'The association of fecal microbiota and fecal, blood serum and urine metabolites in ME'

[Remy]

New study by Armstrong...

Aren't short chain fatty acids typically thought to be helpful??

Introduction

The human gut microbiota has the ability to modulate host metabolism. Metabolic profiling of the microbiota and the host biofluids may determine associations significant of a host–microbe relationship. Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a long-term disorder of fatigue that is poorly understood, but has been linked to gut problems and altered microbiota.
Objectives

Find changes in fecal microbiota and metabolites in ME/CFS and determine their association with blood serum and urine metabolites.
Methods

A workflow was developed that correlates microbial counts with fecal, blood serum and urine metabolites quantitated by high-throughput 1H NMR spectroscopy. The study consists of thirty-four females with ME/CFS (34.9 ± 1.8 SE years old) and twenty-five non-ME/CFS female (33.0 ± 1.6 SE years old).
Results

The workflow was validated using the non-ME/CFS cohort where fecal short chain fatty acids (SCFA) were associated with serum and urine metabolites indicative of host metabolism changes enacted by SCFA. In the ME/CFS cohort a decrease in fecal lactate and an increase in fecal butyrate, isovalerate and valerate were observed along with an increase in Clostridiumspp. and a decrease in Bacteroides spp. These differences were consistent with an increase in microbial fermentation of fiber and amino acids to produce SCFA in the gut of ME/CFS patients. Decreased fecal amino acids positively correlated with substrates of gluconeogenesis and purine synthesis in the serum of ME/CFS patients.
Conclusion

Increased production of SCFA by microbial fermentation in the gut of ME/CFS patients may be associated with deleterious effects on the host energy metabolism.
Keywords

Myalgic encephalomyelitis/chronic fatigue syndromeFecesMicrobiotaShort chain fatty acidsEnergy metabolismAmino acids
Abbreviations

BCFA
Branched-chain fatty acids
IBD
Irritable bowel disease
ME/CFS
Myalgic encephalomyelitis/chronic fatigue syndrome
NOESY
Nuclear overhauser effect spectroscopy
NMR
Nuclear magnetic resonance
PCA
Principal component analysis
SCFA
Short chain fatty acids
TOCSY
Total correlated spectroscopy
Data deposition The data for this study has been deposited at MetaboLights (http://www.ebi.ac.uk/metabolights) with Accession No. MTBLS369.
References

1. Armstrong, C. W., McGregor, N. R., Butt, H. L., & Gooley, P. R. (2014). Metabolism in chronic fatigue syndrome. Advances in Clinical Chemistry, 66, 121–172.CrossRefPubMedGoogle Scholar

 

[Remy]

I've got the whole article now if anyone wants to read it, shoot me a PM.

Microbial SCFA are an important fuel source for cells of the gut wall and also influence the energy metabolism of the host via their increased incorporation into lipids in adipocytes and their increased oxidation to produce glucose and glycogen in muscle cells and hepatocytes (Fig. 4) (Canfora et al. 2015; den Besten et al. 2013b). After removing the effect of con- centration of metabolites from the biofluids by observing the relative abundance (Fig. 3) we still see that the SCFA, except for acetate, are negatively correlated to citrate. Pro- pionate enters the hepatocytes to enhance glucose produc- tion via gluconeogenesis (Fig. 4) and was observed here to positively correlate with serum aspartate and urine glucose. These observations suggest, as expected, that fecal SCFA entering the blood may be altering energy metabolism by increasing gluconeogenesis and decreasing lipogenesis.

The absolute concentrations of three fecal metabolites from the 1H NMR analysis were significantly different between the ME/CFS and non-ME/CFS cohorts (Fig. 1e). Valerate and isovalerate were increased and lactate was decreased in ME/CFS patients. When considering metabolites as a func- tion of total metabolite concentrations (relative abundance data) it was found that valerate and isovalerate were again increased along with an increase of butyrate (Fig. 1e).

An overall increase of SCFA was observed in the ME/ CFS cohort compared to the non-ME/CFS. Acetate, butyrate and propionate are the main three SCFA of the gut and are essential for gut health (Scheppach 1994;
Wong et al. 2006) and all three trended to an increase with butyrate being statistically significant. Butyrate is a major fuel of colonocytes and its increase thought important for gut health (Canani et al. 2011). Isovalerate and valerate are two lesser researched SCFA, but both appear to be impor- tant to ME/CFS. Isovalerate is primarily produced from the fermentation of peptides and amino acids (Cardona et al. 2005), namely leucine (Zarling and Ruchim 1987) while valerate is produced by fermentation of either carbohy- drates or peptides, similarly to acetate, butyrate and propi- onate, but in much smaller quantities and dependent on a select group of bacteria (Bourriaud et al. 2005). Lactate has been shown to be fermented into SCFA by bacteria within the gut (Bourriaud et al. 2005).

The metabolite changes we observed in ME/CFS indi- cate an increase in fermentation, a process that may occur due to a higher pH, a decreased gut transit or a change in the bacterial species of the microbiota. Studies on pH in the gut have concluded that as it becomes more alkaline the concentration of lactate decreases and its fermentation to SCFA increases (Belenguer et al. 2007). Amino acids and peptides are also increasingly fermented to SCFA under alkaline conditions (Rasmussen et al. 1988; Smith and Macfarlane 1998). Levels of all amino acids (except glu- tamine) were decreased in ME/CFS patients compared to controls although none were significant (Fig. 1e). Valerate and isovalerate production from amino acids and peptides has been shown to increase significantly with pH (Walker et al. 2005). Both isovalerate and valerate grouped with glutamine during PCA analysis (Fig. 1f) suggesting that amino acids may be transferring their amino group to pro- duce glutamine when fermented in the colon of ME/CFS patients. The microbial data also appears consistent with an increased fermentation in ME/CFS as Clostridium spp. was observed to be increased in ME/CFS patients. Clostridium species are known to make butyrate from lactate and amino acids to produce SCFA (Smith and Macfarlane 1998). Intestinal permeability is suspected in ME/CFS patients (Giloteaux et al. 2016) and the byproducts of fermenting amino acids may enhance this (Fig. 4).

Previous findings of microbial alterations in ME/CFS suggested an increase in lactic acid producing bacteria (Sheedy et al. 2009). We therefore expected an increase in lactate and a decrease in SCFA as observed in the feces of IBD patients (Huda-Faujan et al. 2010); how- ever, we observed the opposite. Although SCFA are con- sidered to have positive health benefits their increase has been observed in autism spectrum disorder (ASD) (Wang et al. 2012).

It is possible that the previously proposed increase in intestinal permeability (Fremont et al. 2013; Giloteaux et al. 2016) along with the increase in SCFA observed here are producing a significant influx of SCFA, especially propionate, into the bloodstream that may be causing or exacerbating mitochondrial dys- function and oxidative stress in ME/CFS.

In the ME/CFS cohort, Bacteroides spp. decreased and Clostridium increased while fecal butyrate, valerate and isovalerate significantly increased and lactate decreased. These results were consistent with increased microbial fer- mentation at the expense of amino acids in the gut of ME/ CFS patients.

 

[ankaa]

butyrate made me SO sick... weird, b/c "on paper" it looks like something that should help me