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    MacDonald Et Al 2011

    Transféré par

    Carlos Rosales
    Guide

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    oleae Genes and Metabolism 104 (2011) 555-558 Contents lists available at SciVerse ScienceDirect Molecular Genetics and Metabolism ELSEVIER Journal homepage:.www.elsevier.com/locatelymame Specific prebiotics in a formula for infants with Phenylketonuria Anita MacDonald **, Barbara Cochrane », Harm Wopereis °, Nik Loveridge ¢ * Birmingham Chilren's Hesial Bonga, UK ® paylHaspl osc Cle. Cao. UK « Danone Resereh Center for Spend Nurton, Wageninge, Te Netheands "hum Advent Mei! Narn. Liepcl ARTICLE INFO ABSTRACT econo ‘eceives 20 July 2011 Received in tevted fon 10 September 2011 ected 10 Seperber 2017 ‘valabe online 16 September 2011 Objective: This exploratory study investigated the influence of adding a patented, specific mixture of prebione ‘oligosaccharides (seGOS/cFOS [8:1 rato), Danone Research) toa protein subetiute suitable for infants with Phenyiketonuria (PKU) PKU Anamix Infant (Nutri). Design: This was an &-week open-label, single-arm, pllot intervention study in 9 infants (8-week median age) diagnosed with PKU, On study enty, infants were prescribed PKU Anarix Infant to replace an infae Dhenalanine-fee protein substitute without prebiotics (IPS), Blood phenylalanine concentrations were teni- tine tron disorders tored and stool samples analyzed for pH/bacteral groups Infant fra Results: PRY Anamix intane was well tolerated and accepted with no adverse events reported. Overall plastoa [phenylalanine and tytosine concentrations were maintained within target ranges throughout the study (120— 360 nol phenylalanine, 30-100 rn tyresine). Alinfants exhibited micrabota dominated by bifidobacteria (median 58.97% at Week 8), akhough no stabstialy significant change fom baseline was observed at study endpoint Noinfants showed abnormally high levels of Clsrdlum ntolycumdiseburense or potentially path- ‘genic enterobactenacee at any point during te study. Asignfcant reduction in median stool pH versus base- line was observed at Week 4 (pH reduced from 6780 583), but this significance was not present at Week 8 (p= 661), Conclusion: PIU Anamix infant maintains phenylalanine control in fine with established IPS without prebiotics and maintains level of ifdabactrs an lowers stol pH. In exclusively breastfed infants the ater two factors have been associated with a edced rk of infection and may be of particular importance in infants with PKU, 1© 2011 Elsevier inc, All ight reserved atsson therapy Poenyeconura {Introduction Alife-tong low phenylalanine diet remains the first-line treatment In the management of the inherited metabolic disorder Phenylketon- uria (PIG). In the UK. the diet primarily consists of: 1) a measured but restricted allcation of phenylalanine, providing typically less than 10 gidsy of intact protein, 2) a phenylalanine-free protein substitute consisting of all other L-amino acids, vitamins and trace minerals, and 3) allowance of foods naturally low in phenylalanine that are given without measurement. In infants with PKU, phenylalanine tol~ france can vary considerably dependent on the individual, but it has been reported that neonates (<6 months) with PKU have a mean Abbreviations Infant eosin subst (IP) refers to a infant formula without phenylalanine fr ans wit pheryletonr; Prefers prio ogostehaies Prete: XP Analg LCP. ean inane phere ee protein subsite without rebioes ane a subject aking hs before changing a stay formula eee toss PS vthoutpreioes. PR Anam inne. ia prtioce containing infant Phelan re protein suture nde evan (ete ty for), * Corresponding author at: Srmingham Children’ Hospital, tetbouse Cane i ringham.B4 GN, UK Fax: + 4412139) B02, Erma ares: anita macdonlepbch au (A MacDonald), 106.7192 - see font mater © 201 Elsevier In. lights esrved 611020164, ymgme 201109015 intake of between 362 and 464 mlday of breast milk [1] (providing approximately 3-4 of intact protein), which is substantially lower than infanes on a normal diet. Infants with moderate to severe PKU ‘receive up to 75% of their protein requirements (excluding phenylal- nine), along with an equivalent percentage of their vitamins and ‘minerals, from thet (PS, Breast milk is widely recognized as the gold-standard for infant feeding, providing all essential nutrients for growth and development [2], Compared with formula-fed infants, breast-fed infants have an ‘enhanced immune system and reduced risk of infection [3,4]. tis therefore advantageous that the composition of PS continues evalv~ ing to achieve a nutritional composition comparable to chat of human breast mill: Breast milk naturally contains prebiotic ingredi- ents (eg. oligosaccharides), which has led to the supplementation of standard infant