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Effects of Liver Resection on Hepatic Short-Chain Fatty Acid Metabolism in Humans

  • Evelien P. J. G. Neis ,

    e.neis@maastrichtuniversity.nl

    ‡ These authors are joint first authors on this work.

    Affiliations TI Food and Nutrition, 6709 PA Wageningen, The Netherlands, Department of Surgery, NUTRIM School for Nutrition and Translational Research in Metabolism, Maastricht University Medical Centre, 6229 HX Maastricht, The Netherlands

  • Johanne G. Bloemen ,

    ‡ These authors are joint first authors on this work.

    Affiliations TI Food and Nutrition, 6709 PA Wageningen, The Netherlands, Department of Surgery, NUTRIM School for Nutrition and Translational Research in Metabolism, Maastricht University Medical Centre, 6229 HX Maastricht, The Netherlands

  • Sander S. Rensen,

    Affiliation Department of Surgery, NUTRIM School for Nutrition and Translational Research in Metabolism, Maastricht University Medical Centre, 6229 HX Maastricht, The Netherlands

  • Joost R. van der Vorst,

    Affiliation Department of Surgery, Leiden University Medical Centre, 2333 ZA Leiden, The Netherlands

  • Maartje A. van den Broek,

    Affiliations Department of Surgery, NUTRIM School for Nutrition and Translational Research in Metabolism, Maastricht University Medical Centre, 6229 HX Maastricht, The Netherlands, Department of Surgery, Leiden University Medical Centre, 2333 ZA Leiden, The Netherlands

  • Koen Venema,

    Affiliations TI Food and Nutrition, 6709 PA Wageningen, The Netherlands, Beneficial Microbes Consultancy, Wageningen University, 6708 PB Wageningen, The Netherlands

  • Wim A. Buurman,

    Affiliation Department of Surgery, NUTRIM School for Nutrition and Translational Research in Metabolism, Maastricht University Medical Centre, 6229 HX Maastricht, The Netherlands

  • Cornelis H. C. Dejong

    Affiliation TI Food and Nutrition, 6709 PA Wageningen, The Netherlands

Abstract

Aim

To determine whether acute loss of liver tissue affects hepatic short-chain fatty acid (SCFA) clearance.

Methods

Blood was sampled from the radial artery, portal vein, and hepatic vein before and after hepatic resection in 30 patients undergoing partial liver resection. Plasma SCFA levels were measured by liquid chromatography-mass spectrometry. SCFA exchange across gut and liver was calculated from arteriovenous differences and plasma flow. Liver volume was estimated by CT liver volumetry.

Results

The gut produced significant amounts of acetate, propionate, and butyrate (39.4±13.5, 6.2±1.3, and 9.5±2.6 μmol·kgbw-1·h-1), which did not change after partial hepatectomy (p = 0.67, p = 0.59 and p = 0.24). Hepatic propionate uptake did not differ significantly before and after resection (-6.4±1.4 vs. -8.4±1.5 μmol·kgbw-1·h-1, p = 0.49). Hepatic acetate and butyrate uptake increased significantly upon partial liver resection (acetate: -35.1±13.0 vs. -39.6±9.4 μmol·kgbw-1·h-1, p = 0.0011; butyrate: -9.9±2.7 vs. -11.5±2.4 μmol·kgbw-1·h-1, p = 0.0006). Arterial SCFA concentrations were not different before and after partial liver resection (acetate: 176.9±17.3 vs. 142.3±12.5 μmol/L, p = 0.18; propionate: 7.2±1.4 vs. 5.6±0.6 μmol/L, p = 0.38; butyrate: 4.3±0.7 vs. 3.6±0.6 μmol/L, p = 0.73).

Conclusion

The liver maintains its capacity to clear acetate, propionate, and butyrate from the portal blood upon acute loss of liver tissue.

