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British Journal of Nutrition (2014), 111, 2135–2145 Doi:10.1017/S000711451400021X Q the Authors 2014

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British Journal of Nutrition (2014), 111, 2135–2145 Doi:10.1017/S000711451400021X Q the Authors 2014 Downloaded from British Journal of Nutrition (2014), 111, 2135–2145 doi:10.1017/S000711451400021X q The Authors 2014 https://www.cambridge.org/core Iron supplementation promotes gut microbiota metabolic activity but not colitis markers in human gut microbiota-associated rats Alexandra Dostal1, Christophe Lacroix1*, Van T. Pham1, Michael B. Zimmermann2, . IP address: Christophe Del’homme3, Annick Bernalier-Donadille3 and Christophe Chassard1 1Laboratory of Food Biotechnology, Institute of Food, Nutrition and Health, ETH Zurich, Switzerland 170.106.202.8 2Laboratory of Human Nutrition, Institute of Food, Nutrition and Health, ETH Zurich, Switzerland 3UR454 Microbiology Unit, INRA, Clermont-Ferrand Research Centre, St Gene`s-Champanelle, France (Submitted 17 June 2013 – Final revision received 14 November 2013 – Accepted 14 January 2014 – First published online 21 February 2014) , on 01 Oct 2021 at 15:56:07 Abstract The global prevalence of Fe deficiency is high and a common corrective strategy is oral Fe supplementation, which may affect the commensal gut microbiota and gastrointestinal health. The aim of the present study was to investigate the impact of different dietary Fe concentrations on the gut microbiota and gut health of rats inoculated with human faecal microbiota. Rats (8 weeks old, n 40) were divided into five (n 8 each) groups and fed diets differing only in Fe concentration during an Fe-depletion period (12 weeks) and an , subject to the Cambridge Core terms of use, available at Fe-repletion period (4 weeks) as follows: (1) Fe-sufficient diet throughout the study period; (2) Fe-sufficient diet followed by 70 mg Fe/kg diet; (3) Fe-depleted diet throughout the study period; (4) Fe-depleted diet followed by 35 mg Fe/kg diet; (5) Fe-depleted diet followed by 70 mg Fe/kg diet. Faecal and caecal samples were analysed for gut microbiota composition (quantitative PCR and pyrosequen- cing) and bacterial metabolites (HPLC), and intestinal tissue samples were investigated histologically. Fe depletion did not significantly alter dominant populations of the gut microbiota and did not induce Fe-deficiency anaemia in the studied rats. Provision of the 35 mg Fe/kg diet after feeding an Fe-deficient diet significantly increased the abundance of dominant bacterial groups such as Bacteroides spp. and Clostridium cluster IV members compared with that of an Fe-deficient diet. Fe supplementation increased gut microbial butyrate concen- tration 6-fold compared with Fe depletion and did not affect histological colitis scores. The present results suggest that Fe supplementation enhances the concentration of beneficial gut microbiota metabolites and thus may contribute to gut health. Key words: Iron: Gut microbiota: Colitis: Butyrate British Journal of Nutrition https://www.cambridge.org/core/terms Research carried out in the past few years has highlighted the prausnitzii, Eubacterium hallii and Roseburia spp.,(8,9) and is importance of the gut microbiota to intestinal health and host absorbed by the mucosa where it can act as an energy source health in general(1,2). The gut microbiota plays a crucial role in for colonocytes(10). Moreover, butyrate has anti-inflammatory the development and maintenance of the immune system(3), effects, is able to promote apoptosis in cancer cells and has colonisation resistance to environmental bacteria, such as been shown to inhibit virulence in enteropathogens(11,12). pathogens(4), extraction of energy from indigestible food com- Gut microbiota composition and metabolic activity not ponents and production of metabolites that influence gut only affect the host but are also strongly modified by host health(5). SCFA have been widely investigated due to their and environmental factors. Diet composition, such as fibre ability to influence several aspects of host health. Many mem- content, has been shown to have a strong impact on the (13,14) . bers of the gut microbiota produce acetate and propionate. gut microbiota . Recent studies have elucidated the https://doi.org/10.1017/S000711451400021X Acetate is either reused by other bacteria for butyrate for- differences in gut microbial consortium in populations living mation or absorbed by the host and can be used as an in developed and developing countries possibly due to energy source, while propionate is involved in gluconeo- the effects of diet or high prevalence of malnutrition in genesis(6,7). The most investigated end metabolite of the gut developing countries, which can strongly influence the gut microbiota is probably butyrate due to its importance to microbiota(3,15 – 20). One of the most common nutritional mucosal health. Butyrate is mainly produced by the members deficiencies is Fe deficiency, affecting more than two billion of Clostridium clusters IV and XIVa, such as Faecalibacterium people worldwide, especially in developing countries(21,22). Abbreviations: qPCR, quantitative PCR; SRB, sulphate-reducing bacteria. * Corresponding author: