Role of Zinc in Shaping the Gut Microbiome; Proposed Mechanisms and Evidence from the Literature
Received Date: Jan 09, 2018 / Accepted Date: Jan 16, 2018 / Published Date: Jan 23, 2018
Zinc is an important constituent of diet that regulates gut epithelial wall and modify gut microbiome in humans as well as animals. Zinc deficiency may affect 39% children in Pakistan, according to the recent National Nutritional Survey 2011. Although zinc has been used in the prevention and treatment of diarrhea, the relationship of plasma zinc status with potentially pathogenic bacteria has not been studied. In this review, we have discussed evidence suggesting the impact of zinc on gut microbiota and its interaction with gut epithelium. Furthermore, animal and human studies suggesting the role of zinc in modifying gut microbiota have been presented.
Keywords: Zinc deficiency; Gut microbiome; Gut epithelium
Micronutrients are substances required by the body in minute quantities. These low concentration substances play a major role in our metabolism and normal tissue functions. Amongst other micronutrients, zinc is one of the most important micronutrient, required for several body functions such as it restricts the loss of barrier function under malnutrition condition , alcoholic liver disease , chronic inflammatory bowel disease or crohn’s diseases , and is an influential causing agent of growth [4,5]. Daily dietary allowance for zinc is 11 mg/day for men and 8 mg/day for women . But when these values are depleted than their normal range, deficiency symptoms arise which can cause gastrointestinal, skeletal, immune, reproductive, central nervous system disorders [7-9], diarrhea [10,11], pneumonia  and acrodermatitis Enteropathica . Deficiency of zinc in humans was initially declared in 1961 in patients presenting with growth stunting, dissymmetric gonads, skin lesions, and mental dizziness [14,15]. While its deficiency is generally due to inadequate diet or bio-available zinc content , increased requirements (depending on age groups), malabsorption, increased losses and impaired utilization also contribute to the maintenance of plasma zinc levels. It is more common is areas where cereal is high in diet as compared to animal food because red meat is a good source to bio available zinc content . Cross-sectional studies conducted in Pakistan suggest zinc deficiency in our diet and implicate its effects on health . The 2011 National Nutrition Survey of Pakistan reports zinc deficiency in 39% children (39.3% urban and 39.1% rural). Punjab (38.4%), Sindh (38.6%), KP (45.4%), 39.5% Baluchistan (39.5%), AJK (47.2%) and in Gilgit Balitistan (32.6%) showed Provincial data statistics of the zinc deficiency at our population . Keeping in view deficiency states of zinc in our population, interventional strategies have been employed such as fortification of cereals, food products, and zinc preparations in suspension forms.
Although, cereals diets such as wheat contains inhibitors such as phytate  which reduces the availability of absorbable zinc, its fortification is a better option as wheat flour is most common and easily accessed food in resource poor settings compared to other fortification methods. Although main source of zinc is red meat and other animal products, wheat contributes 50% of daily zinc intake in Pakistani population due its frequent use. Studies also suggest that dietary modification such as genetically modified plants can reduce phytate content . Also certain techniques (i.e. sourdough) are helpful in reducing harmful concentration of phytate with the help of enzyme phytase that hydrolyze phytate and release inorganic phosphorous [22,23]. Besides, zinc in suspension form has more bioavailable content than solids (tablets), but transportation, availability and proper measurement may be an issue . Human gut has a very complex diversity of gut microbes existing throughout the intestinal system. Gut bacteria constitute genome that is 10 times more than that of humans’ own genome. They serve several important functions such as generation of Short chain fatty acids (SCFAs), vitamins, development of immunity and protection against allergens . The role of zinc may mostly have addressed by prevention and treatment of diarrhea in children, changes in gut microbial diversity with zinc intervention are anticipated. Relationship between gut bacteria, healthy and malnourished children have been indicated . One recent study on chicks have shown phylum levels difference in gut microbiota composition between normal and chronic zinc deficient chicks . Little is known about changes in gut microbiota such as Enterobacteria with zinc supplementation. Investigating these changes in humans especially children, therefore needs further exploration. Original articles and systematic review papers exploring the relationship of the gut microbiome with zinc status published between year 2000 to 2016, were retrieved for the purpose of literature review using PubMed and Google scholar.
Mechanisms Suggesting the Effect of Zinc on Gut Microbiota and its Interaction with Gut Epithelium
Intracellular zinc is an essential promoter of normal intestinal barrier functions and the regeneration of impaired epithelium . Animal studies suggest that intracellular zinc (IZ) stimulates the release of ghrelin in the stomach of pigs. Ghrelin is a polypeptide hormone required for the regulation of appetite . Besides, IZ reduces the inflammation of intestinal mucosa . Zinc also regulates intestinal permeability through occludin proteolysis and occludin transcription and thus protects intestines from the invading molecular ions and pathogens . Under zinc deficiency states, the intestinal tight junction and membrane function was impaired and also induced the migration of large number of neutrophils that leads to mucosal inflammation . However, this study was performed in-vitro using specific cells (Caco-2 cells) and may not reciprocate to humans or invivo models . In addition, it has been shown that zinc adequately restrict the loss of barrier function under malnutrition states , alcoholic liver disease , chronic inflammatory bowel disease or crohn’s diseases , and infectious diarrhea . There is also some evidence that zinc oxide (ZnO) protects against intestinal diseases such as infectious diarrhoea. Although ZnO has antibacterial effects, the mechanisms of this protective effect have not yet been elucidated .