Introduction

Short-chain fatty acids (SCFA, i.e. acetate, propionate, and butyrate) have lately attracted considerable attention since they are thought to underlie the effect of gut bacteria on body weight and metabolism.[1] These organic acids constitute the main products of bacterial fermentation of indigestible carbohydrates in the human colon.[2] Once produced, SCFA are for approximately 90% metabolized inside colonocytes. Another 5% is excreted with feces, and the remainder is thought to be released into the portal vein.[3, 4] In the liver, acetate and butyrate are metabolized to acetyl-coA before entering the tricarboxylic acid (TCA) cycle to generate ATP and NADH.[5] Propionate, on the other hand, functions primarily as a precursor of gluconeogenesis in liver cells.[6]

Currently, there is growing interest in functional foods that affect the composition of gut microbiota, and which may lead to the generation of these SCFA.[7, 8] Indeed, SCFA generated by the intestinal fermentation of dietary fibers seem to have many positive actions on health in terms of (body weight regulation, gut micromorphology, and insulin homeostasis.[3, 912] As a result of the increasing evidence for a potential role of SCFA as a metabolic tool, various studies have reported on beneficial effects of SCFA or SCFA precursor supplementation in (pre-) clinical settings.[1315] We recently reported on a possible clinical application of butyrate to increase intestinal anastomotic strength.[16] Whereas these studies support the use of SCFA for improving gut health in man, it is pivotal to better understand human SCFA metabolism before therapeutic SCFA supplementation can be widely implemented, particularly given that high systemic concentrations of especially propionate and butyrate are toxic.[17, 18]

Our group has previously shown that release of intestinal SCFA appears to be equaled by hepatic uptake [19], even in patients with a cirrhotic dysfunctional liver.[19] However, a potential drawback of the latter study was the possible shunting of blood from the portal to the systemic circulation in patients with liver cirrhosis, making exact quantification of hepatic SCFA metabolism in this population difficult.

To address this problem, we now studied SCFA metabolism in a controlled situation of acute loss of liver function where shunting does not play a role, i.e. surgical removal of major parts of the liver.

Materials and Methods

Study population

We included thirty patients planned to undergo liver resection to remove colorectal cancer metastasis at Maastricht University Medical Centre+ (MUMC+). All patients provided informed consent. Patients with known parenchymal liver disease, inborn errors of metabolism, diabetes mellitus type I, and/or use of antibiotics four weeks prior to the operation were excluded from the study. All patients were on a stable, Western diet. Immediately preoperatively, patients received a single intravenous dose of 2200 mg amoxicillin/clavulanic acid as antibiotic prophylaxis.

The study was approved by the Local Medical Ethics Committee of Maastricht University Medical Center and was performed in accordance with the ethical standards of the Helsinki Declaration of 1975. Written informed consent was obtained from all subjects before participation in this study.

Study protocol

Anaesthesia was performed according to institutional routines as has been described previously.[20, 21] Briefly, the procedure included placement of two peripheral venous catheters, an epidural catheter for per- and postoperative analgesia, an arterial line, and a central venous line. Anesthesia was maintained using sevoflurane and propofol. Liver resections were performed as described before and classified as major (i.e. ≥ 3 segments) or minor (< 3 segments).[20] Liver resection started with mobilization of the liver, whereupon intraoperative ultrasound (Aloka, Zug, Switzerland) determined the definitive surgical procedure. Liver transection was performed using a Cavitron Ultrasonic Surgical Aspirator (CUSA, system 200 Macrodissector; Cavitron Surgical Systems, Stamford, CT). Argon beam coagulation (Force GSU Systems; Valleylab, Boulder, CO), clips and sutures were used to achieve hemostasis. When the portal and hepatic veins were exposed (mostly within one hour after skin incision, but before liver transection), blood was drawn from the portal vein and a hepatic vein by direct puncture simultaneously with arterial blood sampling, as described before.[20] Directly after hepatic transection, blood was sampled again from the portal vein, a hepatic vein and the radial artery simultaneously. Blood was collected in EDTA vacuum tubes (BD Vacutainer, Franklin Lakes, NJ) and placed on ice. Blood was centrifuged at 3,500 g and plasma was stored at -800 C until analysis. Finally, the liver resection specimens were weighed.

Sample preparation and liquid chromatography-mass spectrometry (LC-MS)

Deproteinization and subsequent preparation of plasma samples for analysis of SCFA was performed as recently reported.[22] Briefly, plasma samples were deproteinized using methanol, after which they were centrifuged at 50,000 g for 10 minutes at 4°C. The clear supernatant was transferred to a 300 μl glass micro-insert into a WISP-style vial. Analysis was performed using LC-MS. SCFA concentrations were determined using the external standard method by calibration curves of SCFA. The detection limits for acetate, propionate, and butyrate were 0.1, 0.05, and 0.05μmol/L, respectively. The coefficients of variance were 4.2%, 9.8%, and 5.1% for acetate, propionate, and butyrate, respectively.

