International Journal o f Molecular Sciences Article Absorption and Metabolism of the Natural Sweeteners Erythritol and Xylitol in Humans: A Dose-Ranging Study Valentine Bordier 1,2, Fabienne Teysseire 1,2, Frank Senner 3, Götz Schlotterbeck 3, Jürgen Drewe 4 , Christoph Beglinger 1,2, Bettina K. Wölnerhanssen 1,2,*,† and Anne Christin Meyer-Gerspach 1,2,*,† 1 St. Clara Research Ltd., St. Claraspital, 4002 Basel, Switzerland 2 Faculty of Medicine, University of Basel, 4001 Basel, Switzerland 3 Institute for Chemistry and Bioanalytics, School of Life Science, FHNW University of Applied Sciences and Arts Northwestern Switzerland, 4132 Muttenz, Switzerland 4 Department of Clinical Pharmacology and Toxicology, University Hospital Basel, 4001 Basel, Switzerland * Correspondence: bettina.woelnerhanssen@unibas.ch (B.K.W.); annechristin.meyergerspach@unibas.ch (A.C.M.-G.); Tel.: +41-61-685-8585 (B.K.W. & A.C.M.-G.) † These authors contributed equally to this work. Abstract: The natural sweeteners erythritol and xylitol might be helpful to reduce sugar consumption and therefore prevent obesity and diabetes. The aim of the present study was to determine the absorption and metabolization into erythronate of different concentrations of erythritol and xylitol. Seventeen healthy lean participants received intragastric solutions of 10, 25, or 50 g erythritol or 7, 17, or 35 g xylitol on three study days in a randomized order. The study was double blinded with respect to the doses administered. We assessed plasma concentrations of erythritol, xylitol, and erythronate at fixed time intervals after administration with gas chromatography-mass spectrometry. We found: (i) a dose-dependent and saturable absorption of erythritol, (ii) a very low absorption of xylitol, Citation: Bordier, V.; Teysseire, F.; (iii) a dose-dependent metabolization of erythritol into erythronate, and (iv) no metabolization of Senner, F.; Schlotterbeck, G.; Drewe, J.; Beglinger, C.; Wölnerhanssen, B.K.; xylitol into erythronate. The implications of the metabolization of erythritol into erythronate for Meyer-Gerspach, A.C. Absorption human health remain to be determined and more research in this area is needed. and Metabolism of the Natural Sweeteners Erythritol and Xylitol in Keywords: erythritol; xylitol; erythronate; natural sweeteners; absorption; metabolism; obesity; Humans: A Dose-Ranging Study. Int. diabetes J. Mol. Sci. 2022, 23, 9867. https:// doi.org/10.3390/ijms23179867 Academic Editors: Antonella 1. Introduction D’Anneo and Marianna Lauricella The still-steady rise in sugar consumption is a key contributor to the dramatic global Received: 27 July 2022 rise in obesity and associated metabolic disorders, especially type 2 diabetes mellitus. The Accepted: 26 August 2022 WHO has proposed a reduction in sugar intake as a preventive and therapeutic strategy to Published: 30 August 2022 curb these disorders [1]. A possible solution to achieve a reduction in sugar intake is the Publisher’s Note: MDPI stays neutral partial substitution of table sugar and added sugars with low-caloric, naturally occurring with regard to jurisdictional claims in bulk sweeteners, also called polyols. Polyols are mono- and polysaccharides in which a published maps and institutional affil- carbonyl group is replaced by an alcohol (hydroxyl) group. Polysaccharide polyols are iations. difficult to digest and metabolize due to their hydroxyl groups and their glycosidic linkages other than α1-4 and α1-6 [2]. Monosaccharide polyols, such as erythritol and xylitol, are partly absorbed by passive diffusion along a concentration gradient in