In nature, the bioavailability of essential trace elements such as zinc are less, therefore bacterial species have evolved themselves through high affinity ligand binding proteins and transporter systems . It has been demonstrated that Campylobacter survival is linked through ZnuABC transporter system while this setup is not being seen during limited microbiota as compared to normal flora of gut microbes . Less attention has been paid to the mechanism of zinc transporters such as Zn transportation in free form or in chelates across the epithelium membrane . As the gut mucosa acts as an intestinal barrier against pathogenic microbes and foreign invading bacteria , zinc has an ultimate effect on its normal function and permeability to invading pathogens and microbes. How gut can accomplish prevention to specific molecular ions and integral membrane proteins as well as pathogens and their relationship with gut diversity under the influence of dietary zinc is yet another area of study which needs further investigation.
Animal Studies Suggesting Relationship of Zinc in Relation to Gut Microbiota
There is much evidence about animal studies which is based on supplementations and dietary modification/fortifications of zinc. Zinc given in the pre-weaning stage influences growth, consumption of feed intake by an animal, weight gain and improve overall health of the gut by increasing the counts of beneficial bacteria and reducing Enterotoxigenic bacteria’s such as Salmonella typhimurium . However, this effect was not seen in post weaning stages . Other study on Salmonella infection suggested a reduction in growth and feed intake of an animal beside changes in its cecal microbial community [4,5]. Zinc has a two-pronged effect on gut as it not only enhances gut health but also affects immune system during attachment of certain virulence factors . However, Sometimes high doses of zinc may need to be avoided after weaning as some studies also suggest that post-weaning zinc supplementation has no effect on average daily food intake (ADFI), average daily live weight gain (ADG) and food conversion ratio (FCR) of piglets .
Furthermore, increase in the concentration of phytase enzyme is important in dietary supplementation of post-weaning piglets as its absence or reduced concentration is linked to increased E. coli numbers in wheat bran (WB) . However, no evidence regarding mechanism of increase in E. coli after ZnO blockage is not clear. It may be that zinc oxide increases resistance to Gram negative bacteria , the mechanism of which needs further investigation [43,44].
Studies on chicks have suggested that there may have a decrease of cecal zinc concentration at germ free chicks when compared to their counterparts. Beside alteration occur at the phylum levels in gut microbiota composition between normal and chronic zinc deficient chicks . Evidence (Table 1) shows overall summary of listed studies.
|Study Ref||Study Design||Participants||Intervention||Main Outcomes||Additional Remarks|
|Shao Y, ||Randomized trial||180, 1-day-old Male broiler chicks||Unchallenged, S. Typhimurium-challenged, and S. Typhimurium-challenged were treated with 120 mg/kg of zinc supplementation in the diet.||Zinc supplementation enhanced growth, intestinal shape, and intestinal microbiota in S. Typhimurium-challenged broilers.|
|S.Reed ||Randomized trial||12 chicks||2 treatment groups: 1) Zn(+): 42 µg/g zinc. 2) Zn(−): 2.5 µg/g zinc||Phylum level difference in gut microbiota composition between normal and chronic zinc deficient chicks||Further research needed in zinc clinical biomarker.|
|David T Bolick, ||Male Mice, 28 days old||Challenged with EAEC||EAEC pathogens count were increased in zinc-deficient mouse|
|Broom, ||2 × 2 factorial experiment||208 piglets||3100 mg ZnO/kg feed), and E. faecium SF68 supplementation 1.4 × 109 CFU/kg feed||ZnO and E. faecium SF68 are found to be not effective in the trial conditions.||Further research is needed to study the immunomodulatory role of zinc|
|Molist, ||2 × 2 factorial experiment||64 piglets||WB (0 vs. 40 g/kg) and ZnO (0 vs. 3 g/kg) in the diet||ZnO shown good results in feed intake, growth and reduced the incidence of diarrhea, the negative impact was correlated with wheat bran (WB) as it increases E. coli count.||Does not provide evidence that how ZnO blockage causes increase of E. coli|
|Vahjen, ||336 piglets||57 (low), 164 (intermediate) or 2425 (high) mg kg-1 analytical grade ZnO||Dietary zinc are suggested to be avoided after 2 weeks of post-weaning in pigs, as due to the possible increase of antibiotic resistance in Gram-negative bacteria|
|Herrero‐Fresno, ||4 pigs||Repetitive extragenic palindromic-PCR (REP-PCR)||Correlation was not observed between REP-profiles, ST-types and resistance/virulence patterns||This is the first study analyzing in depth the genetic variability of commensal E. coli from pigs|
Table 1: Animal studies suggesting role of in modifying gut microbiota; [ZnCP=Zinc-bearing Clinoptilolite; EAEC=Enteroaggregative Escherichia coli; dZD=Zinc deficient diet; ST=Sequence type; ZnO=Zinc oxide, REP=Repetitive extragenic palindromic; CFU=Colony forming unit].