CT-volumetry

Liver volumetry was performed in a subset of 16 patients using open source software OsiriX®, as described before.[23] Briefly, series of axial images in the portal venous phase from the preoperative computed tomography (CT) scans were used for volumetry. A slice thickness of approximately 3–5 mm, depending on the CT-scanner was used. The outline of the total liver, future resection specimen, and tumors were traced manually on each slice with specific tools belonging to OsiriX®. Whereas intrahepatic vascular and biliary structures were included, the gall bladder and the inferior caval vein were excluded for all slices. After selecting all regions of interest within one series, total liver volume, resection volume, and metastases volumes were calculated. Then, 3D images were created and virtual resections were performed according to the treatment plan. Functional volume was calculated as total volume minus tumor volume. Subsequently, these volumes were used to estimate the remnant liver volume in order to assess differences in SCFA clearance per gram functional liver tissue pre- and post- hepatic resection.

Flux calculations

Arteriovenous differences (ΔAV) and net organ fluxes (flow * ΔAV) were calculated across the liver, portal drained viscera (PDV), and splanchnic area. Plasma flows for flux calculations were derived from previously performed measurements in a similar patient group.[20] As we demonstrated before that total hepatic plasma flow does not change after major hepatectomy [24], the same plasma flow data were used before and after resection. The corresponding AV differences were calculated as follows: ΔAVPDV = [PV]–[A] and ΔAVsplanchnic area = [HV]–[A]. Fluxes were calculated as FPDV = portal plasma flow * [PV-A], Fsplanchnic = splanchnic plasma flow * [HV]-[A], Fliver = Fsplanchnic-FPDV. In these equations [PV], [A], and [HV] indicate portal venous, radial artery, and hepatic venous concentrations respectively, whereas Fsplanchnic, Fliver, FPDV denote splanchnic flux, liver flux, and PDV flux, respectively. Positive fluxes indicate net release and negative fluxes indicate net uptake. To estimate hepatic functional reserve, hepatic SCFA exchange was also calculated per gram of liver tissue using the volumetry data and assuming 1 mL corresponds with 1 gram of liver tissue.

Statistical analysis

Data are presented as mean (SEM). To test if fluxes were statistically different from zero, the nonparametric Wilcoxon signed-rank test was used with a hypothetical value of zero. The nonparametric Wilcoxon signed-rank matched pairs test was used to test if there were differences in fluxes and concentrations before and after partial hepatectomy. Correlations were calculated with Spearman’s correlation coefficients. A p-value of <0.05 was considered statistically significant. For statistical analysis, Prism 5.0 for Windows (Graphpad Software Inc. San Diego, CA) was used.

Results

Patient population

Baseline characteristics of the thirty patients included in the study are presented in Table 1. Sampling was performed in all patients according to protocol. Thirteen patients underwent major liver resection, whereas 17 patients underwent minor liver resection. The median time required for transection was 110 minutes.

SCFA production by the gut is not affected by partial liver resection

The gut produced significant amounts of acetate, propionate, and butyrate before liver transection, as evidenced by portal venous concentrations exceeding the arterial concentrations. The corresponding fluxes were 39.4±13.5, 6.2±1.3, and 9.5±2.6 μmol·kg bw-1·h-1 for acetate, propionate, and butyrate, respectively (p<0.01 for all SCFA, Fig 1). As expected, the production of acetate, propionate, and butyrate by the gut directly after partial liver resection was not statistically different from baseline production, with corresponding fluxes of 42.8±9.6, 8.9±1.5, and 11.9±2.3 μmol·kg bw-1·h-1, respectively (p = 0.67, p = 0.59, and p = 0.24 respectively; Fig 1).