the small intestine [3]. These monosaccharide polyols are gaining popularity among patients with overweight and Copyright: © 2022 by the authors. diabetes thanks to their low glycemic indexes [2], which gives them anti-hyperglycemic Licensee MDPI, Basel, Switzerland. and anti-diabetic properties [4]. In addition, erythritol and xylitol induce the secretion This article is an open access article of gastrointestinal satiation hormones (such as cholecystokinin (CCK) and glucagon-like distributed under the terms and peptide-1 (GLP-1)) and promote satiety and slow gastric emptying [5–7]. Furthermore, the conditions of the Creative Commons two polyols actively benefit oral health [5]. Attribution (CC BY) license (https:// Erythritol is a four-carbon sugar alcohol (C H creativecommons.org/licenses/by/ 4 10 O4, see Figure 1) with a molar mass of 4.0/). 122.12 g/mol and a glycemic index of 0 (in comparison, sucrose and glucose have glycemic Int. J. Mol. Sci. 2022, 23, 9867. https://doi.org/10.3390/ijms23179867 https://www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2022, 23, x FOR PEER REVIEW 2 of 13 glucagon-like peptide-1 (GLP-1)) and promote satiety and slow gastric emptying [5–7]. Furthermore, the two polyols actively benefit oral health [5]. Int. J. Mol. Sci. 2022, 23, 9867 Erythritol is a four-carbon sugar alcohol (C4H10O4, see Figure 1) with a molar ma2sso fo1f3 122.12 g/mol and a glycemic index of 0 (in comparison, sucrose and glucose have glycemic indexes of 65 and 100, respectively). In 1996, Bornet et al. [8] found that plasma and urine leinvdeelsx einscorfe6a5seadn dw1it0h0i,nr etswpoe chtiovuerlys )p. Irnop1o9r9t6io, nBaolrlnye toe tthale. [a8m] foouunntd otfh eartyptlharsimtoal ianngdesutreidn.e Tlehveeyl sfoinucnrdea tsheadt wthiteh tionttawl uorhinoaurys pexrocpreotritoinon raelalychteodt h7e8a%m oofu intgoefsteerdy tehryittohlriintogle astfetedr. 2T4h ehy [f9o].u And chthroant itch einttoatkael uofr ienrayrtyhreixtocrl eotvioenr srevacehne da7y8s% shofwinegde tshtaetd 7e8r%yt hofr iitnogleasftedr 2e4ryhth[9ri]t.oAl wchasro enxicreintetadk ien othf e ruyrtihnrei t[o1l0o].v Merusnervoe net daal.y [s11sh] osuwmedmtahraizte7d8 %thaotf eirnygtehsrtietodl eisr yrtahpriidtolyl waba-s seoxrcbredte udpi ntot h9e0%ur binye th[1e0 g].aMstruoninroteest ianla. l[ 1tr1a]cstu amndm qauriaznetdittahtaivteelryy ethxrcirteotleids uranpcihdalyngaebdso wrbitehd tuhpe utorin90e%. Wbhyetherg tahset rroeimntaeisntinga l1t0r%ac toaf nthdeq euraynthtirtiatotilv deolysee xisc rfetremdeunntecdh ai n gtheed cwoliothn tohre euxrcirneete. dW uhnechthaenrgtehde vrieam thaein sitnogol1 i0s %unokfntohwene riny thurimtoalndso. Hseoiws efveremr, ein taend inin vtihtreo csoeltotinngo,r eerxyctrhertietodl uwnacsh sahnogwedn vtoia bteh ceosmtopolleitseluyn rkensioswtan ti ntoh buamctaenrisa.lH feorwmevnetra,tinona nwinthvinit r2o4 she t[t1i2n]g. , Ienr ycothnrciltuosl iwona,s asvhaoiwlanblteo dbaetaco smugpgleetsetl ythraets iesrtyanthtrtiotobl aicst emriaailnfleyr mabesnotrabteiodn iwn itthei nin2t4eshti[n1e2,] . nIont cmonetcalubosiloizne,da bvyai tlhabe lbeoddayt,a asnudg egxecsrtettheadt uenrychtharnigtoeldi svima athinel kyidabnseoyr. bHedowinevthere, iin tae sstiidne , enxoptemrimeteanbto loizf etdhebiyr sthtuedbyo doyn, amnedtaebxoclriect emdaurknecrhsa nogf eaddivpiaostihtye kgiadin,e yH. oHootwmeavne er,t inal.a [s1i3d]e reexcpenetrliym sehnetdo lfigthhte oirns atun duynkonnomwent pabaothliwc amy aorfk eerrysthorfitaodli mpoestiatbyogliasimn,. IHn othoetmir asntuedtya, tl.h[r1e3e] hreeacletnhtyly msahleeds ilnigghestteodn aa nsinugnlken doowsen opf a5t0h wg aeyryothf reitroylt