formulae with components that have similar ef- fects [5,6]. Dietary prebiotics are defined as “a selectively fermented Ingredient that results in specific changes, in the composition and/or activity of the gastrointestinal microbiota, thus conferring Denefit(s) upon hose health” (7.8). Ian infane is unable to exclusively receive breast milk, the compo- sition ofthe intestinal microbiota can be influencee in two ways: by 596 ‘A. Macdonalét | Molecular Genes an Metaotion 104 (2077) 585-559 ingesting living health-promoting bactetia that are able ro survive the Gl tract and colonize the colon (probiotic approach) [9 or by dietary ingredients that are able to reach the colon and selectively stimulate health-promoting bacteria (prebiotic approach) [10,11]. Prebiotic ol- igosaccharides therefore, as an important component of breast mill, are of particular importance in any infant formula. With highly re- stricted intakes of breast rullk and standard infant formula being the comerstone of the management of PKU, itis important to identify whether infants with PKU are at a higher risk of developing a less than optimal intestinal microbiota, through decreased intake of pre- biotic oligosaccharides Studies have demonstrated that standard infant formula supple- ‘mented with short-chain galactooligosaccharides (scGOS) and long- chain fructoligosaccharides in the ratio 9:1 increases bifidobacteria, and lactobacili levels and decreases fecal pH [12-16]. Clinical studies have also reported that these changes tothe gastrointestinal microbiota ‘may be associated with beter gastrointestinal transit (stool frequency and consistency) and a reduced risk of infection 12,1725]. I therefore, appears appropriate that prebiotic components, iz. scGOS/IeFOS (9:1 ratio), are added to an 15. Little is known about the Gl function and bowel habits of infants with amino acid disorders, although MacDonalé et al, reported that categivers of children with PKU perceived them to have mare issues with constipation, diarthea and stomach pains [26], possibly associated ‘with a high intake of high osmolar protein substitutes. While these ef- fects alone is undesirable, abnormal bowel function can disrupt feeaing, which may ultimately affect metabolic contro. Therefore, understand- ing the potential influence of gut modulating ingredients could ulti rately contibute to improved control in metabolic patients. ‘Due to the rarity of PKU, there has been no research into the effica cy and tolerability of added prebiotic oligosaccharides to an IPS. Here ‘we report the Findings from the first exploratory study to investigate the tolerability and efficacy of an IPS with prebiotics (PKU Anamix In- fant: Nutricia). The study objectives were 10 evaluate any effets on the blood phenylalanine control, gastro-intestinal (Gl) tolerance (i.e. stool frequency and characteristics) and GI microbiota of infants with PKU, ‘who changed from an IPS without prebiotics to PKU Anamix Infant (Advanced Medical Nutition, Liverpo0). 2. Methods This was an 8-week, open-label, pilot intervention study in infants aged between 4 weeks and 6 months with a diagnosis of PKU requir- ing a low phenylalanine diet A one week extended baseline period ‘was included in the study design: during this time infants entered the study, but remained on an IPS without prebiotics. Alter this ex- tended baseline period, subjects transferred onto PKU Anamix infant. Patients were recruited from two specialist PKU centers in the UK (Birmingham Children’s Hospital and the Royal Hospital for Sick Chil- Gren, Glasgow). Inclusion criteria included satisfactory blood phenylal- anine control for >2 weeks, whilst receiving IPS without prebiotics and either breast milk or commercial infant formula (with or without prebi- ‘otics} in amounts dependent on plasma phenylalanine concentrations and individual tolerance to natural protein, Exclusion criteria included the presence ofa serious concurrent iliness, intake of solids, abnormally low birth weight (<2000 g), prematurity (<37 weeks gestation), treat- ‘ment with antbioties <2 weeks prior to study entry, or investigator concerns relating tothe willingness or ability of the subject to comply, with protocol requirements. The srudy objectives were to investigate pheny/alanine control (efficacy) and tolerability ofthe PKU Anamix In- fant and to observe any effect on gastrointestinal microbiota and stool consistency, ‘On entry into the study, infants were prescribed PKU Anamix Infant fora total of 8 weeks (Weeks 0-8), to replace the previous IPS without PB (Weeks —1-0). Three day intake diaries were completed by care- aivers during weeks —1, 4 and 8. Blood phenylalanine and tyrosine concentrations were monitoted weekly throughout the study. Care- givers, who had received training from specialist nurses, collected blood spots from infants