Increased hepatic acetate and butyrate uptake after partial liver resection

Acetate, propionate, and butyrate were all taken up by the liver both before (acetate: -35.1±13.0 μmol·kg bw-1·h-1, p<0.01, propionate: -6.4±1.4 μmol·kg bw-1·h-1, p<0.001, butyrate: -9.9±2.7 μmol·kg bw-1·h-1, p<0.001) and after partial liver resection (acetate: -39.6±9.4 μmol·kg bw-1·h-1, p<0.001, propionate: -8.4±1.5 μmol·kg bw-1·h-1, p<0.001, butyrate: -11.5±2.4 μmol·kg bw-1·h-1, p<0.0001; Fig 2). Whereas the increases in acetate and butyrate uptake after liver resection were significant (p = 0.0011, p<0.0001, respectively), the increase in propionate uptake was not (p = 0.50).

Splanchnic SCFA fluxes and systemic concentrations

Since acetate and propionate release from the gut equalled hepatic uptake both before and after partial liver resection, there was no significant acetate or propionate release from the splanchnic area at either time point. The corresponding splanchnic fluxes were 4.5±3.8 μmol·kg bw-1·h-1 before and 4.2±1.8 μmol·kg bw-1·h-1 after partial liver resection for acetate, and 0.1±0.2 μmol·kg bw-1·h-1 before and 0.4±0.2 μmol·kg bw-1·h-1 after partial liver resection for propionate (both p>0.05, Fig 3). A small but significant release of butyrate from the splanchnic area was found only after partial liver resection (0.4±0.1 μmol·kg bw-1·h-1, p = 0.0103). Arterial acetate, propionate, and butyrate concentrations were not significantly different before versus immediately after partial liver resection; Table 2.

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Fig 3. Short chain fatty acid fluxes across the splanchnic area.

https://doi.org/10.1371/journal.pone.0166161.g003

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Table 2. Arterial SCFA concentrations before and after resection (n = 30).

https://doi.org/10.1371/journal.pone.0166161.t002

No effect of partial liver resection on SCFA uptake per gram liver tissue

Before resection, mean total liver volume was 1692±88 mL and mean functional liver volume (total liver volume minus tumor volume) was 1584±116 mL. Mean estimated remnant liver volume after resection was 1186±106 mL. The resection specimens weighed on average 475±60 g, which was equivalent to 28% of total liver volume. Uptake of acetate, propionate, and butyrate by the liver before partial resection did not correlate with the percentage functional remnant liver volume (rs = 0.32 for acetate (p = 0.20), rs = 0.22 for propionate (p = 0.38) and rs = 0.21 for butyrate (p = 0.39). Similarly, after partial resection, the uptake of acetate, propionate, and butyrate by the liver was not correlated with the percentage functional remnant liver volume (rs = -0.08 for acetate (p = 0.73), rs = 0.16 for propionate (p = 0.51) and rs = 0.13 for butyrate (p = 0.60). Furthermore, no differences were found between arterial acetate, propionate, and butyrate concentrations in patients that underwent a minor resection compared to patients that underwent a major resection; Table 3. When assessing the flux per gram liver tissue before and after liver resection, no significant change in uptake per gram liver tissue was seen for any SCFA (p = 0.87 for acetate, p = 0.88 for butyrate and p = 0.12 for propionate).

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Table 3. Arterial concentrations before and after minor (n = 17) and major resection (n = 13).

https://doi.org/10.1371/journal.pone.0166161.t003

Discussion

The present study was undertaken to investigate the effect of partial liver resection, as a model for controlled loss of liver function, on interorgan exchange of short chain fatty acids (SCFA). Our data confirm that the gut produces significant amounts of acetate, propionate, and butyrate. Intestinal production of acetate exceeds the production of butyrate which, in turn, is higher than the production of propionate. These gut derived SCFA are subsequently to a large extent taken up by the liver. Hepatic uptake of acetate and butyrate even increases after partial liver resection.

