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Choline in cystic fibrosis: relations to pancreas insufficiency, enterohepatic cycle, PEMT and intestinal microbiota

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Abstract

Background

Cystic Fibrosis (CF) is an autosomal recessive disorder with life-threatening organ manifestations. 87% of CF patients develop exocrine pancreas insufficiency, frequently starting in utero and requiring lifelong pancreatic enzyme substitution. 99% develop progressive lung disease, and 20–60% CF-related liver disease, from mild steatosis to cirrhosis. Characteristically, pancreas, liver and lung are linked by choline metabolism, a critical nutrient in CF. Choline is a tightly regulated tissue component in the form of phosphatidylcholine (Ptd’Cho) and sphingomyelin (SPH) in all membranes and many secretions, particularly of liver (bile, lipoproteins) and lung (surfactant, lipoproteins). Via its downstream metabolites, betaine, dimethylglycine and sarcosine, choline is the major one-carbon donor for methionine regeneration from homocysteine. Methionine is primarily used for essential methylation processes via S-adenosyl-methionine.

Clinical impact

CF patients with exocrine pancreas insufficiency frequently develop choline deficiency, due to loss of bile Ptd’Cho via feces. ~ 50% (11–12 g) of hepatic Ptd’Cho is daily secreted into the duodenum. Its re-uptake requires cleavage to lyso-Ptd’Cho by pancreatic and small intestinal phospholipases requiring alkaline environment. Impaired CFTR-dependent bicarbonate secretion, however, results in low duodenal pH, impaired phospholipase activity, fecal Ptd’Cho loss and choline deficiency. Low plasma choline causes decreased availability for parenchymal Ptd’Cho metabolism, impacting on organ functions. Choline deficiency results in hepatic choline/Ptd’Cho accretion from lung tissue via high density lipoproteins, explaining the link between choline deficiency and lung function. Hepatic Ptd’Cho synthesis from phosphatidylethanolamine by phosphatidylethanolamine-N-methyltransferase (PEMT) partly compensates for choline deficiency, but frequent single nucleotide polymorphisms enhance choline requirement. Additionally, small intestinal bacterial overgrowth (SIBO) frequently causes intraluminal choline degradation in CF patients prior to its absorption. As adequate choline supplementation was clinically effective and adult as well as pediatric CF patients suffer from choline deficiency, choline supplementation in CF patients of all ages should be evaluated.

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Abbreviations

ABC:

ATP binding cassette

AI:

Adequate intake

Apo-A1:

Apolipoprotein A1

ARA/C20:4n-6:

Arachidonic acid

ASM:

Acid sphingomyelinase

AT-II:

Alveolar cell type II

ATP:

Adenosine triphosphate

B2 :

Riboflavin

B3 :

Niacin

B6 :

Pyridoxine

B9 :

Folate

B12 :

Cobalamin

BADH:

Betaine-aldehyde dehydrogenase

BHMT:

Betaine homocysteine methyltransferase

cAMP:

Cyclic adenosine monophosphate

CBS:

Cystathionine-β-synthase

CD95:

Cluster of differentiation 95 (Fas receptor)

CDP:

Cytidine diphosphate

CGL:

Cystathionine-γ-lyase

CH2-FolH4 :

5,10-Methylene-tetrahydrofolate

CH3-FolH4 :

5-Methyl-tetrahydrofolate

CHDH:

Choline dehydrogenase

CF:

Cystic Fibrosis

CFRLD:

CF-related liver disease

CFTR:

Cystic Fibrosis Transmembrane Conductance Regulator

CoA:

Coenzyme A

CTL2-4:

Sodium-independent low-affinity-high capacity transporter 2–4

DHA/C22:6n-3:

Docosahexaenoic acid

DIOS:

Distal intestinal obstruction syndrome

DMG:

Dimethylglycine; DMGDH, dimethylglycine dehydrogenase

DNA:

Deoxyribonucleic acid

DRV:

Dietary Reference Value

EFSA:

European Food Safety Authority

EPA/C20:5n-3:

Eicosapentanoic acid

FMO3:

Flavin-containing monooxygenase 3

GSH:

Reduced glutathione; GSSG, oxidized glutathione

HCO3 − :

Hydrogen carbonate

HDL:

High density lipoprotein

IoM:

Institute of Medicine

KM :

Michaelis constant

LPCAT:

Lyso-Ptd’Cho acyl transferase

LXR:

Liver X receptor

MS:

Methionine synthase

MS/MS:

Tandem mass spectrometry

MTHFR:

Methylene tetrahydrofolate reductase

NAM:

National Academy of Medicine

NO:

Nitrogen monoxide

PEMT:

Phosphatidylethanolamine-N-methyltransferase

PLB:

Brush-border phospholipase B

PLRP2:

Pancreatic lipase-related protein 2

Ptd’Cho:

Phosphatidylcholine

Ptd’Cho16:0/16:0:

Dipalmitoyl-Ptd’Cho

Ptd’Cho16:0/18:1:

Palmitoyl-oleoyl-Ptd’Cho

Ptd’Cho16:0/18:2:

Palmitoyl-linoleoyl-Ptd’Cho

Ptd’Cho16:0/14:0:

Palmitoyl-myristoyl-Ptd’Cho

Ptd’Cho16:0/16:1:

Palmitoyl-palmitoleoyl-Ptd’Cho

Ptd’Cho16:0/20:4:

Palmitoyl-arachidonoyl-Ptd’Cho

Ptd’Cho16:0/22:6:

Palmitoyl-docosahexaenoyl-Ptd’Cho

Ptd’Etn:

Phosphatidylethanolamine

REE:

Resting energy expenditure

SAH:

S-adenosyl homocysteine

SAM:

S-adenosylmethionine

SDH:

Sarcosine dehydrogenase

SIBO:

Small intestinal bacterial overgrowth

LC26A4:

Solute carrier family 26 member 4 (pendrin)

SLC26A6:

Solute carrier family 26 member 6

SMS:

Sphingomyelin synthase

S1P:

Sphingosine-1-phosphate

SCL5A7/CTL1:

High-affinity choline/sodium cotransporter

SNP:

Single nucleotide polymorphism

SPH:

Sphingomyelin

sPLA2IB:

Pancreatic phospholipase A2 IB

sPLA2X:

Small intestinal phospholipase A2

TMAO:

Trimethylamine oxide

TMA:

Trimethylamine

UL:

Upper limit of recommended intake

VLDL:

Very low density lipoproteins

Zn + :

Zinc

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  1. Department of Neonatology, University Children’s Hospital, Faculty of Medicine, Eberhard-Karls-University, Calwer Straße 7, 72076, Tübingen, Germany

    Wolfgang Bernhard

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Based on current and previous work of the author (WB) and his group, the University of Tübingen, Medical Faculty, submitted a patent application for the combined administration of choline, ARA and DHA for prevention of developmental disorders associated with very preterm birth. The co-inventor of said patent application (WB) indicates that he does not have any conflict of interest to disclose.

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Bernhard, W. Choline in cystic fibrosis: relations to pancreas insufficiency, enterohepatic cycle, PEMT and intestinal microbiota. Eur J Nutr 60, 1737–1759 (2021). https://doi.org/10.1007/s00394-020-02358-2

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