new diet concepts in propionic acidaemia and methyl ... · propanediol pathway is an important...
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New diet conceptsin Propionic acidaemia andMethyl malonic acidaemia
Human gut microbiota
▪ complex microbial community consisting of 100 trillion microbes in the intestine
▪ gut microbiota is essential to the health and well-being of the host
▪ gut microbiota fluctuates in response to nutritional uptake rather than remaining stable
▪ diet and medication is a key modulator in gut microbiota composition
GeographyBirth mode Breast feeding
Diet
Drugs
Exercise
Disease Ageing
Gut microbiota
Dietary intake, especially of
nondigestible carbohydrates, alters
the species composition of the gut microbiota both short term and
long term
Dietary intake, especially of
nondigestible carbohydrates, alters
the species composition of the gut microbiota both short term and
long term…. leads to production of
short chain fatty acids:
acetic acidbutyric acid
propionic acid
Dietary intake, especially of
nondigestible carbohydrates, alters
the species composition of the gut microbiota both short term and
long term…. leads to
production of short chain fatty
acids:acetic acid
butyric acidpropionic acid
Propionate mainly produces glucose in
the liver.Acetate and butyrate are incorporated into other fatty acids and
cholesterol
Probiotic intake
Dietary fibre intake
Altered pH
Protein intake
Sugar intake
Fat intake
Antibiotics
↓ SCFA production
↑ lipopolysaccharide production
↑TMAO production
Gut inflammation
Cognitive decline
↑ risk of diarrhoea
Insulin resistance
↑ CVD risk ↓ risk of infections
Insulin sensitivity
↓ gut inflammation
Improved lipid metabolism
↓ kidney toxins
↑ antioxidant production
↑SCFA production
Disease Health
Main principles of MMA/PA therapy
▪ prevent recurrent episodes of ketoacidosis and hyperammonaemia
▪ reduce accumulation of toxic tissue metabolites (organic acid compounds)
▪ support anabolism, normal growth and nutritional status
Objectives of nutritional treatment
▪ substrate restriction: isoleucine, methionine, threonine and valine by natural protein restriction
▪ +/-MMA/PA-free amino acids
▪ maintain adequate energy intake
▪ limit fasting time to oxidation of odd chain fatty acids
▪ micronutrient/LCP supplementation
▪ maintain adequate hydration
▪ prevent catabolism during illness
Sources of propionate in MMA and PA
Propiogenic precursors
Amount
Diet and muscle turnover of propiogenic amino acids: methionine, threonine, valine, isoleucine
approx 50%
Oxidation of odd-numbered long chain fatty acids
approx 25%
Gut microbiota approx 25%
Cholesterol small
Propionate production
▪ Biochemical pathways (acrylate, propanediol, and succinate) contribute to propionate formation by gut bacteria
▪ Propanediol pathway is an important source of gut propionate▪ Present in Lachnospiraceae related to Ruminococcus spp. and Roseburia inulinivorans
Fucose and rhamnose are metabolized by the propanediol pathway
Gut microbiota in MMA/PA patients
Lack of information about the composition and or/functioning of the gut microbiota in MMA/PA patients
Breast feeding
Antibiotics Carnitine Constipation
Gut microbiota
Low fibre intake
Tube feedingLow fluidintake
Protein amountand source
Impact of antibiotics
▪ aim: ↓ intestinal microbiota responsible for propionate production
▪ appear to ↓ levels of propionate in MMA/PA urine and plasma
▪ limited ‘supporting’ scientific data
▪ MMA/PA guidelines (2014) recommend metronidazole as an option to ↓ intestinal microbiota responsible for propionate production
Impact of antibiotics
▪….but decrease bacterial population and diminish species diversity
▪ affecting balance of normal gut microbiota
odrug resistance
o toxicity/safety concerns
ometronidazole not effective in reducing faecal excretion of SCFA production (Hoverstad et al 1986)
L- carnitine
▪ L-carnitine compensates for secondary carnitine deficiency
▪ not absorbed until reaches the large intestine
▪ uptake of carnitine by the colon influenced by the gut microbial population
▪ low fibre intake can stimulate carnitine breakdown by enteric microbiota
▪ changed to trimethylamine (TMA)
▪ further metabolised to trimethylamine N-oxide (TMAO)
▪ TMAO has been linked to atherosclerosis
Constipation common in MMA/PA
▪ constipation contributes to metabolic instability
▪ constipation appears to precede decompensation
▪ ↑ time of bacterial contact with the stool in the gut
▪ ↓ fibre intake
▪ inadequate fluid
▪ ↓ gut motility
▪ ↓ physical activity /developmental delay
▪ muscle hypotonia
Laxative therapy
▪ Patients (n =4) with PA given Senokot /gut motility agents:
- ↓ ammonia
- ↓ urinary excretion of propionyl glycine
- ↑ free and total carnitine
- suggestion: less propionate generated by shortening the time of bacterial contact with stool in the gut
Prasad C, Nurko S, Borovoy J, et al. J Pediatr 2004;144:532-5
Why low fibre intake in MMA/PA?