Together with data from our previous studies [19], the present data indicate that the liver is able to take up acetate, propionate and butyrate proportionally to gut production, both before and after partial liver resection. These findings are in concordance with previous work by our group showing excess hepatic capacity in e.g. hepatic urea synthesis and ammonia clearance.[20]

Complete hepatic clearance of the main SCFA acetate, propionate, and butyrate (even after partial hepatectomy) is important to avoid the possible toxicity of SCFA. However, it may also be considered as less beneficial given recent data on the metabolic signaling activities of these SCFA. In fact, an enteroendocrine pathway has been proposed by which SCFA control gut hormone expression. SCFA are ligands for G-protein-coupled receptors (GPCRs) GPR43 and GPR41 expressed on enteroendocrine L-cells.[25] In response to SCFA activation of these GPCRs, the gut hormones glucagon-like peptide (GLP-1) and Peptide YY (PYY) are secreted.[26] PYY subsequently regulates intestinal motility and thereby nutrient absorption from the gut, whilst GLP-1 affects satiety.[27] The secretion of GLP-1 is reduced in type 2 diabetes and seems to be reduced in obese subjects as well.[28] Furthermore, mice lacking GPR43 exhibit reduced SCFA-triggered GLP-1 secretion and an impairment of glucose tolerance.[29] More recently, Kimura et al. demonstrated that GPR43 links SCFA production by gut microbiota to host energy homeostasis.[30] They showed that GPR43- deficient mice are obese on a normal diet, whereas mice overexpressing GPR43 specifically in adipose tissue remain lean even when fed a high-fat diet. Besides, SCFA have been shown to influence obesity-induced chronic low-grade inflammation. In addition, acetate, propionate, and butyrate can directly decrease the secretion of adipose tissue-derived proinflammatory cytokines and chemokines. Butyrate, in particular, can also indirectly influence proinflammatory cytokine and chemokine production by influencing signaling pathways like the nuclear factor-kB pathway and by inhibition of histone deacetylases.[31, 32] Butyrate is part of a well-known class of epigenetic regulators known as histone deacetylase inhibitors (HDACi), which modulate the accessibility of genes to transcription factors. Hence, dietary manipulation of histone structure and function of critical genes associated with physiologic and pathologic processes [33] may be a solution to the puzzle of the relation between dietary fiber and the prevention and treatment of different diseases. In this regard, there is a growing interest in butyrate as its impact on epigenetic mechanisms will lead to potential clinical implications.[34]

SCFA might also enhance the intestinal barrier function, further supporting their anti-inflammatory potential. In several studies using intestinal cell lines, SCFA (particularly butyrate), have been shown to improve epithelial barrier function and gut permeability by modulating expression of tight junction proteins and mucins. [35, 36] As such, SCFA, and the microbiota that produce them, are considered to modulate human metabolism by acting as signaling molecules [3739].

Whereas hepatic acetate and butyrate uptake was increased after liver resection, no significant changes appeared to occur in the uptake per gram liver tissue. This might be related to the fact that the uptake per gram liver tissue could only be calculated in a subgroup of patients and the substantial variation in hepatic SCFA uptake between patients. Our data further showed that the uptake of acetate, propionate, and butyrate by the liver was not correlated with the percentage functional remnant liver volume. This may indicate that the magnitude of hepatic SCFA clearance is dependent on gut production, i.e. SCFA availability. Of note, it should be taken into account that the patients were fasting overnight before the operation, so the intestinal SCFA production was lower during the sampling than the usual average production rate. In a sheep model, Bergman et al.[40] found that acetate concentrations were indeed significantly lower in the fasted state compared to the fed state, despite the intensive microbial SCFA production in the rumen of ruminants. In contrast to this study in which the sheep were fasted for three days, the patients in our study had just an overnight fast which may suggest that the influence of fasting on SCFA availability in our study was less pronounced.

Our current data obtained in a unique model of acute loss of liver function underscore the large capacity of the liver to metabolize SCFA released from the gut. It should, however, be taken into consideration that it only reflects a short term acute loss of liver function as blood samples were taken immediately after the partial liver resection. Additional intervention studies must be performed to ensure that supplementation of SCFA in patients is safe. Of note, administering precursors of SCFA (i.e. inulin or fructo-oligosaccharides) has been reported to lead to increased intraluminal SCFA concentrations, but systemic changes in SCFA concentrations have not been reported to date.[41, 42]

Conclusion

This in vivo study in humans confirmed that the gut produces significant quantities of the main SCFA acetate, propionate, and butyrate. Acute hepatic tissue loss did not influence systemic concentrations of SCFA, implying that the liver has a large reserve capacity to metabolize propionate, acetate, and butyrate to prevent any increase of arterial concentrations. This was underscored by the increased hepatic uptake of acetate and butyrate after partial liver resection which, in turn, may be interpreted as circumstantial evidence for the safety of SCFA supplementation even in patients with limited liver tissue.