C. Lacroix, fax þ41 44 632 14 03, email [email protected] Downloaded from 2136 A. Dostal et al. Fe deficiency affects cognitive and motor development in microbiota composition and metabolic activity, as well as https://www.cambridge.org/core children and increases the maternal/perinatal mortality gut inflammation, were assessed after killing the rats at the rate(23). It also has an impact on gut microbiota composition end of the study. and metabolic activity. In a recent rat study, we have shown a decrease in the abundance of Roseburia spp./Eubacterium rectale and Bacteroides spp. along with a large decrease Materials and methods in the concentrations of caecal butyrate and propionate in Rats and diets highly Fe-deficient young rats(24). Earlier studies in mice have also demonstrated that low gut luminal Fe concentrations A total of forty germ-free female Fischer 344 rats were bred . IP address: have an impact on gut microbiota composition leading to a at the INRA facilities of Clermont-Ferrand-Theix, France. decrease in the abundance of Desulfovibrio spp. and an They were kept in sterile isolators with positive pressure (25) (40,43) increase in that of Turicibacter spp. while elevating the over the entire trial period as described previously . 170.106.202.8 counts of lactobacilli(26). Using an in vitro colonic fermen- Rats were fed an irradiated standard diet for germ-free rodents tation model mimicking the proximal colon of a child, we (SAFE) and given free access to sterilised water. Rats were have also confirmed strong dysbiosis of the gut microbiota maintained pairwise in standard Macrolon cages under a , on under very-low-Fe conditions(27). 12 h light–12 h dark cycle under constant temperature and 01 Oct 2021 at 15:56:07 Usual strategies for Fe-deficiency anaemia correction are humidity. At 5 weeks of age, rats were inoculated with a Fe supplementation and Fe fortification of foods; FeSO4 is human faecal microbiota slurry obtained from a healthy volun- often used, which is highly bioavailable(28). However, absorp- teer (age 6 years) not treated with antibiotics 3 months before tion of Fe is usually low (5–20 %) and takes place mainly in faecal sample collection. The faecal sample was processed the duodenum, while the main fraction of Fe reaches the within 6 h of defecation and maintained under anaerobic (21) colon, where it might affect the gut microbiota . Indeed, conditions. After 1000-fold dilution with an anaerobic mineral , subject to the Cambridge Core terms of use, available at gut microbiota composition in Fe-deficient rats supplemented solution, 1 ml of faecal slurry was orally inoculated into germ- with Fe has been found to be partially recovered and gut free rats. The microbiota was allowed to establish for 3 weeks microbiota metabolic activity to be strongly promoted(24). while the rats were being fed a control diet with normal Fe Animal studies in rats and pigs have also reported dysbiosis concentrations equivalent to a standardised American Institute of the gut microbiota due to Fe supplementation(26,29), of Nutrition (AIN)-93G purified diet(44) before starting the recently confirmed in human studies. School children in different feeding regimens. Coˆte d’Ivoire have been found to have higher numbers All diets were produced by Dyets Inc. and based on a of Enterobacteriaceae and decreased numbers of lacto- standard AIN-93G diet differing only in Fe concentration bacilli in faeces after Fe supplementation for 6 months and (Table S1, available online). The study set-up (Fig. 1) was increased concentrations of calprotectin, a marker for gut designed according to the classical Fe depletion–repletion inflammation (30). Infants given an Fe-supplemented diet for assay of Forbes et al.(42) and comprised five different groups 3 months have been found to have higher relative abundances of rats. A ‘control’ group of rats (n 8) was fed a regular AIN- (31) of Bacteroides spp. and lower abundances of lactobacilli . 93G diet containing a mean of 37·6 (SEM 0·9) mg Fe/kg diet British Journal of Nutrition An unanswered question raised by these studies is whether from ferric citrate over the entire trial period of 16 weeks, https://www.cambridge.org/core/terms dietary Fe alone is a modulation factor for the gut microbiota while a ‘Fe-deficient’ group of rats (n 8) was fed an Fe-deficient and intestinal inflammation or whether Fe status and suscepti- diet containing 2·9 (SEM 0·2) mg Fe/kg diet. A further two groups bility to gut inflammation could also play a role in the of rats, ‘35 ppm Fe’ group (n 8) and ‘70 ppm Fe’ group (n 8), observed changes in gut microbiota composition. Both were first fed a Fe-deficient diet for 12 weeks and were then changes in host Fe homeostasis and gut inflammation can supplemented with either a 35 ppm Fe diet containing 32·2 (32 – 34) alter the gut microbiota composition . Our previous (SEM 1·0) mg Fe/kg diet from FeSO4 or a 70 ppm Fe diet contain- study using Sprague–Dawley rats with a rodent microbiota ing 66·1 (SEM 7·8) mg Fe/kg diet from FeSO4 and ferric citrate to has investigated the changes in gut microbiota composition mimic Fe supplementation with two different Fe sources and due to Fe supplementation in a highly Fe-deficient host(24).
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