Ammonia toxicity: from head to toe?

Dasarathy, Srinivasan; Mookerjee, Rajeshwar P.; Račkayová, Veronika; Thrane, Vinita Rangroo; Vairappan, Balasubramaniyan; Ott, Peter; Rose, Christopher F.

doi:10.1007/s11011-016-9938-3

Cited by 196 publications

(165 citation statements)

References 142 publications

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“…The activity of GS is low in muscle tissue but being the largest organ in the body, it plays a substantial compensatory role when ammonia detoxification in the liver is significantly reduced . Hence, in relation to complications and especially the treatment of hepatic encephalopathy (HE), optimizing skeletal muscle mass may be an important target …”

Section: Introductionmentioning

confidence: 99%

Progressive resistance training prevents loss of muscle mass and strength in bile duct‐ligated rats

Aamann

Ochoa‐Sanchez

Oliveira

et al. 2018

Liver International

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Background Loss of muscle mass and strength is common in cirrhosis and increases the risk of hyperammonaemia and hepatic encephalopathy. Resistance training optimizes muscle mass and strength in several chronic diseases. However, the beneficial effects of resistance training in cirrhosis remain to be investigated. Bile duct‐ligated (BDL) rats develop chronic liver disease, hyperammonaemia, reduced muscle mass and strength. Our aim was to test the effects of resistance training on muscle mass, function and ammonia metabolism in BDL‐rats. Methods A group of BDL‐rats underwent a progressive resistance training programme and a group of non‐exercise BDL‐rats served as controls. Resistance training comprised of ladder climbing with a progressive increase in carrying weights attached to the tail. Training was performed 5 days a week during 4 weeks. Muscle strength and body composition were assessed using grip strength and EchoMRI. Weight and circumference of the gastrocnemius muscle (normalized to bodyweight), plasma ammonia and glutamine synthetase protein expression and activity were assessed. Results BDL + exercise rats had significantly larger gastrocnemius circumference compared to non‐exercise BDL‐rats: ratio 0.082 vs 0.075 (P < 0.05). Gastrocnemius muscle weight was higher in exercisers than controls: 0.006 vs 0.005 (P < 0.05). A tendency towards a lower plasma ammonia in the exercise group compared to controls was observed (P = 0.10). There were no differences in lean body mass, GS protein expression and activity between the groups. Conclusion Resistance training in rats with chronic liver disease beneficially effects muscle mass and strength. The effects were followed by non‐significant reduction in blood ammonia; however, a tendency was observed.

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Section: Introductionmentioning

confidence: 99%

Progressive resistance training prevents loss of muscle mass and strength in bile duct‐ligated rats

Aamann

Ochoa‐Sanchez

Oliveira

et al. 2018

Liver International

Self Cite

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“…To optimize NH 4 Cl for tracing studies, we investigated whether exposure to increased concentrations of NH 4 Cl was toxic to tumor cells. Physiological concentrations of ammonia in plasma range between 0–50 μM in healthy human adults, 50–150 μM in newborns, and up to 1.0 mM in patients with hyperammonemia (25). Supraphysiological concentrations of ammonia are toxic to neurons, and sometimes assumed to also be toxic to tumor cells (7, 26, 27).…”

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confidence: 99%

Metabolic recycling of ammonia via glutamate dehydrogenase supports breast cancer biomass

Spinelli

Yoon

Ringel

et al. 2017

Science

344

325

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Ammonia is a ubiquitous by-product of cellular metabolism, however the biological consequences of ammonia production are not fully understood, especially in cancer. We find that ammonia is not merely a toxic waste product, but is recycled into central amino acid metabolism to maximize nitrogen utilization. Cancer cells primarily assimilated ammonia through reductive amination catalyzed by glutamate dehydrogenase (GDH), and secondary reactions enabled other amino acids, such as proline and aspartate, to directly acquire this nitrogen. Metabolic recycling of ammonia accelerated proliferation of breast cancer. In mice, ammonia accumulated in the tumor microenvironment, and was used directly to generate amino acids through GDH activity. These data show that ammonia not only is a secreted waste product, but a fundamental nitrogen source that can support tumor biomass.

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“…Our results demonstrate that the mouse brain is sensitive to changes in the gut microbiota composition with respect to inflammatory expression; microglial, glial, and neuronal activation; and GABA signaling. These multimodal changes have been shown to impact the pathogenesis of HE in humans and in animal models of cirrhosis . In these animal models and humans, hepatic inflammation is present, which could contribute to the brain inflammation and can often serve as the trigger for development of HE .…”

Section: Discussionmentioning

confidence: 99%

Neuroinflammation in Murine Cirrhosis Is Dependent on the Gut Microbiome and Is Attenuated by Fecal Transplant

et al. 2019

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Cirrhosis and hepatic encephalopathy (HE) is associated with an altered gut–liver–brain axis. Fecal microbial transplant (FMT) after antibiotics improves outcomes in HE, but the impact on brain function is unclear. The aim of this study is to determine the effect of colonization using human donors in germ‐free (GF) mice on the gut–liver–brain axis. GF and conventional mice were made cirrhotic using carbon tetrachloride and compared with controls in GF and conventional state. Additional GF mice were colonized with stool from controls (Ctrl‐Hum) and patients with cirrhosis (Cirr‐Hum). Stools from patients with HE cirrhosis after antibiotics were pooled (pre‐FMT). Stools from the same patients 15 days after FMT from a healthy donor were also pooled (post‐FMT). Sterile supernatants were created from pre‐FMT and post‐FMT samples. GF mice were colonized using stools/sterile supernatants. For all mice, frontal cortex, liver, and small/large intestines were collected. Cortical inflammation, synaptic plasticity and gamma‐aminobutyric acid (GABA) signaling, and liver inflammation and intestinal 16s ribosomal RNA microbiota sequencing were performed. Conventional cirrhotic mice had higher degrees of neuroinflammation, microglial/glial activation, GABA signaling, and intestinal dysbiosis compared with other groups. Cirr‐Hum mice had greater neuroinflammation, microglial/glial activation, and GABA signaling and lower synaptic plasticity compared with Ctrl‐Hum mice. This was associated with greater dysbiosis but no change in liver histology. Pre‐FMT material colonization was associated with neuroinflammation and microglial activation and dysbiosis, which was reduced significantly with post‐FMT samples. Sterile pre‐FMT and post‐FMT supernatants did not affect brain parameters. Liver inflammation was unaffected. Conclusion: Fecal microbial colonization from patients with cirrhosis results in higher degrees of neuroinflammation and activation of GABAergic and neuronal activation in mice regardless of cirrhosis compared with those from healthy humans. Reduction in neuroinflammation by using samples from post‐FMT patients to colonize GF mice shows a direct effect of fecal microbiota independent of active liver inflammation or injury.

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Ammonia toxicity: from head to toe?

Cited by 196 publications

References 142 publications

Progressive resistance training prevents loss of muscle mass and strength in bile duct‐ligated rats

Progressive resistance training prevents loss of muscle mass and strength in bile duct‐ligated rats

Metabolic recycling of ammonia via glutamate dehydrogenase supports breast cancer biomass

Neuroinflammation in Murine Cirrhosis Is Dependent on the Gut Microbiome and Is Attenuated by Fecal Transplant

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