harnidto gl amveet faibnogleirs-mp.ricIkn bthloeoird sstaumd-y, ptlherse eath reeagluthlayrm inatleersvianlgs easftteedr iansgiensgtiloend.o Tsheeo fau50thgoresr yotbhsreitrovleadn adng iamvme fiednigaetre- pinrcicrkeabsleo oind bslaomodp leersyatthrreitgoul lcaornincetenrtvraatlisoanfst,e rfoinllgoewsetido nb.yT ahne ainucthreoarsseo ibns eerrvyetdhraonnaimtem coednicaetnetrinactiroenass.e Tinhebyl osoudggeersytt hthraitto ilncgoenscteedn terraytitohnrist,oflo ilsl oowxieddizbeyd ainntion tchreea ssuegianr eerryytthhrroonsaet (eCc4oHn8cOe4n),t rwathioicnhs . iTs hiney tusurng goexsitdtihzaetdi ntgoe esrteydtherroyntahtreit o(Cl i4sHo7Oxi5d−)i.z eTdhein atoutthhoerssu sguagrgeerystt htrhoaste 5(–C140H%8 Oof4 )t,hweh iinc-h gies in turn oxi − sted amountd oizf eedryttohreitroylt ihsr moneatatebo(Cliz4eHd7 Oin5to )e.ryTthhreoanuatthe o[1r3s]s. uTghgesees trethsualtts5 –le1a0d% too nf etwhe qiunegsetsitoends aamboouutn tthoe fmereytathboriltiozlatisiomn eotfa ebroyltihzeridtoiln atonde rtyhteh rroolnea otef e[1ry3t]h. rTihtoels aenrde siutsl tms leetaadbot-o linteews, eqsupeesctiiaollnys earbyothurtotnhaetem, feotra bhoulmizaanti ohneaoltfhe irny trhelraittoiolna ntod otbheesirtoyl eanodf deriaybthetreitso. l and its metabolites, especially erythronate, for human health in relation to obesity and diabetes. FFiigguurree 11. .CChheemmicicaal lsstrtruucctuturreess ooff eerryytthhrrititooll aanndd xxyylliittooll. . XXyyliltiotol liiss aa ffiivee--ccaarrbboonn ssugaarr allcoholl ((C55H112O2O5,5 s, ese eFFigiguurer e11) )wwitihth aa mmoolalarr mmaasss ooff 115522..1155 gg//mmool laanndd aa gglylycecemmicic ininddeexx oof f1133. .DDuuee toto itist shhigighheer rmmoolalarr mmaasss, ,xxyyliltiotol lisis aabbssoorrbbeedd inin ssmmaallleler rpproroppoortritoionns sthtahna nereyrtyhtrhitroitlo. lT.hTerhee arerea orenloyn al yfeawf estwudsiteusd iinevseisntvigeasttiingga ttihneg atbh-e saobrpsotiropnti aonda mndetambeotlaisbmol iosfm xyoliftoxly. lIinto 1l9. 7I3n, A19sa7n3,o Aets aln. o[1e4t] satlu. d[1ie4d] sthtued iinetdesthineali natbessotirnpa-l taiobns oorfp otiroanl xoyfloitroall bxy laitsoplirbaytiaosnp airnadti oanalnydsisa noaf liylesiasl ocof nilteeanl tc ionn ftievnet hineafilvtheyh seualbtjheyctsu. Tbjheecyts . fTouhenyd ftohuant dxytlhitaotl xayblsiotorlpatibosno rpantigoendr farnogme d49f–ro9m5%4.9 H–9o5w%e.vHero, wthevye dr,idth neoyt dfiinddn aontyfi xnydliatonly ixny plitlaoslminap slasmmpalessa monpele sanodne tawnod htwouorhso aufrtsera fitnegr einstgieosnt,i ono, rn odrid itdhtehye ynontoitciec essigignnifiificcaanntt aamoouunnttss iinn uurriinnee uupp ttoo 2244 hh aaftfeter rininggeesstitoionn. .AAftfeter rbbeeiningg aabbsosorbrbeedd, ,mmoonnoossaacccchhaarrididee ppoolylyoolsls ccaann bbee eexxccrreetteed uunncchhaannggeed vviiaa tthhee kkiidnneeyyss,, ooxxiiddiizzeeddd dirireecctltyly, o, or rm meteatbaobloizliezdedin inth tehlei vlievretro tgol gyclyocgoegneonr ogrl ugcluocsoes[e1 5[1].5T].h Tehlea tltaetrteisr wis hwaht aAt sAansaoneot eatl. a[l1. 4[]1s4u] gsugegsgteesdteads aash ay phoytphoetshisesfiosr ftohre tahbes eanbcseenocfex yolfi txoyl liintotlh einb ltohoed b, lwoohdil,e wathlielaes tath alelfaostf thhaelfi nogfe tshteed inqgueasntteidty qwuaasnatibtsyo rwbaesd . aObsthoerbreeds.t iOmtahteers eosftixmylaitteosl ionft xesytliintoall ianbtseostripntailo nabrsaonrgpetiofrno mran4g8%e f[r1o5m] o4v8e%r 5[135%] o[1v6e]r u5p3%to [7156%] u[p1 7t]o. 7X5y%lit o[1l7i]s. fXerymliteonlt aisb fleerbmyecnotlaobnliec bmyi ccrooloorngiac nmisimcrsoaonrgdainsicsomnss iadnedre ids acopnrseibdieorteicd, aas pitrepbrioomtioc,t eass tiht epproromliofetersa ttihoen