at standardized times, always before the Fist feed in the morning. These were subsequently analyzed by the partci- pating hospital using tandem mass spectrometry. ‘tool samples were collected at Weeks —1 (extended baseline pe tod), 4 and 8 by the caregiver using specialized vials/scoops and stored at ~20°C. Two samples were collected. if possible, for each time point. Samples were subsequently packed in insulated com tainers containing solid COs (ie. dry ice) and posted to Danone Re- search BV. (Wageningen, The Netherlands) where they were analyzed for fecal pH and dominant bacterial groups: bfidobocteria, lactobacli-enterococci, bacteroides distasonis/fragilis, Clostridium histolyticumylituseburense,E.retale/Ccoccoides group and a subset of tencerobacteriaceae (E, col, Shigella, Salmonella, Klebsiella) by means of fluorescence in situ hybridization (FISH) as described by Knol et 21. [27]. In addition, caregivers recorded stool frequency, size (small, ‘moderate, large or huge), appearance (hard lumps, lumpy/allantoid allantoid cracked, allantoid/smooth, soft blobs, Muffy pieces, watery) and consistency (firm/hard, formed, soft/unformed, semi-liquid and watery) at Weeks ~1, 1,4 (no intake recorded) and 8, This was com- pleted using an adapted stool chart that combined the Bristol Stool Scale [28] with an independent chart from the Children's Hospital, Bicmingham, UK (Murphy, personal communication). Any adverse events or sesious adverse events were recorded by the investigator using a standard clinica sil report form, ‘Due tothe rarity of the condition and the exploratory nature of the study, sample size calculations were not performed and only descrip- tive statistics were undertaken. These analyses were performed on the intent to treat population (ITT), which included all subjects who completed the changeover to the IOS with PB. Comparisons for statis- ‘ical significance were performed using Sigma Stat Statistical Analysis, Software: stucent’ t-tests were applied to normally distributed data and Wilcoxon Signed Rank Tests applied co non-parametric data. Ethical approval was obtained from the South Birmingham ethical committe. Prior to enrolment inthe study, written informed consent was obtained from the primary caregiver ofeach subject 3. Results Intotal nine infants were recruited and completed the sty, six of ‘whom were female, The median age 2 baseline was 7.85 weeks (range 714-19.) At study entry (in addition to TPS without PB), infants re- ceived theie intact protein from either breast milk (n=3), a combina- tion of breast milk and infant formula containing prebiotics (n=3), solely infant formula containing prebiotics (n=2), or standard infant formula without prebiotics (a= 1). Overall, the daily amount of breast rmilkjformula consumed remained sila throughout the study. There appeared to be a trend towatds infants receiving a greater amount of| PKU Anamix infant at Week 8 than at baseline (associated witn increas- ing energy requirements and infant growth), with mean pre-study pro- tein intakes from IPS without prebiotics of 8.71 of protein equivalent per day (g/PE/day) (range 433-117 g/day), and mean intakes of PKU ‘Anamix Infant at week 8 of 11.3 g PE/day (range 69-149 g PE/day). A similar pattern was exhibited in standard infant formula intake, with 'mean pre-study protein intakes from standard formula of 4.16 g PE/day (range 3.64 g-483 g PE/day) and mean week 8 intakes of 88 g PE/day (range 08-48 g PE/day). Mean protein intakes from breast milk cannat be included in these figures as only values of "minutes on breast” are available for those subjects. One infant (subject 3) initiated solids uring Week 8 ofthe trial, at 20 weeks of age. Values forall primary and secondary assessments at each study visit are summarized in Table 1. Overall, phenylalanine and tyro sine blood concentrations were maintained within target ranges (120-360 juno phenylalanine, 30-100 umol/t tyrosine) through- out the study (Table 1). Median weight-or-age Z-scores remained [A Macon t Molar Genetics nd Metabo 104 (2071) $56-859 sr 90 eee a ecto: “sao Goce scmscenecnase pence an epee g2 |} | Ty concatnton Sears ms ce core aa ae 2 See ‘against prescribed intake: 95% at Week 4 and 98% at Week 8). 