Acknowledgments

The authors would like to thank Marc Bemelmans and Ronald van Dam, liver surgeons, and Simon Dello, PhD-student, for their valuable help during collection of the samples. The authors also thank Hans van Eijk for his excellent technical assistance.

Author Contributions

  1. Conceptualization: JGB MAB WAB CHD.
  2. Data curation: EN JGB CHD.
  3. Formal analysis: EN JGB SR.
  4. Funding acquisition: WAB CHD.
  5. Investigation: EN JGB JRV MAB KV.
  6. Project administration: WAB CHD.
  7. Resources: WAB CHD.
  8. Supervision: SR WAB CHD.
  9. Validation: WAB CHD.
  10. Visualization: EN JGB SR.
  11. Writing – original draft: EN JGB SR JRV MAB KV WAB CHD.
  12. Writing – review & editing: EN JGB SR JRV MAB KV WAB CHD.

References

  1. 1. den Besten G, van Eunen K, Groen AK, Venema K, Reijngoud DJ, Bakker BM. The role of short-chain fatty acids in the interplay between diet, gut microbiota, and host energy metabolism. Journal of lipid research. 2013;54(9):2325–40. pmid:23821742; PubMed Central PMCID: PMC3735932.
  2. 2. Roberfroid M. Prebiotics: the concept revisited. J Nutr. 2007;137(3 Suppl 2):830S–7S. pmid:17311983.
  3. 3. Topping DL, Clifton PM. Short-chain fatty acids and human colonic function: roles of resistant starch and nonstarch polysaccharides. Physiol Rev. 2001;81(3):1031–64. pmid:11427691.
  4. 4. Pryde SE, Duncan SH, Hold GL, Stewart CS, Flint HJ. The microbiology of butyrate formation in the human colon. FEMS Microbiol Lett. 2002;217(2):133–9. pmid:12480096.
  5. 5. Hu LI, Lima BP, Wolfe AJ. Bacterial protein acetylation: the dawning of a new age. Molecular microbiology. 2010;77(1):15–21. pmid:20487279; PubMed Central PMCID: PMC2907427.
  6. 6. Vernay MY. Propionate absorption and metabolism in the rabbit hindgut. Gut. 1987;28(9):1077–83. pmid:3678966; PubMed Central PMCID: PMC1433235.
  7. 7. Watzl B, Girrbach S, Roller M. Inulin, oligofructose and immunomodulation. Br J Nutr. 2005;93 Suppl 1:S49–55. pmid:15877895.
  8. 8. Preidis GA, Versalovic J. Targeting the human microbiome with antibiotics, probiotics, and prebiotics: gastroenterology enters the metagenomics era. Gastroenterology. 2009;136(6):2015–31. pmid:19462507; PubMed Central PMCID: PMC4108289.
  9. 9. Kristensen NB, Harmon DL. Effect of increasing ruminal butyrate absorption on splanchnic metabolism of volatile fatty acids absorbed from the washed reticulorumen of steers. J Anim Sci. 2004;82(12):3549–59. pmid:15537776.
  10. 10. Wachtershauser A, Stein J. Rationale for the luminal provision of butyrate in intestinal diseases. Eur J Nutr. 2000;39(4):164–71. pmid:11079736.
  11. 11. Wilson AJ, Gibson PR. Short-chain fatty acids promote the migration of colonic epithelial cells in vitro. Gastroenterology. 1997;113(2):487–96. pmid:9247468.
  12. 12. Cavaglieri CR, Nishiyama A, Fernandes LC, Curi R, Miles EA, Calder PC. Differential effects of short-chain fatty acids on proliferation and production of pro- and anti-inflammatory cytokines by cultured lymphocytes. Life sciences. 2003;73(13):1683–90. pmid:12875900.
  13. 13. Welters CF, Heineman E, Thunnissen FB, van den Bogaard AE, Soeters PB, Baeten CG. Effect of dietary inulin supplementation on inflammation of pouch mucosa in patients with an ileal pouch-anal anastomosis. Dis Colon Rectum. 2002;45(5):621–7. pmid:12004211.