parnodlimfeertaatbioonli canadct imvietytaobfobliecn aecfiticviaitlyb aocf tbeerinaeafincdiatlh beapcrteordiua catniodn tohfe sphroordt-ucchtaioinn foaft styhoarcti-dcshasuinc hfaattsyb auctiydrsa stuec[h1 8a,s1 9b]u. tLyirvaetese [y18s,u19m].m Laivriezseedy tshuememviadreiznecde athned suggested a consensus of around 49% for absorptive capacity, less than 2% for urinary excretion, and approximately 50% for fermentation [2]. However, like for erythritol, the metabolism of absorbed xylitol still needs further investigation to understand its effect on the human body better and evaluate its potential as a sugar substitute for patients with obesity and diabetes. Int. J. Mol. Sci. 2022, 23, 9867 3 of 13 We administered different doses of each substance to healthy volunteers to investigate the enteral absorption of erythritol and xylitol and their potential metabolization into erythronate. We showed that the absorption of erythritol and its metabolization into erythronate occur in a dose-dependent manner. The absorption of xylitol was low, and no metabolization into erythronate took place. 2. Results All participants tolerated the study treatments well, and there were no adverse events that led to study discontinuation. Therefore, complete data from 2 × 12 participants were available for analysis. There was no abdominal pain, nausea, flatulence, or vomiting reported after any dose of erythritol or xylitol. One participant had diarrhea after 10 g erythritol. Four participants reported feelings of bloating (after 25 g and 50 g erythritol and after 17 g and 35 g xylitol) and two participants reported increased eructation (after 10 g erythritol and after 7 g xylitol). A subjective increase in bowel sounds was reported by nine participants after 10 g erythritol, seven after 25 g erythritol, and eight after 50 g erythritol; and nine participants after 7 g xylitol, eight after 17 g xylitol, and nine after 35 g xylitol. 2.1. Absorption of Erythritol and Xylitol The absorption of erythritol occurred in a dose-dependent manner. The area under the curve from 0 to 180 min (AUC180) and the maximum erythritol plasma concentrations (Cmax) increased in response to the three intragastric loads (AUC180: 10 g vs. 25 g, p < 0.001; 10 g vs. 50 g, p < 0.001; 25 g vs. 50 g, p < 0.001; Cmax: 10 g vs. 25 g, p < 0.001; 10 g vs. 50 g, p < 0.001; 25 g vs. 50 g, p = 0.001, see Table 1). Table 1. Absorption of erythritol. A: 10 g Erythritol B: 25 g Erythritol C: 50 g Erythritol (n = 11) (n = 12) (n = 12) p-Values A vs. B: p < 0.001 AUC180 (mM·min) 201.0 ± 12.7 450.6 ± 29.3 707.1 ± 53.9 A vs. C: p < 0.001 B vs. C: p < 0.001 A vs. B: p < 0.001 Cmax (µM) 1810.6 ± 124.6 3676.9 ± 251.2 5404.3 ± 450.6 A vs. C: p < 0.001 B vs. C: p = 0.001 Absorption rate ka (min−1) 0.126 ± 0.183 0.374 ± 0.257 0.036 ± 0.031 All n.s. A vs. B: n.s. Absorption half-life tka,1/2 (min) 5.40 ± 1.16 4.88 ± 0.86 14.23 ± 2.66 A vs. C: p = 0.004 B vs. C: p = 0.002 Elimination rate k10 (min−1) 0.008 ± 0.002 0.008 ± 0.001 0.002 ± 0.001 All n.s. Elimination half-life tka,1/2 (min) 46.09 ± 5.68 51.41 ± 3.62 42.69 ± 5.24 All n.s. Volume of distribution V1 (L) 38.50 ± 4.27 37.74 ± 2.43 50.95 ± 5.62 All n.s. Data are expressed as mean ± SEM and reported from baseline. Linear mixed effect model analysis with Šidak correction for multiple testing. AUC180: area under the curve from 0 to 180 min, Cmax: maximum plasma concentration, n.s.: not significant. The absorption of erythritol was significantly slower with the 50 g load compared to the lower doses (absorption half-life tka,1/2: 10 g vs. 50 g, p = 0.004, 25 g vs. 50 g, p = 0.002, see Table 