24 sol He 43.1. Bacterial assessments 3 aol | ee [No statistically significant change from baseline was observed inei- © 20. on gan os Gane fem ereingreroemating, ES 20 (fig, 1, Table 1). However, there was an indication that bifidobacteria levels were markedly increased in two subjects who recorded very yee wee Wane Jow concentrations of bifidobacteria at baseline (3.6% and 6.7% at base- line, increased by 548% and 27.9% respectively, (Table 2)). One of FE 1 Changes in ea ifbaceris eves (mean of total bacterin 958 C) com these infants (subject 8) received solely standatd infant formula with- _P#"e wih pial concentrations ound in helt, areas-fed infants (2528-31 ‘out prebiotics prior to the study (Table 2) Group mean lactbacili-enterococci levels were reduced through- Results confirm that this formula was well tolerated and maintained phe- ‘out the study (Table 1), but the overall values were ily tobe signif. aylalanine control. The safety of adding prebiotics (scGOS/CFOS [9:1 icantly influenced by one infant who presented with high lactobacilli _rati}) to infant formulae has been well documented in previous clinical enterococci levels at baseline (25.0%). Without this outlier, mean studies [12-15,30.31]. The results from this study confirmed these find- ‘sroup values would have been signcanty lower both at study iniia~ ings, with no adverse events or gastrointestinal Complications (et diar- tion and at study end (group mean at initiation of 364% including out- rhea) and low levels of bacterial groups containing potential pathogens lier versus 097% not including outlier and study end of 2.36% and (Clostridium histolyicumyliuseburense and enterobacteriaceae) (0.88% respectively). The total group median value did not significantly No significant changes in bifidobacteria or lactobacilienterococc change throughout the study period concentrations were observed overall The lack of statistical significance ‘Noinfants showed abnormally high levels of Clostridium histobeicum/ was expected, as this was (a) an exploratory pilot study with a small Huseburense or enterobacteriaceae containing potential pathogens [26]) population and therefore lacked the statistical power to detact such di Atay point during the study. The infant who recorded the highest con- ferences, and (b) only one infant was on a prebioticee diet on entry ‘centrations of Clostridium histlycicumiltuseburense and enterobacteri- into the study. Despite this, comparisons with historical data show bif- ‘eae at baseline (9.2% and 1.05%, respectively) was receiving infant dobacteria and lactobacili-enerococct levels at the end of the study to fortnuia without prebiotics prior tothe study, and showeda marked de- be similar to those reported for hevithy breast-fed infants (60-75% tease in both groups at Week 8 (to 2.8% and <0.1% [below detection and 0.8-4%, respectively) [2932-34], and greater than those reported limit), Table 2) accompanied by a marked increase in bifidobacteria for infants on infant fermula without prebiotics (48.0%-53.4% and (279%, Table 2). (0.4%) [30.31]. This. én turn, may be advantageous by reducing the Fisk of infection [3423-25] 32, Stool characteristics Ieis interesting to note that the single infant that did not receive a prebiotic-containing diet prior to the study reported the greatest de- A significant reduction in median stool pH versus baseline was ob- crease in the group of Clostridium histolyicumiliuseburense (including. seeved at Week 4 (p =0,002; Table 1, Fig.2), but this was not observed potentially pathogenic species such as C.perfingens an C.difice) at Week 8, Overall analysis ofthe primary caregiver description of stool and a subset of enterobacteriaceae(E. cl, Shigella, Salmonella and Kleb. Consistency. type and frequency showed that moderate/normal sized sella), together with the second-greatest increase in bifidobacteria ‘Rufly' stools were maintained throughout the study but that stool con-_ levels This isin line with previously published reports [1623], Howev- sistency improved, Mean categorical variable analysis showed an over- er, as this sa single patient observation, trends cannot be surmised and, alltransition from semi-liquid stools 2: baseline to softjunformed stools the results require confirmation in futher studies, at Week 8. This effect occurred in four of the nine infants. “Typically the fecal pH of breast-fed infants is moce acidic than that of formula-fed infants (5 compared with 7.5). which is associated 4. Discussion with reduced growth of intestinal pathogens [35], Stool pH was signifi- cantly reduced during the study at week 4, which is consistent with ‘This is the frst study to investigate an infant protein substitute findings from previous studies 12.13] but this effect is diminished at containing prebiotic oligosaccharides (scGOS/IcFOS [9:1 ratio). week 8. However, the reduction of pH does not reflect the results of ‘able Primary and secondary assessments forthe total study population (median and mean value SD. 9) by ty visi “semen ‘week Ody form Week| Week commence) Sood phenylalanine rol 5 78a i004 205 5641200, 185 2osB 21518, Soo tyrone, ol m7 45i3 1. 3254308) 975 gears: ‘yobactenas| eax 53677023, ‘482 essa 1336 san 61a1 21830 crobeal-enterocaclt 098 boteao2 109 lesan rs rets2se ‘osm hilycufisburense 058 ts2829) 089 oa? ovaenas Entrobacenacae§ 058 a1 2030 05 046 058030, eceredes dstsonifags

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