  14. 14. Tedelind S, Westberg F, Kjerrulf M, Vidal A. Anti-inflammatory properties of the short-chain fatty acids acetate and propionate: a study with relevance to inflammatory bowel disease. World J Gastroenterol. 2007;13(20):2826–32. pmid:17569118.
  15. 15. Chambers ES, Viardot A, Psichas A, Morrison DJ, Murphy KG, Zac-Varghese SE, et al. Effects of targeted delivery of propionate to the human colon on appetite regulation, body weight maintenance and adiposity in overweight adults. Gut. 2014. pmid:25500202.
  16. 16. Bloemen JG, Schreinemacher MH, de Bruine AP, Buurman WA, Bouvy ND, Dejong CH. Butyrate enemas improve intestinal anastomotic strength in a rat model. Dis Colon Rectum. 2010;53(7):1069–75. pmid:20551761.
  17. 17. Manns JG, Boda JM. Insulin release by acetate, propionate, butyrate, and glucose in lambs and adult sheep. Am J Physiol. 1967;212(4):747–55. pmid:6024435.
  18. 18. Feliz B, Witt DR, Harris BT. Propionic acidemia: a neuropathology case report and review of prior cases. Arch Pathol Lab Med. 2003;127(8):e325–8. pmid:12873194.
  19. 19. Bloemen JG, Venema K, van de Poll MC, Olde Damink SW, Buurman WA, Dejong CH. Short chain fatty acids exchange across the gut and liver in humans measured at surgery. Clin Nutr. 2009;28(6):657–61. pmid:19523724.
  20. 20. van de Poll MC, Siroen MP, van Leeuwen PA, Soeters PB, Melis GC, Boelens PG, et al. Interorgan amino acid exchange in humans: consequences for arginine and citrulline metabolism. The American journal of clinical nutrition. 2007;85(1):167–72. pmid:17209193.
  21. 21. van de Poll MC, Ligthart-Melis GC, Boelens PG, Deutz NE, van Leeuwen PA, Dejong CH. Intestinal and hepatic metabolism of glutamine and citrulline in humans. The Journal of physiology. 2007;581(Pt 2):819–27. pmid:17347276; PubMed Central PMCID: PMC2075174.
  22. 22. van Eijk HM, Bloemen JG, Dejong CH. Application of liquid chromatography-mass spectrometry to measure short chain fatty acids in blood. J Chromatogr B Analyt Technol Biomed Life Sci. 2009;877:719–24. pmid:19230798.
  23. 23. van der Vorst JR, van Dam RM, van Stiphout RS, van den Broek MA, Hollander IH, Kessels AG, et al. Virtual liver resection and volumetric analysis of the future liver remnant using open source image processing software. World J Surg. 34(10):2426–33. pmid:20652701.
  24. 24. van de Poll MC, Wigmore SJ, Redhead DN, Beets-Tan RG, Garden OJ, Greve JW, et al. Effect of major liver resection on hepatic ureagenesis in humans. Am J Physiol Gastrointest Liver Physiol. 2007;293(5):G956–62. pmid:17717046.
  25. 25. Brown AJ, Goldsworthy SM, Barnes AA, Eilert MM, Tcheang L, Daniels D, et al. The Orphan G protein-coupled receptors GPR41 and GPR43 are activated by propionate and other short chain carboxylic acids. J Biol Chem. 2003;278(13):11312–9. pmid:12496283.
  26. 26. Kimura I, Inoue D, Hirano K, Tsujimoto G. The SCFA Receptor GPR43 and Energy Metabolism. Front Endocrinol (Lausanne). 2014;5:85. pmid:24926285; PubMed Central PMCID: PMC4046487.
  27. 27. De Silva A, Bloom SR. Gut Hormones and Appetite Control: A Focus on PYY and GLP-1 as Therapeutic Targets in Obesity. Gut Liver. 2012;6(1):10–20. pmid:22375166; PubMed Central PMCID: PMC3286726.
  28. 28. Faerch K, Torekov SS, Vistisen D, Johansen NB, Witte DR, Jonsson A, et al. GLP-1 Response to Oral Glucose Is Reduced in Prediabetes, Screen-Detected Type 2 Diabetes, and Obesity and Influenced by Sex: The ADDITION-PRO Study. Diabetes. 2015;64(7):2513–25. pmid:25677912.