1), suggesting a saturable process. Neither the elimination rate constant k10 of erythritol and its half-life tk10,1/2 nor the volume of erythritol distribution (V1) were significantly different between the treatment doses (Table 1). Figure 2 shows the concentration-time curves and the dose-response diagram for AUC180 (dose-response: R2 = 0.996, p = 0.02) and Cmax (dose-response: R2 = 0.999, p = 0.01) of erythritol after administration of the three loads. Int. J. Mol. Sci. 2022, 23, x FOR PEER REVIEW 4 of 13 Elimination rate k10 0.008 ± 0.002 0.008 ± 0.001 0.002 ± 0.001 All n.s. (min−1) Elimination half-life 46.09 ± 5.68 51.41 ± 3.62 42.69 ± 5.24 All n.s. tka,1/2 (min) Volume of distribution 38.50 ± 4.27 37.74 ± 2.43 50.95 ± 5.62 All n.s. V1 (L) Data are expressed as mean ± SEM and reported from baseline. Linear mixed effect model analysis Int. J. Mol. Sci. 2022, 23, 9867 with Šidak correction for multiple testing. AUC180: area under the curve from 0 to 180 min, Cm4aox:f 13 maximum plasma concentration, n.s.: not significant. Figure 2. Dose-dependent absorption of erythritol. Upper part: concentration–time curves after Figaudrme 2in. iDstorsaet-idonepoefntdheentth arbeseolropatdiosn; loofw ereyrtpharirtto:l.d Uospep-reers ppaornt:s ceofnocretnhteraatiroena–utinmdee rcuthrveecsu arfvteerf arodm- 0 mintois1tr8a0timonin of( AthUe Cth1r8e0e) laonaddst;h leowmearx pimarut:m dodseev-rieastipoonnssefr foomr tbhaes aerleinae u(nCdmera txh).e Dcuartvaea frreomex p0 rteos s1e8d0 as min (AU±C180) and the maximum deviations from baseline (Cmax). Data are expressed as mean ± SEMm.e Danata wSEeMre. bDeastt afiwt weriethb eas ntofint-wlinitehaar dnoosne--lrineseparondsoes em-roedspelo. nse model. Xylitol absorption was low and could not be detected in any of the participants after theX7ylgitdolo aseb,soonrplytiionns womase loofwth aenpda crotiucilpda nnotst abfet edrettheect1e7dg ind oansey aonfd thine palalrptiacritpicainptasn atfstearft er thet h7e g3 5dgosdeo, soen(ldy aitna snoomt seh oofw tnh)e. participants after the 17 g dose and in all participants after the 35 g dose (data not shown). 2.2. Metabolization of Erythritol and Xylitol into Erythronate The metabolization of erythritol into erythronate occurred in a dose-dependent manner. The AUC180 and Cmax for erythronate plasma concentrations increased in response to the three intragastric loads of erythritol (AUC180: 10 g vs. 25 g, p = 0.069; 10 g vs. 50 g, p = 0.001; 25 g vs. 50 g, p = 0.002; Cmax: 10 g vs. 25 g, n.s.; 10 g vs. 50 g, p < 0.001; 25 g vs. 50 g, p = 0.01, see Table 2). Figure 3 shows the concentration–time curves of erythronate and the dose–response diagram for AUC180 (dose–response: R2 = 0.999, p = 0.018) and Cmax (dose–response: R2 = 0.989, p = 0.045) of erythronate after administration of the three loads of erythritol. Neither the formation rate (k12), nor the elimination rate k20 of erythronate and its half-life tk20,1/2, nor the volume of erythronate distribution (V2) were significantly different between the treatment doses (Table 2). Int. J. Mol. Sci. 2022, 23, x FOR PEER REVIEW 5 of 13 2.2. Metabolization of Erythritol and Xylitol into Erythronate The metabolization of erythritol into erythronate occurred in a dose-dependent man- ner. The AUC180 and Cmax for erythronate plasma concentrations increased in response to the three intragastric loads of erythritol (AUC180: 10 g vs. 25 g, p = 0.069; 10 g vs. 50 g, p = 0.001; 25 g vs. 50 g, p = 0.002; Cmax: 10 g vs. 25 g, n.s.; 10 g vs. 50 g, p < 0.001; 25 g vs. 50 g, p = 0.01, see Table 2). Figure 3 shows the concentration–time curves of erythronate and the dose–response