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Integrative Metabolic Signatures for Hepatic Radiation Injury.

Kurland IJ, Broin PÓ, Golden A, Su G, Meng F, Liu L, Mohney R, Kulkarni S, Guha C - PLoS ONE (2015)

Bottom Line: Liver metabolites associated with 50 Gy WLI included pentose phosphate, purine, and pyrimidine metabolites in liver.Metabolites associated with tryptophan and indoles may reflect radiation-induced gut microbiome effects.Pathway analysis also suggested that the unique metabolic changes observed after liver irradiation was an integrative response of the intestine, liver and kidney.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Diabetes Center, Stable Isotope and Metabolomics Core Facility, Albert Einstein College of Medicine, Bronx, New York, United States of America.

ABSTRACT

Background: Radiation-induced liver disease (RILD) is a dose-limiting factor in curative radiation therapy (RT) for liver cancers, making early detection of radiation-associated liver injury absolutely essential for medical intervention. A metabolomic approach was used to determine metabolic signatures that could serve as biomarkers for early detection of RILD in mice.

Methods: Anesthetized C57BL/6 mice received 0, 10 or 50 Gy Whole Liver Irradiation (WLI) and were contrasted to mice, which received 10 Gy whole body irradiation (WBI). Liver and plasma samples were collected at 24 hours after irradiation. The samples were processed using Gas Chromatography/Mass Spectrometry and Liquid Chromatography/Mass Spectrometry.

Results: Twenty four hours after WLI, 407 metabolites were detected in liver samples while 347 metabolites were detected in plasma. Plasma metabolites associated with 50 Gy WLI included several amino acids, purine and pyrimidine metabolites, microbial metabolites, and most prominently bradykinin and 3-indoxyl-sulfate. Liver metabolites associated with 50 Gy WLI included pentose phosphate, purine, and pyrimidine metabolites in liver. Plasma biomarkers in common between WLI and WBI were enriched in microbial metabolites such as 3 indoxyl sulfate, indole-3-lactic acid, phenyllactic acid, pipecolic acid, hippuric acid, and markers of DNA damage such as 2-deoxyuridine. Metabolites associated with tryptophan and indoles may reflect radiation-induced gut microbiome effects. Predominant liver biomarkers in common between WBI and WLI were amino acids, sugars, TCA metabolites (fumarate), fatty acids (lineolate, n-hexadecanoic acid) and DNA damage markers (uridine).

Conclusions: We identified a set of metabolomic markers that may prove useful as plasma biomarkers of RILD and WBI. Pathway analysis also suggested that the unique metabolic changes observed after liver irradiation was an integrative response of the intestine, liver and kidney.

No MeSH data available.


Related in: MedlinePlus

Role of intestinal microbiome in the response to liver Irradiation.Normalized levels of 3-indoxyl-sulfate and 3-hydroxycinnamic acid levels from liver samples are plotted. Radiation dose-dependent increase was observed in these metabolites, indicating possible role of gut microbiome on liver injury. 3-indoxyl-sulfate and 3-hydroxycinnamic acid were both increased in the liver following exposure to radiation. These metabolites are by-products of the intestinal flora, and coupled with those in the Tryptophan pathway point to a possible gut microbiome response to radiation.
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pone.0124795.g014: Role of intestinal microbiome in the response to liver Irradiation.Normalized levels of 3-indoxyl-sulfate and 3-hydroxycinnamic acid levels from liver samples are plotted. Radiation dose-dependent increase was observed in these metabolites, indicating possible role of gut microbiome on liver injury. 3-indoxyl-sulfate and 3-hydroxycinnamic acid were both increased in the liver following exposure to radiation. These metabolites are by-products of the intestinal flora, and coupled with those in the Tryptophan pathway point to a possible gut microbiome response to radiation.

Mentions: Aside from the plasma amino acid biomarkers mentioned, plasma bradykinin showed a ~20-fold increase in response to IR, and plasma indoxyl sulfate, a 3-fold increase in response to HIR at 50 Gy. Both could be important plasma biomarkers of the abdominal irradiation response (see Discussion). Some plasma biomarkers that were correlated with hepatic biomarkers are shown in Fig 9, others in Table 1. Tryptophan and several degradation products—kynurenine and kynurenate—were significantly decreased in liver tissue in response to radiation (Fig 13), while the metabolite indoxyl sulfate was increased (Fig 14). Plasma biomarkers such as indolelactate, hydroxycinnamate and tryptophan metabolites indicated a role for gut microflora in the radiation response, and certainly the importance of indoxyl sulfate as a biomarker was indicated by high correlation between liver and plasma samples at both 10 Gy and 50 Gy (S1 and S2 Datasets). Plasma biomarkers x-1971, x-6132, x-10363, x-2277, x-3522, x-2269, x-7828 and x-5650, important for class separation (see Figs 4–8), were positively correlated with 3 microbial related metabolites, 3-indoxyl sulfate, indole-3-lactic acid and 3-hydroxycinnamic acid (Fig 8) reinforcing the importance of plasma microbial biomarkers for detecting the radiation response. Reinforcing the importance of microbial biomarkers in the radiation injury response were microbial metabolites such as 3 indoxyl sulfate, indole-3-lactic acid, phenyllactic acid, pipecolic acid, and hippuric acid, which were seen in both WBI and WLI plasma.


