Contribution of Gut Bacterial Metabolism to Human Metabolic Disease

Bain, Murray D.; Borriello, S. P.; Tracey, B. M.; Jones, Mark R.; Reed, P. J.; Chalmers, R. A.; Stacey, T. E.

doi:10.1016/s0140-6736(88)91898-3

Cited by 65 publications

(37 citation statements)

References 5 publications

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“…T h e m e a n values a n d t h e level o f significance (Wilcoxon signed rank s u m test) were calculated b y including all subjects for t h e excretion o f methylcitrate, 3-hydroxypropionate, a n d total metabolites a n d MMA subjects alone for methylmalonate excretion. ND, n o t inhibition of gut bacterial propionate production with metronidazole suggests that about 20 pmol/kg/h, or 25%, of propionate production may be attributable to gut bacteria (3,4,27). This leaves an unaccounted portion of about 20 Fmol/kg/h, or 25% of propionate production during fasting.…”

Section: Resultsmentioning

confidence: 99%

“…However, the therapeutic response to dietary restriction of these amino acids is often less than optimal, suggesting that production of propionate from other sources may be significant in these conditions (1,2). Gut bacterial propionate production appears to make a substantial contribution to metabolic imbalance in MMA as evidenced by the reduction in propionate metabolite excretion in urine after inhibition of gut bacterial activity with neomycin or metronidazole (3,4).…”

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confidence: 99%

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Increased Urinary Metabolite Excretion during Fasting in Disorders of Propionate Metabolism

Thompson¹,

Chalmers²

1990

Pediatr Res

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ABSTRACT. Odd-chain fatty acids are recognized precursors of propionate in man, but their clinical significance in disorders of propionate metabolism has not been well studied. Urinary excretion of methylmalonate, methylcitrate, propionylglycine, and 3-hydroxypropionate was measured in five children with methylmalonic acidemia and three with propionic acidemia during frequent or continuous feeding and after 10-18 h of fasting. There was a significant (p < 0.01) increase in the mean total measured metabolite excretion during fasting (fed 38.1 pmol/kg/h, fasting 54.6 in methylmalonic acidemia, fed 1.45, fasting 2.98 in propionic acidemia). Percentage rises in each subject were similar for all measured metabolites. These increases in metabolite excretion are most easily explained by mobilization and oxidation of odd-chain fatty acids in the fasting state. Prolonged fasting should be avoided in children with disorders of propionate metabolism. (Pediatr Res 27: 413-416,1990) Abbreviations MMA, methylmalonic acidemia PA, propionic acidemia MMA and PA have long been recognized as disorders of valine, isoleucine, methionine, and threonine metabolism (1). However, the therapeutic response to dietary restriction of these amino acids is often less than optimal, suggesting that production of propionate from other sources may be significant in these conditions (1, 2). Gut bacterial propionate production appears to make a substantial contribution to metabolic imbalance in MMA as evidenced by the reduction in propionate metabolite excretion in urine after inhibition of gut bacterial activity with neomycin or metronidazole (3, 4).A further source of propionate that is well defined but has not previously received attention is that arising from fat metabolism. Both the side-chain of cholesterol and odd-chain fatty acids are recognized precursors of propionate (5). Cholesterol turnover in man is, however, only about 2 ymol/kg/h (6, 7), which is well below measured rates of propionate production in MMA and PA (8) and is unlikely to be quantitatively significant. However, odd-chain fatty acids accumulate in many tissues in disorders of propionate metabolism (9-1 1). Propionate is an obligate intermediate in odd-chain fatty acid oxidation, and catabolism of fatty acids is greatly increased in the fasting state. To gain a measure of the relative importance of odd-chain fatty acid me- tabolism in MMA and PA, we have examined urinary metabolite excretion in the fed and fasted states. MATERIALS AND METHODSFive children with MMA and three with PA were studied. The clinical details appear in Table I. The subjects were diagnosed on the basis of clinical presentation, urinary metabolite excretion pattern and in vitro enzyme assays. Methylmalonyl-CoA mutase activity ranged from

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Section: Resultsmentioning

confidence: 99%

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confidence: 99%

Increased Urinary Metabolite Excretion during Fasting in Disorders of Propionate Metabolism

Thompson¹,

Chalmers²

1990

Pediatr Res

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“…In the ruminant and rat most of the propionic acid in intermediary metabolism originates from microbial fermentation in the gut. 106 Moderate food restriction has historically been linked to increased longevity and decreased disease incidence. 107 Dietary restriction is known to extend longevity in the rat, mouse and guinea pig, altering many basic physiological processes, including metabolism and hormone balance.…”

Section: Metabonomic Studies Of Physiological Variationmentioning

confidence: 99%

NMR-based metabonomic approaches for evaluating physiological influences on biofluid composition

et al. 2004

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Strategies such as genomics, proteomics and metabonomics are being applied with increasing frequency in the pharmaceutical industry. For each of these approaches, toxicological response can be measured by terms of deviation from control or baseline status. However, in order to accurately define drug-induced response, it is necessary to characterize the normal degree of physiological variation in the absence of stimuli. Here, 1 H NMR spectroscopic-based analyses of the metabolic composition of urine in experimental animals under various normal physiological conditions are reviewed. In particular, the effects of inter-animal and diurnal variation, gender, age, diet, species, strain, hormonal status and stress on the biochemical composition of urine are explored. Pattern recognition methods facilitate the comparison of urine NMR spectra over a given time-course, enabling the establishment of changes in profile and highlighting the dynamic metabolic status of an organism. Thus metabonomic approaches based on information-rich spectroscopic data sets can be used to evaluate normal physiological variation and for investigation of drug safety issues.

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“…The protein products of these genes are the a and b subunits of the mitochondrial propionyl-CoA carboxylase (PCC) enzyme (Huang et al, 2010). The propionyl-CoA substrate of PCC is generated by several mechanisms: (1) catabolism of the amino acids isoleucine, valine, methionine, and threonine; (2) beta oxidation of odd chain fatty acids (Lehnert et al, 1994); and (3) production by gut bacteria (Bain et al, 1988;Leonard, 1997). In patients with reduced PCC activity levels, propionyl-CoA accumulates in the body, eventually causing downstream elevations in several compounds, including propionylcarnitine (C3), methyl citrate (MeCit), and glycine.…”

Section: Introductionmentioning

confidence: 99%

Effects of Adeno-Associated Virus Serotype and Tissue-Specific Expression on Circulating Biomarkers of Propionic Acidemia

et al. 2014

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Propionic acidemia (PA) is an autosomal recessive inborn error of metabolism caused by deficiency of propionyl-CoA carboxylase (PCC). This enzyme is composed of six PCCA and six PCCB subunits and mediates a critical step in catabolism of odd chain fatty acids and certain amino acids. Current treatment options for PA are limited to stringent dietary restriction of protein consumption and some patients undergo elective liver transplantation. We previously generated a hypomorphic model of PA, designated Pcca

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Contribution of Gut Bacterial Metabolism to Human Metabolic Disease

Cited by 65 publications

References 5 publications

Increased Urinary Metabolite Excretion during Fasting in Disorders of Propionate Metabolism

Increased Urinary Metabolite Excretion during Fasting in Disorders of Propionate Metabolism

NMR-based metabonomic approaches for evaluating physiological influences on biofluid composition

Effects of Adeno-Associated Virus Serotype and Tissue-Specific Expression on Circulating Biomarkers of Propionic Acidemia

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