diagram for AUC180 (dose–response: R2 = 0.999, p = 0.018) and Cmax (dose– response: R2 = 0.989, p = 0.045) of erythronate after administration of the three loads of erythritol. Neither the formation rate (k12), nor the elimination rate k20 of erythronate and Int. J. Mol. Sci. 2022, 23, 9867 its half-life tk20,1/2, nor the volume of erythronate distribution (V2) were significantly dif5-of 13 ferent between the treatment doses (Table 2). FiguFrieg 3u.r De o3s.eD-doespe-ednedpeenntd menettamboeltiazbaotiloizna toifo neroyftherriytothl riintotol ienrtyotherroynthartoe.n Uatpep. eUrp ppaerrt:p caornt:cecnontrcaetniotrna–tion– timet icmurevceus ravfetsera fatdemr aindimstirnaitsiotrna toiof nthoef tthhreeeth erreyetherryittohlr ilotoaldlso; aldosw; elor wpearrtp: adrots:ed–oressep–orensspeo fnosre afroeraa rea undeurn tdher ctuhrevceu frrvoemf r0o mto 018t0o m18i0n m(AinU(CA1U80C) 1a8n0d) amnadxmimauxmim duemvidateivoinasti fornosmf rboamsebliansee l(iCnme (aCxm). aDxa)t.aD ata are eaxrperexspserdes ases dmaesamn e±a SnE±M.S EM. Table 2. Metabolization of erythritol into erythronate. A: 10 g Erythritol B: 25 g Erythritol C: 50 g Erythritol (n = 11) (n = 12) (n = 12) p-Values A vs. B: p = 0.069 AUC180 erythronate (µM·min) 1034.4 ± 122.8 2664.8 ± 241.6 5151.9 ± 763.2 A vs. C: p = 0.001 B vs. C: p = 0.002 A vs. B: n.s. Cmax erythronate (µM) 9.1 ± 1.5 21.0 ± 1.9 45.4 ± 9.1 A vs. C: p < 0.001 B vs. C: p = 0.01 Int. J. Mol. Sci. 2022, 23, x FOR PEER REVIEW 6 of 13 Table 2. Metabolization of erythritol into erythronate. A: 10 g Erythritol B: 25 g Erythritol C: 50 g Erythritol p-Values (n = 11) (n = 12) (n = 12) AUC erythronate A vs. B: p = 0.069 180 (µM·min) 1034.4 ± 122.8 2664.8 ± 241.6 5151.9 ± 763.2 A vs. C: p = 0.001 B vs. C: p = 0.002 Int. J. Mol. Sci. 2022, 23, 9867 A vs. B: n.s. 6 of 13 Cmax erythronate (µM) 9.1 ± 1.5 21.0 ± 1.9 45.4 ± 9.1 A vs. C: p < 0.001 B vs. C: p = 0.01 Formation rate k12 Table 2. Cont.0.0003 ± 0.00009 0.0002 ± 0.00030 0.0002 ± 0.00002 All n.s. (min−1) A: 10 g Erythritol B: 25 g Erythritol C: 50 g Erythritol Elimination rate k20 p-Values0.0229 ± 0.001(n9 = 11) 0.0188 ± 0.00(n12= 12) 0.0210 ± 0.(0n0=181 2) All n.s. −1- Format(imoninrate) k12 (min−1) 0.0003 ± 0.00009 0.0002 ± 0.00030 0.0002 ± 0.00002 All n.s. Elimination half-life Elimint ation (rmatienk) 20 (min −1-) 14.34 ± 01.05242 9 ± 0.0019 16.89 ±0 1.0.21838 ± 0.0012 15.590 ±.0 121.406± 0.0018 All nA.sl.l n.s. k20,1/2 EVliomliunmateio onfh dailfs-tlriifbeutkt2i0o,1n/2 (min) 14.34 ± 1.54 16.89 ± 1.23 15.59 ± 1.46 All n.s. Volume of distribution V2 (L)54.39 ± 145.46.13 9 ± 14.61 49.33 ± 74.69.93 3 ± 7.69 39.21 ±3 59..2314 ± 5.34 All nA.s. V2 (L) ll n.s. Dattaaa arreee xepxrpersessesdeads amse mane±anS ±E MSEaMnd arnepdo retepdofrrtoemd fbraosmeli nbea.sLeilnineaer. mLiinxedare mffeicxtemdo edfefel catn amlyosdisewl aitnhaŠliydsaiks cwoirtrhec Štiiodnakfo cromrruelctitpiolent efostri nmg.ulAtiUpCle1 t8e0s:tianrega. AunUdCer1t8h0e: caurervae ufnrodmer0 thtoe 1c8u0rvmei nfr, oCm a0x t:om 1a8x0i muimn, pClmasamxa: cmonacxeimntruamtio pn,lans.sm.: an octosnigcneinfitcraantito. n, n.s.: not significant. TThhee mmeettaabboolliicc rraattiioo AAUUCCerythrit/oAl/UACUCerythr ownaates whiagshhighest with the 10 g eerythritol erythronate est with the 10 g erythrriytotlh lroitaodl laonadd daencdreadseecdre wasitehd hwigihtherh digohseesr (draotsieos A(rUaCtio AfoUr C1108 0g:f 2o3r61.20 ±g 4: 62.33 6v.s2. ±25 4g6: .138v7.s6.180 ±2 252.g4: 1v8s7. .650± g2: 21.462v.s3. 