SCFA in gut health. Kristin Verbeke. On behalf of the Prebiotic Task Force of ILSI Europe

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1 SCFA in gut health Kristin Verbeke Translational Research in Gastrointestinal Disorders KU Leuven On behalf of the Prebiotic Task Force of ILSI Europe

2 Acetic acid Major anions in the large intestine Propionic acid Pass information from the diet and microbiota to the host inhibitors of HDAC ligands for GPR receptors Butyric acid

3 Gut health Bischoff S., BMC Medicine 2011; 9:24 3

4 Barrier function Epithelial cells Mucus Immune system antimicrobials Natividad et al. Pharmacological Research 2013; 69:

5 SCFA affect tight junctions Natividad et al. Pharmacological Research 2013; 69: Feldman et al. Advanced Drug Delivery Reviews 2005; 57:

6 SCFA affect tight junctions Peng et al. J Nutr 2009;139:

7 Butyrate stabilizes HIF-1 Kelly et al. Cell host & microbe 2015; 17:

8 SCFA stimulate proglucagon-derived peptide 2 (GLP-2) occludin ZO-1 jejunum colon antagonist agonist Cani et al. Gut 2009; 58:

9 Barrier function Epithelial cells Mucus Immune system antimicrobials Natividad et al. Pharmacological Research 2013; 69:

SCFA affect mucus production Stimulation of MUC2 gene expression Inhibition of histone deacetylation Synthesis of PGE1 Ex vivo stimulation of mucus production in human biopsies In vivo (humanised

10 SCFA affect mucus production Stimulation of MUC2 gene expression Inhibition of histone deacetylation Synthesis of PGE1 Ex vivo stimulation of mucus production in human biopsies In vivo (humanised rats): increased mucin production In vivo (humans): no effect on MUC2 expression in HS (n=16) and UC patients (n=35) in remission after butyrate enemas (60 ml, 100 mm butyrate) for 2 wks Finnie et al. Gut. 1995;36(1):93-9. Van den Abbeele et al. Environm microbiol 2011 ;13: Hamer et al. Eur J Gastroenterol & hepatol 2010; 22:

involved in glycosylation Confirmation with PCR upregulation of galectin-1

11 SCFA affect mucus quality human intestinal epithelial goblet cells treated with 2 mm butyrate microarrays carrying cdna specific for 252 enzymes involved in glycosylation Confirmation with PCR upregulation of galectin-1 gene (LGALS1) expression Gaudier et al. Biochem biophys res comm 2004; 325:

12 Barrier function Epithelial cells Mucus Immune system antimicrobials Natividad et al. Pharmacological Research 2013; 69:

13 SCFA affect MAPK and NF-ĸB pathway Li et al. Eur J Pharmacol 2018; 831:

14 Involvement of the inflammasome pathway Macia et al. Nat Commun 2015; 6:

15 SCFA mediate colonic T reg Directly by interaction with T cells SCFA exposure ameliorates colitis in a T cell transfer model of colitis SCFA restore colonic T reg populations and function in germfree mice Smith et al. Science 2013;341: SCFA augment colonic T reg populations and function in SPFmice 15

SCFA mediate colonic T reg Via modulation

increases the expression of IDO and Aldh

conversion to a tolerogenic phenotype in

16 SCFA mediate colonic T reg Via modulation of DC function DC exposed to butyrate increases the expression of IDO and Aldh 1A2 DC exposed to butyrate promote conversion to a tolerogenic phenotype in T-cells Gurav et al. Biochem J 2015; 469: DC exposed to butyrate suppress conversion into pro-inflammatory IFN-γ + T-cells 16

17 SCFA stimulate siga production Wildtype mice GPR43 -/- mice GPR43 -/- mice have lower faecal IgA and less IgA+ B-cells in their lamina propria Supplementation with acetate increased faecal IgA and IgA+ cells only in WT mice expression of Aldh1a2 was increased in acetate-treated DC acetate induction of RA expression enhances B cell IgA production RA treatment promoted B cell IgA production Wu et al. Mucosal immunology. 2017; 10:

18 Efficacy of SCFA in treatment of ulcerative colitis n Enema treatment Results Reference mm butyrate and placebo 100 ml, ph=7, b.d. for stool frequency, blood discharge, Scheppach wks. Wash out: 2wks endoscopic & histological scores 45 CS, 5 ASA or 130 mm SCFA (46:23:31*) 60 ml, ph=7, SCFAs equally efficacious to CS or 5 ASA Senagore 1992 b.d. for 6wks mm SCFA (53:20:27) vs. placebo 100 ml b.d. for SCFAs intestinal bleeding, urgency and Vernia wks patient self evaluation score mm SCFA (46:23:31) vs. 100 mm butyrate vs. No differences between groups. Scheppach 1996 Placebo 60 ml, ph=5.5, b.d. for 4 8 wks Butyrate for 8 wks fewer colonic segments affected endoscopically mm butyrate vs. placebo 60 ml, ph=7 for 6 wks No differences between butyrate and placebo Steinhart 1996 treatment mm SCFA (53:20:27) vs. placebo 100 ml, ph=7 no therapeutic value Breuer 1997 b.d. for 6 wks mm SCFA (46:23:31) vs. 100 mm butyrate vs. Placebo 60 ml, ph=5.5, b.d. for 4 8 wks Butyrate trend for reduced density of neutrophils in lamina propria. SCFA and butyrate cell proliferation in upper crypt Scheppach mm butyrate vs. placebo 60 ml, ph=5.5, b.d. for 4 8 wks Butyrate number of nuclear translocated NF κb positive macrophages, number of neutrophils and Disease Activity Index Luhrs ASA and saline vs. 5 ASA and 80 mm butyrate 80 ml b.d. for 6wks 5 ASA in combination with butyrate more patients into remission, bowel movements, urgency and patient s self evaluation Vernia 2003 Hamer et al. Aliment Pharmacol & Ther 2008; 27:

19 Barrier function Epithelial cells Mucus Immune system antimicrobials Natividad et al. Pharmacological Research 2013; 69:

20 Butyrate stimulates cathelicidin-ll37 HCA-7 cells HT-29 cells Hase et al. Infection and immunity 2002; 70: Schauber et al. Immunology 2006; 118:

21 Motility and transit: animal models Propionate and butyrate but not acetate induce contraction of colonic muscle ex vivo in rats Effects of SCFA are dose-dependent Effects of SCFA might differ between species Potential mechanisms: Secretion of PYY Interaction with GPR41 and GPR43 Stimulation of 5-HT release Saline 100 mm SCFA 500 mm SCFA Tazoe et al. J Physiol Pharmacol. 2008;59 Suppl 2: Mitsui et al. Neurogastroenterol Motil 2005; 17: Fukumoto et al. Am J Physiol Regul Integr Comp Physiol 2003; 284:R Cherbut et al. Am J Physiol 1998; 275: G

22 Motility and transit: humans Jouet et al. Neurogastroenterol Motil 2013; 25:

23 Calcium absorption: mechanisms luminal ph Ca-complexation Upregulation of proteins involved in paracellular Cauptake Transcription of TRP6 transcellular Ca-uptake Upregulation of calbindin-d9k Presence of Ca-H exchanger in distal colon Kashimura et al. Biol Trace Elem Res 1996; 54: Fukushima et al. J Nutr 2009; 139:20-5. Fukushima et al. J Nutr Sci Vitaminol 2012; 58: Lutz T, Scharrer E. Exp Physiol 1991; 76:

24 Calcium absorption Healthy subjects (n=6) Rectal infusions (300 ml) of 50 mm CaCl 2 56,3 mm acetate or 18.7 mm propionate or both Ca absorption linearly related to Ca concentration in the presence and absence of Ac and Pr, involves a non-saturable diffusion process Ca absorption is increased by Ac and Pr, and Ac and Pr absorption are stimulated by Ca. Trinidad et al. Nutrition Research. 1993;13: Trinidad et al. Am J Clin Nutr 1996;63: Trinidad et al. Adv Exp Med Biol 1997;427: Trinidad et al. Nutrition. 1999;15:

25 Calcium absorption p=0.04 Abrams et al. Am J Clin Nutr 2005; 82:

26 Conclusions In vitro and animal experiments provide compelling evidence for a role of SCFA in the improvement of gut barrier function although not completely resolved, molecular mechanisms have been studied extensively and in great detail In humans, it remains difficult to demonstrate improved barrier due to SCFA No studies directely assessed the impact of SCFA intervention on barrier function in humans Mixed results from studies that modulate the microbiota and presumably SCFA production Most studies did not measure SCFA or only measured faecal SCFA Assays that measure barrier function in vivo (most often permeability tests) suffer from considerable variability and might be not sensitive enough 26

27 Conclusions (II) At physiological concentrations, SCFA seem not to affect colonic motility in humans SCFA not only increase intestinal absorption of calcium but also result in higher bone mineral content and density. 27

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