Integrative Metabolic Signatures for Hepatic Radiation Injury.

Kurland IJ, Broin PÓ, Golden A, Su G, Meng F, Liu L, Mohney R, Kulkarni S, Guha C - PLoS ONE (2015)

Role of intestinal microbiome in the response to liver Irradiation.Normalized levels of 3-indoxyl-sulfate and 3-hydroxycinnamic acid levels from liver samples are plotted. Radiation dose-dependent increase was observed in these metabolites, indicating possible role of gut microbiome on liver injury. 3-indoxyl-sulfate and 3-hydroxycinnamic acid were both increased in the liver following exposure to radiation. These metabolites are by-products of the intestinal flora, and coupled with those in the Tryptophan pathway point to a possible gut microbiome response to radiation.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4457483&req=5

pone.0124795.g014: Role of intestinal microbiome in the response to liver Irradiation.Normalized levels of 3-indoxyl-sulfate and 3-hydroxycinnamic acid levels from liver samples are plotted. Radiation dose-dependent increase was observed in these metabolites, indicating possible role of gut microbiome on liver injury. 3-indoxyl-sulfate and 3-hydroxycinnamic acid were both increased in the liver following exposure to radiation. These metabolites are by-products of the intestinal flora, and coupled with those in the Tryptophan pathway point to a possible gut microbiome response to radiation.
Mentions: Aside from the plasma amino acid biomarkers mentioned, plasma bradykinin showed a ~20-fold increase in response to IR, and plasma indoxyl sulfate, a 3-fold increase in response to HIR at 50 Gy. Both could be important plasma biomarkers of the abdominal irradiation response (see Discussion). Some plasma biomarkers that were correlated with hepatic biomarkers are shown in Fig 9, others in Table 1. Tryptophan and several degradation products—kynurenine and kynurenate—were significantly decreased in liver tissue in response to radiation (Fig 13), while the metabolite indoxyl sulfate was increased (Fig 14). Plasma biomarkers such as indolelactate, hydroxycinnamate and tryptophan metabolites indicated a role for gut microflora in the radiation response, and certainly the importance of indoxyl sulfate as a biomarker was indicated by high correlation between liver and plasma samples at both 10 Gy and 50 Gy (S1 and S2 Datasets). Plasma biomarkers x-1971, x-6132, x-10363, x-2277, x-3522, x-2269, x-7828 and x-5650, important for class separation (see Figs 4–8), were positively correlated with 3 microbial related metabolites, 3-indoxyl sulfate, indole-3-lactic acid and 3-hydroxycinnamic acid (Fig 8) reinforcing the importance of plasma microbial biomarkers for detecting the radiation response. Reinforcing the importance of microbial biomarkers in the radiation injury response were microbial metabolites such as 3 indoxyl sulfate, indole-3-lactic acid, phenyllactic acid, pipecolic acid, and hippuric acid, which were seen in both WBI and WLI plasma.

Bottom Line: Liver metabolites associated with 50 Gy WLI included pentose phosphate, purine, and pyrimidine metabolites in liver.Metabolites associated with tryptophan and indoles may reflect radiation-induced gut microbiome effects.Pathway analysis also suggested that the unique metabolic changes observed after liver irradiation was an integrative response of the intestine, liver and kidney.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Diabetes Center, Stable Isotope and Metabolomics Core Facility, Albert Einstein College of Medicine, Bronx, New York, United States of America.

ABSTRACT

Background: Radiation-induced liver disease (RILD) is a dose-limiting factor in curative radiation therapy (RT) for liver cancers, making early detection of radiation-associated liver injury absolutely essential for medical intervention. A metabolomic approach was used to determine metabolic signatures that could serve as biomarkers for early detection of RILD in mice.

Methods: Anesthetized C57BL/6 mice received 0, 10 or 50 Gy Whole Liver Irradiation (WLI) and were contrasted to mice, which received 10 Gy whole body irradiation (WBI). Liver and plasma samples were collected at 24 hours after irradiation. The samples were processed using Gas Chromatography/Mass Spectrometry and Liquid Chromatography/Mass Spectrometry.

Results: Twenty four hours after WLI, 407 metabolites were detected in liver samples while 347 metabolites were detected in plasma. Plasma metabolites associated with 50 Gy WLI included several amino acids, purine and pyrimidine metabolites, microbial metabolites, and most prominently bradykinin and 3-indoxyl-sulfate. Liver metabolites associated with 50 Gy WLI included pentose phosphate, purine, and pyrimidine metabolites in liver. Plasma biomarkers in common between WLI and WBI were enriched in microbial metabolites such as 3 indoxyl sulfate, indole-3-lactic acid, phenyllactic acid, pipecolic acid, hippuric acid, and markers of DNA damage such as 2-deoxyuridine. Metabolites associated with tryptophan and indoles may reflect radiation-induced gut microbiome effects. Predominant liver biomarkers in common between WBI and WLI were amino acids, sugars, TCA metabolites (fumarate), fatty acids (lineolate, n-hexadecanoic acid) and DNA damage markers (uridine).

Conclusions: We identified a set of metabolomic markers that may prove useful as plasma biomarkers of RILD and WBI. Pathway analysis also suggested that the unique metabolic changes observed after liver irradiation was an integrative response of the intestine, liver and kidney.

No MeSH data available.


Related in: MedlinePlus