5±0 2g0:.116, 2d.3if±fer2e0n.1c,edsi fnfeorte nsicgens infoictasnigtn).i fTichaen tC). The Cmax, erythmriatoxl/, Cery /Cmtahxr, iteorylthronmatae xr, eartyitoh rownaates raalstoio hwigahseaslts wo ihthig thhees t10w git hertyhtehr1i0togl leoraydth croitmolplaoraedd ctoo mthpea hreigdhteor tdhoesehsi g(rhaetriod Cosesmax f(orar t1io0 Cg:m 2a2x9f.0o r± 1206.g5: v2s2. 92.50 g±: 12963..51 v±s 2. 32.35 vgs:. 15903 g.1: 1±532.83 .±3 2v0s..4,5 d0igff:er1e5n3c.8es± no2t0 s.4ig, ndiiffifcearnent)c. eTshneoset sdiegcnriefiacsainntg) .mTehteasbeodliecc rraetaiosisn wg imthe htaigbholeirc draotsieoss owf ietrhyhthigrihteorl idnodsiecsatoef tehraytt hanri tionlcirnedasicinatge ftrhaac-t atinonin ocfr eearysitnhgritforal cist imonetoafbeorliyztehdr iitnotloi sermytehtarobnoalitzee. dFiignutoree 4r ysthhorwonsa tthee. mFiegtuarbeol4ics rhaotwioss tdhee- mpeentdabinogli conra tthioe sddifefepreenndt idnogsoesn otfh eerdytifhfreirteonl.t Tdhoisse pshoefneormytehnroitno li.s Tahlsios rpehfleencotemde bnyo tnhies naolsno- rlienfleeacrt eddosbey-rtehsepnoonns-el ifnoera Ar dUoCse-r aesnpdo Cnse for AUC180 and Cmax, as shown in the lower part180 max, as shown in the lower part of Figure 2. of Figure 2. Figure 4. Metabolic ratios erythritol/erythronate for the three doses of erythritol. AUC180: area under the curve from 0 to 180 min, Cmax: maximum deviation from baseline. Data are expressed as mean ± SEM. The concentrations of erythronate in response to the intragastric loads of xylitol were under the detection limit of the analytical assay, indicating no metabolization of xylitol into erythronate at the doses applied in this study. Int. J. Mol. Sci. 2022, 23, x FOR PEER REVIEW 7 of 13 Figure 4. Metabolic ratios erythritol/erythronate for the three doses of erythritol. AUC180: area under the curve from 0 to 180 min, Cmax: maximum deviation from baseline. Data are expressed as mean ± SEM. The concentrations of erythronate in response to the intragastric loads of xylitol were under the detection limit of the analytical assay, indicating no metabolization of xylitol Int. J. Mol. Sci. 2022, 23, 9867 into erythronate at the doses applied in this study. 7 of 13 3. Discussion 3. DiTshciuss sstiuodny aimed to determine the absorption of different intragastric doses of eryth- ritol aTnhdi sxsytluitdoyl aanimd etdhetior dpeotteernmtiianle mtheetaabbosloizrapttiioonn ionftod ieffreyrtehnrtoinnatrtea ginas htreiacldthoys evsooluf nertyeethrsr.i - Ttohlea rnedsuxltysl isthool wan tdhtaht:e ii)r tphoet eanbtsioarlpmtieotna boof leizryatthiornitoinl tios deroysteh-droenpaetnediennht eaanldth syavtuorlaubnltee; eiri)s . tThhe eabressourplttsiosnh oowf xtyhliatto:l (iis) ltohwe; aibiis) oerrpyttihornitoolf ies rmytehtaribtoollizisedd oinseto-d eerpyethnrdoennattea,n tdhes matuetraabbole- ; l(iizia) ttihoen aisb sdoorspet-idoenpoenf dxeynlitt oalnids hloigwh;e(ri iwi)iethry hthigrhit odloissesm oeft aebroyltihzreidtoli;n atonde riyvt)h trhoenraet eis, tnhoe mmeettaabboolliizzaattiioonn iosf dxoysleit-odle ipnetnod eernyttahnrodnhaitgeh. eTrhwe iitmh philgichatdioonsess foofr ehruytmhrainto hl;eaanltdh (rive)mthaienr etois bneo dmeteetramboinliezdat. ion of xylitol into erythronate. The implications for human health remain to be deTtheerm abinseodrp. tion results for erythritol are in line with other human studies showing that eTryhteharibtsool rips triaopnidrelysu altbssoforbr eedry [t8h–r1it0o].l Haroewinevlienre, twheit hexotethnet rchanu monalny sbtue deisetsimshaotewdi ning ctohmatpearryisthonri ttool ains irnatpriadvleynaobusso crobnetdro[8l.