▪ low protein diet
▪ lack of cereal fibre
▪ lack of appetite
▪ nausea
▪ vomiting
▪ tube feeds
olow fibre intake =↓ production of short chain fatty acids
Fibre intake in MMA/PA
3 m 6 m 9 m 1 2 m1 5 m1 8 m 2 y 3 y 4 y 5 y 6 y 7 y 8 y 9 y 1 0 y 1 1 y 1 2 y 1 3 y 1 4 y 1 5 y
0
5
1 0
1 5
2 0
A g e (m o n th s / y e a rs )
Fib
re
in
tak
e (
g/d
ay
)
n=14
Suggested BNF /RNI for fibre from age 5y =18g/day
Tube feeding
▪ amino acids (elemental diets) lack dietary fibre so may suppress colonic fermentation
▪ natural protein source: may be reluctance to use protein source with added fibre/prebiotics
3 m 6 m 9 m 1 2 m1 5 m1 8 m 2 y 3 y 4 y 5 y 6 y 7 y 8 y 9 y 1 0 y 1 1 y 1 2 y 1 4 y 1 5 y 1 6 y
0
1
2
3
A g e (m o n th /y e a r )
To
tal
pro
tein
in
tak
e (
g/k
g/d
)
fro
m n
atu
ra
l a
nd
pre
cu
so
r-f
re
e L
-am
ino
ac
ids
n a tu ra l p ro te in g /k g /d a y
p re c u s o r - fre e L a m in o
a c id s g /k g /d a y
s a fe le v e l o f p ro te in in ta k e
W H O /F A O /U N U 2 0 0 7
13y
n =1 0
n = 1 3
n =1 2
n =1 2n =1 3 n =1 2n = 8
n =1 0
n = 9
n = 3
n = 1n = 1
n = 7n = 4
n = 2
n = 4 n = 4n = 3
n = 4
n = 4
n = 1
p = 0 .0 3
Protein intake of MMA/PA children
Nutrini Multifibre
▪ 50% soluble, 50% insoluble fibre
▪ soy polysaccharides
▪ resistant starch
▪ inulin
▪ arabic gum
▪ cellulose
▪ oligo fructose
Natural protein source with Multifibre
1 2 3 4 5 6 7 8 9 10 11 120
20
40
60
80
100
% in
take
Fluid intake: median 67% of recommended fluid for age n=12
Fluid intake of children on tube feeds
▪when giving tube feeds only, it is difficult to maintain adequate fluid intake
Gut microflora
Human milk oligosaccharides
❖Bifidobacteria❖Lactobacilli
Breast fed infant
Formula fed infants
❖Enterobacteriaceae❖Enterococci❖Bacteroides❖Clostridia❖Bifidobacteria
Bifidobacterium sp. ferment dietary oligosaccharides = SCFAs production
Lower breast feeding
▪ From birth, MMA/PA microbiota likely to be different
▪ Low rate of breast feeding in MMA/PA
▪ At best, expressed breast milk provides part of requirements
▪ glucose liberated from polymers in emergency diets
▪ theoretically may increase production of propionate in the gut
Emergency feeds based on glucose polymer
Trial background
Necessary to build knowledge as an important first step to find alternative ways to reduce propionate production and constipation in PA
▪ no evidence about gut microbiota composition in PA patients
▪ dietary fibres required to alleviate constipation
▪ known to influence the composition and activity of gut microbiota and,
consequently, the production of SCFA
▪ no evidence on an optimal fibre composition in PA patients
Project aims
1. What is the phylogenetic composition of the gut
microbiota of PA patients?
a.How large are the inter-individual differences
between PA patients?
b.How large are the intra-individual difference in PA
patients in a time span of 3 months?
2. Which fibres, or fibre combinations, reduce propionate
production in faecal slurries from PA patients in a batch
fermentation system?
Design and sampling timeline
PA patients, Age >3 yr and preferably <10 yr (upper age limit is 35 yr)
Inclusion:Having PA (or having a sibling with PA) and age >3 yr and preferably <10 yr (upper age limit is 35 yr).Exclusion:PA patients with confounding intestinal diseases (e.g. colon rectal cancers, Crohn's disease, Ulcerative colitis).
Planned characterization assays
▪ Physiological parameters
(PH, SCFA, Lactate, Secretory IGA)
▪Microbiota community profiling
(Next Generation Sequencing technology ‘MiSeq’ )
▪ Fibre fermentations on PA patient samples
Additional exploratory analysis
(Gene qPCR, Proteomics, Metabolomics)
MF6/ fibre blend
Oligofructose
Arabic gumInulin
Resistant starchSoy polysaccharides
Cellulose
▪ Fibre blend provides the range and type of fibres habitually consumed in the normal diet
▪ Customized MF6 + Guar gum: ~71% soluble and ~ 29% insoluble fibres
Amino acid supplements with fibre blend for MMA/PA
Study question and methods
McFall-Ngai et al. 2013 PNAS
What is the effect of fibre mixture on propionic acid production?
In vitro fermentation system: i-screen
Results: propionate profile
Fibres tested:
phGGA: Optifiber
phGGB: Benefiber
6 fibre mix (No GG): Nutrini MF6 mix 8
6 fibre mix (GG):Anamix MF6
▪ Fibre mixture in Anamix Junior has lower propionate production potential in this
fermentation system as compared to other tested fibre blends
Microbiota composition showed minordifferences between the fibre mixtures
Principal Coordinate Analysis, based on operational taxonomic unit abundance, of microbiota beta-diversity as measured in weighted UniFrac distances
MF6-AnamixMF6-mix 8BenefibreOptifibre
▪ Microbiota composition is comparable between fibre blends
Discussion
▪ propionate, precursor of propionyl-CoA, is one of the main short chain fatty acids produced by gut microbiota
▪ several aspects of treatment may ‘negatively’ impact on gut microbiota
▪ no evidence about gut microbiota composition in PA/MMA patients
▪ studies now looking at microbiota composition and impact of different fibres on propionate production
Discussion