  29. 29. Tolhurst G, Heffron H, Lam YS, Parker HE, Habib AM, Diakogiannaki E, et al. Short-chain fatty acids stimulate glucagon-like peptide-1 secretion via the G-protein-coupled receptor FFAR2. Diabetes. 2012;61(2):364–71. pmid:22190648; PubMed Central PMCID: PMC3266401.
  30. 30. Kimura I, Ozawa K, Inoue D, Imamura T, Kimura K, Maeda T, et al. The gut microbiota suppresses insulin-mediated fat accumulation via the short-chain fatty acid receptor GPR43. Nat Commun. 2013;4:1829. pmid:23652017; PubMed Central PMCID: PMC3674247.
  31. 31. Meijer K, de Vos P, Priebe MG. Butyrate and other short-chain fatty acids as modulators of immunity: what relevance for health? Curr Opin Clin Nutr Metab Care. 2010;13(6):715–21. pmid:20823773.
  32. 32. Hamer HM, Jonkers D, Venema K, Vanhoutvin S, Troost FJ, Brummer RJ. Review article: the role of butyrate on colonic function. Aliment Pharmacol Ther. 2008;27(2):104–19. pmid:17973645.
  33. 33. McKay JA, Mathers JC. Diet induced epigenetic changes and their implications for health. Acta Physiol (Oxf). 2011;202(2):103–18. pmid:21401888.
  34. 34. Berni Canani R, Di Costanzo M, Leone L. The epigenetic effects of butyrate: potential therapeutic implications for clinical practice. Clin Epigenetics. 2012;4(1):4. pmid:22414433; PubMed Central PMCID: PMC3312834.
  35. 35. Suzuki T, Yoshida S, Hara H. Physiological concentrations of short-chain fatty acids immediately suppress colonic epithelial permeability. Br J Nutr. 2008;100(2):297–305. pmid:18346306.
  36. 36. Elamin EE, Masclee AA, Dekker J, Pieters HJ, Jonkers DM. Short-chain fatty acids activate AMP-activated protein kinase and ameliorate ethanol-induced intestinal barrier dysfunction in Caco-2 cell monolayers. J Nutr. 2013;143(12):1872–81. pmid:24132573.
  37. 37. Lin HV, Frassetto A, Kowalik EJ Jr, Nawrocki AR, Lu MM, Kosinski JR, et al. Butyrate and propionate protect against diet-induced obesity and regulate gut hormones via free fatty acid receptor 3-independent mechanisms. PLoS One. 2012;7(4):e35240. pmid:22506074; PubMed Central PMCID: PMC3323649.
  38. 38. Murphy EF, Cotter PD, Healy S, Marques TM, O'Sullivan O, Fouhy F, et al. Composition and energy harvesting capacity of the gut microbiota: relationship to diet, obesity and time in mouse models. Gut. 2010;59(12):1635–42. pmid:20926643.
  39. 39. Al-Lahham SH, Roelofsen H, Priebe M, Weening D, Dijkstra M, Hoek A, et al. Regulation of adipokine production in human adipose tissue by propionic acid. Eur J Clin Invest. 2010;40(5):401–7. pmid:20353437.
  40. 40. Bergman EN, Wolff JE. Metabolism of volatile fatty acids by liver and portal-drained viscera in sheep. Am J Physiol. 1971;221(2):586–92. pmid:5560311.
  41. 41. Matsumoto N, Riley S, Fraser D, Al-Assaf S, Ishimura E, Wolever T, et al. Butyrate modulates TGF-beta1 generation and function: potential renal benefit for Acacia(sen) SUPERGUM (gum arabic)? Kidney international. 2006;69(2):257–65. pmid:16408114.
  42. 42. Duncan SH, Belenguer A, Holtrop G, Johnstone AM, Flint HJ, Lobley GE. Reduced dietary intake of carbohydrates by obese subjects results in decreased concentrations of butyrate and butyrate-producing bacteria in feces. Applied and environmental microbiology. 2007;73(4):1073–8. pmid:17189447; PubMed Central PMCID: PMC1828662.