:

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Section: Pre- Pro- and Antibioticsmentioning

confidence: 99%

The intestinal microbiota, energy balance, and malnutrition: emphasis on the role of short-chain fatty acids

Fluitman

Clercq

Keijser

et al. 2017

Expert Review of Endocrinology & Metabolism

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“…Some patients received antibiotics at admission. GI side effects occur during the use of antibiotics; however, in a recent placebo-controlled human study, it was shown that 7-day antibiotics use did not affect intestinal barrier function [54]. Blood gas analysis at the second test day would have supported our understanding of the patients’ condition.…”

Section: Discussionmentioning

confidence: 99%

Increased Small Intestinal Permeability during Severe Acute Exacerbations of COPD

et al. 2018

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Background: Disturbances of intestinal integrity, manifested by increased gastro-intestinal (GI) permeability, have been found in chronic obstructive pulmonary disease (COPD) patients during physical activity, often associated with intermittent hypoxic periods. Evidence about extrapulmonary organ disturbances, especially of the GI tract, during hospitalised acute exacerbation of COPD (AE-COPD) with hypoxaemic respiratory failure (RF) is lacking. Objective: The aim was to assess changes in GI permeability in patients with AE-COPD and during recovery 4 weeks later. Methods: All patients admitted to our hospital with AE-COPD accompanied by hypoxaemia at admission (PaO₂ <8.7 kPa or O₂ saturation <93%) were screened between October 2013 and February 2014. Patients with a history of GI or renal disease, chronic heart failure, or use of non-steroidal anti-inflammatory drugs in the 48 h before the test were excluded. GI permeability was assessed by evaluating urinary excretion ratios of the orally ingested sugars lactulose/L-rhamnose (L/R ratio), sucrose/L-rhamnose (Su/R ratio) and sucralose/erythritol (S/E ratio). Results: Seventeen patients with severe to very severe COPD completed the study. L/R ratio (×10³) at admission of AE-COPD was significantly higher than in the recovery condition (40.9 [29.4–49.6] vs. 27.3 [19.5–47.7], p = 0.039), indicating increased small intestinal permeability. There were no significant differences in the individual sugar levels in urine nor in the 0- to 5-h urinary S/E and Su/R ratios between the 2 visits. Conclusion: This is the first study showing increased GI permeability during hospitalised AE-COPD accompanied by hypoxaemic RF. Therefore, GI integrity in COPD patients is an attractive target for future research and for the development of interventions to alleviate the consequences of AE-COPD.

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“…The skin harbors a rich microbiome (41), and it is an open question as to whether the skin microbiome can be a source of acetate for a subset of melanoma. While this paper was under review, a series of reports showed that gut microbiome contributes to acetate-mediated metabolic syndrome (42)(43)(44)(45). The reliance on aerobic glycolysis of melanoma cells increases lactate secretion, which reprograms the tumor microenvironment to evade the immune system and promote tumor growth (46).…”

Section: Discussionmentioning

confidence: 99%

Glucose-independent Acetate Metabolism Promotes Melanoma Cell Survival and Tumor Growth

Lakhter

Hamilton

Konger

et al. 2016

Journal of Biological Chemistry

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Tumors rely on multiple nutrients to meet cellular bioenergetics and macromolecular synthesis demands of rapidly dividing cells. Although the role of glucose and glutamine in cancer metabolism is well understood, the relative contribution of acetate metabolism remains to be clarified. We show that glutamine supplementation is not sufficient to prevent loss of cell viability in a subset of glucose-deprived melanoma cells, but synergizes with acetate to support cell survival. Glucose-deprived melanoma cells depend on both oxidative phosphorylation and acetate metabolism for cell survival. Acetate supplementation significantly contributed to maintenance of ATP levels in glucose-starved cells. Unlike acetate, short chain fatty acids such as butyrate and propionate failed to prevent loss of cell viability from glucose deprivation. In vivo studies revealed that in addition to nucleo-cytoplasmic acetate assimilating enzyme ACSS2, mitochondrial ACSS1 was critical for melanoma tumor growth in mice. Our data indicate that acetate metabolism may be a potential therapeutic target for BRAF mutant melanoma.Malignant cells undergo metabolic reprograming to fuel proliferation in a nutrient-limited environment. Tumor cells metabolize glucose in the presence of oxygen, a process known as the Warburg effect or aerobic glycolysis (1). The Warburg effect is generally considered as a metabolic hallmark of cancer (2), yet therapeutic targeting of underlying pathways has remained challenging. For example, BRAF inhibitors are the first line therapy for treatment of patients with mutant BRAFdriven melanoma (3). However, rapid development of resistance to these inhibitors involves reduction in glucose uptake and glycolysis (4,5). Recent studies demonstrated that tumor cells are dependent on glutamine metabolism to support cell proliferation (6). Glutamine metabolism enables maintenance of tricarboxylic acid (TCA) 2 cycle intermediates and plays a critical role in suppressing oxidative stress by supplying antioxidants. Although glutamine can synergize with glucose metabolism to support tumor cell proliferation, metabolic tracing studies in glucose-deprived cells revealed that an unknown source of carbon cooperated with glutamine in maintaining TCA cycle intermediates (7). Collectively, these studies suggest that malignant cells rapidly adapt to nutrient limitation by resetting their metabolism to maintain cell proliferation, thus hampering effective treatments.Similar to DNA synthesis, energy production and lipid synthesis are crucial biochemical processes in rapidly dividing cancer cells. Acetyl-CoA, a mitochondrial metabolite responsible for the TCA cycle and energy production is also the primary substrate for lipid synthesis. ATP citrate lyase (ACLY) plays a central role in mobilizing acetyl-CoA from the mitochondria to the cytoplasm. ACLY overexpression is frequently observed in tumors and its inhibition reduces tumor growth (8). Although BRAF inhibitor resistant melanoma shows reduced glucose uptake (4, 5), as opposed to the Warburg e...

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Effects of Gut Microbiota Manipulation by Antibiotics on Host Metabolism in Obese Humans: A Randomized Double-Blind Placebo-Controlled Trial

Cited by 106 publications

References 0 publications

The intestinal microbiota, energy balance, and malnutrition: emphasis on the role of short-chain fatty acids

The intestinal microbiota, energy balance, and malnutrition: emphasis on the role of short-chain fatty acids

Increased Small Intestinal Permeability during Severe Acute Exacerbations of COPD

Glucose-independent Acetate Metabolism Promotes Melanoma Cell Survival and Tumor Growth

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