– T1h0e]. dHosoew-deevpeer,ntdheenet xatbesnotrcpatnionon olfy ebryetehsrtiitmol aftoeudnidn hceorme pcaornisfiornmtso tahne irnetsruavltesn oofu Bs ocornnetrt oelt. Tahl. e[8d]o, swe-hdoe psehnodweendt aibnscorerpastiionng opflaesrymtha reitroylthforuitnodl choenrceecnotrnafitiromnss tahse ar efusunlcttsioonf Bofo rinngetesettedal .d[o8s]e, sw (h0o.4 sohro 0w.8e dg/ikngc rbeaosdiyn gwpeliagshmt)a. Meroyrteh riimto-l pcoorntcaenntltyra, twioen osbasseravefudn tchtaiot nthoef aibnsgoersptteidond oofs eesry(t0h.4ritoorl 0w.8asg s/lkogwbero dwyithw tehige hhti)g. hMesot rdeoisme - (p5o0 rgta) nstulyg,gwesetionbgs ear svaetdurtahbaltet hperoacbessosr. pTthioen sloofwereyr tahbrsitoorlpwtiaosn smloiwghetr ewxipthlatinh eghaisgtrhoeisnttedsotsi-e n(5a0l sgy)msupgtogmessti snugcah saast unraaubsleeap, rboocrebsos.ryTghme is,l obwloeartianbgs,o arnpdti odniamrrihgehat oebxspelravinedg aastt hroiginht edsotisneasl [s5y,2m0p].t oTmhes hsuycphoathsensaisu soefa a, bsoartbuorarybglem ai,bbsolorapttiinogn, aonf derdyitahrrrhiteoal oabt sheirgvhe d oastehsi gish cdoomsepsa[t5i,b2l0e] . wThiteh hthyepsoet ohbeseisrvoaftaiosnast.u rable absorption of erythritol at high doses is compatible with theseXoyblistoerl,v oanti othnes. other hand, was poorly absorbed in the present study. This contrasts with Xreysluitlotsl ,sohnowthiengo tahbesrohrapntido,nw oafs apt oleoarslyt 5a0b%so rinb ehdeainlththye spurbejseecntst s[1tu4]d. yI.nT choins tcroanst,r athstes pwreitvhioruesu slttusdsyh ouwseidn ga atebssto sropltuiotinono fcoant sleisatsint g5 0o%f xiynlihtoeal lwthityhs aunb ejeqcutsal[ 1a4m].oIunnct onf tgrlausct,otshee, wprheivchio iuss dsitfufedryenuts efrdoamt ethstes coulurrteionnt cdoensisgisnt.i nTgheo faxdydlitoiolnw oitfh galunceoqsue aml aigmhot uhnatvoef agflfuectoesde , twheh iacbhsoisrpdtiifofenr eonf txfyrloitmol.t hMeocruerorvenert, dthesei ganu.thTohres aedstdimitiaotnedo fabgsluorcpotsieonm bigyh atshpairvaetiaofnfe actnedd atnhaelyabsisso ropf tiloenalo cfoxnytleitnotl .(iM.e.o, rdeoisvaeprp, tehaeraanucteh)o; rosf enstoitme,a thedeya bdsiodr pntoito nfinbdy asnpyi rxaytiloitnola nind palnaaslmysai ssaomf iplelaels coonet eanntd(i t.ew.,od hisoauprpse afrtaenr cien)g; eosftni onte [,1t4h]e. y did not find any xylitol in plasma sampElreysthornietoaln isd mtwetoahboluizrseda fitnetroi negryetshtiroonna[1te4,] .confirming the findings of Hootman et al. [13]. IEnr yatdhdriittoiol ins, mweet aebxotleiznedd tihnetosee rfyinthdrionngast eb,yc osnhfoirwmiing theatf itnhdisin mgseotafbHoolioztamtiaon eits adl.o[s1e3-]. dInepaedndditeinont ,awnde eixntcernedastehse swe ifitnhd hinigghs bdyosheso wofin egryththatritthoils. mThetea bmoelitzaabtoiolinzaistidoons ep-rdoecpeesnsd oecn-t caunrdreidn,c rheoawseesvweri,t hinh migihnidmosael saomfoeuryntthsr: ilteosls. Tthhaenm 1e%ta obfo elirzyatthiorintoplr wocaess sconccvuerrrteed, ihnotow eervye-r, tihnromniantiem—awl ahmicohu isn tlse:ssle tshsatnh Hanoo1%tmoafne erty athl. rwitohlow reapsocrotnedv ear tceodnvinetrosieorny rtahtreo nofa t5e–—10w%h. iIcnh tihseliers sstuthdayn, oHnolyo ttmhraene emt eanl. wehroe rinepclourdteedd aancdon thveeyrs rioecnerivateedo 5f05 g– 1o0f% or.aIln etrhyethirrsittould 4y3, monilny atfhtreere hmaveinngw ceornesiunmcleudd e2d ga onfd lathbeelyedre gceluivcoedse5. 0Aglthoofuogrha ltherey dthorsieto ils 4s3immilianr,a tfhteer lhimavitiendg scaomnpsulem seizde2, tgheo frolaubtee,l eadndg ltuhceo tsiem. iAnglt hoof uagdhmtihneistdroastieonis asrime iimlapr,otrhteanlitm diitfefedresnamceps lien stihzee , stthuedryo duetes,igann.d Btohteh tsimtuidnigeso afgardeme tihnaistt roantliyo nona rae simmaplol ratmanotudnitf foefr eenrycethsriintotlh ies smtuedtaybdoelisziegdn . (B<1o0th%s).t uWdiee sthaignrke eththata teroyntlhyriotnola iss mcoanllvaemrteodu nbtyo af ne rayltchorhitooll disehmyedtarobgoelinzaesde (t