Human Studies Suggesting Role of Zinc in Modifying Gut Microbiota
In humans, zinc medicines are mainly used for the prevention and treatment of loose bowels , and less often in connection with the improvement of immune response , and metabolic and epithelial permeability .
Limited evidence is available on the effect of zinc on the richness and diversity of gut microbiota in humans. Some evidence suggests that zinc supplementation have a negative impact on the counts of diarrhoea-causing agents such as E. coli . Moreover it has also been seen that beneficial bacteria e.g. Lactobacillus (probiotic) and Streptococcus  in gut are increased with zinc supplementation. Evidence (Table 2) shows overall summary of listed studies.
|Study||Study type||Participants||Treatment||Main Outcomes|
|S K Roya, ||Randomized double blind controlled trial||111 children, 3 to 24 months’ old||Treatment Group: 20 mg zinc/day Control Group: Zinc-free diet||Weight gain in children with the treatment of diarrheal complication through zinc intervention|
|Sunil Sazawal, ||Double-blind, randomized, Controlled trial||937 children, 6 to 35 Months of age||20 mg zinc/day||For infants and young children Zinc supplementation reduce duration and the severity of diarrhoea.|
Table 2: Humans studies suggesting role of zinc supplementation on gut microbiota.
In conclusion, this literature review provides potential mechanisms that could explain the possible relationship of zinc supplementation on the gut microbiota and its interaction with gut epithelium, reduction of inflammation of intestinal mucosa and improvement in host immune system. Although the impact of zinc supplementation on potentially pathogenic gut microbiota in humans such as Campylobacter jejuni is limited.
Usama wrote the manuscript, Muhammad Jaffar Khan and Sadia Fatima reviewed the manuscript and supervised Usama. This review article is the part of Usama Master’s Thesis.
- Rodriguez P, Darmon N, Chappuis P, Candalh C, Blaton MA, et al. (1996) Intestinal paracellular permeability during malnutrition in guinea pigs: Effect of high dietary zinc. Gut 39: 416-422.
- Zhong W, McClain CJ, Cave M, Kang YJ, Zhou Z (2010) The role of zinc deficiency in alcohol-induced intestinal barrier dysfunction. Am J Physiol Gastrointest Liver Physiol 298: G625-G633.
- Sturniolo GC, Di Leo V, Ferronato A, D'Odorico A, D'Incà R (2001) Zinc supplementation tightens “leaky gut” in Crohn's disease. Inflamm Bowel Dis 7: 94-98.
- Shao Y, Lei Z, Yuan J, Yang Y, Guo Y, et al. (2014) Effect of zinc on growth performance, gut morphometry, and cecal microbial community in broilers challenged with Salmonella enterica serovar typhimurium. J Microbiol 52: 1002.
- Wang LC, Zhang TT, Wen C, Jiang ZY, Wang T, et al. (2012) Protective effects of zinc-bearing clinoptilolite on broilers challenged with Salmonella pullorum. Poult Sci 91: 1838-1845.
- Trumbo P, Yates AA, Schlicker S, Poos M (2001) Dietary reference intakes: vitamin A, vitamin K, arsenic, boron, chromium, copper, iodine, iron, manganese, molybdenum, nickel, silicon, vanadium, and zinc. J Am Diet Assoc 101: 294-301.
- Honscheid A, Rink L, Haase H (2009) T-lymphocytes: A target for stimulatory and inhibitory effects of zinc ions. Endocr Metab Immune Disord Drug Targets 9: 132-144.
- Rink L, Gabriel P (2000) Zinc and the immune system. Proc Nutr Soc 59: 541-552.
- Hambidge KM, Walravens PA (1982) Disorders of mineral metabolism. Clin Gastroenterol 11: 87-117.
- Hambidge KM (1992) Zinc and diarrhea. Acta Paediatr Suppl 381: 82-86.
- Shankar AH, Genton B, Baisor M, Paino J, Tamja S, et al. (2000) The influence of zinc supplementation on morbidity due to Plasmodium falciparum: A randomized trial in preschool children in Papua New Guinea. Am J Trop Med Hyg 62: 663-669.
- Bhutta ZA, Black RE, Brown KH, Gardner JM, Gore S, et al. (1999) Prevention of diarrhea and pneumonia by zinc supplementation in children in developing countries: Pooled analysis of randomized controlled trials. J Pediatr 135: 689-697.
- Hambidge M (2000) Human zinc deficiency. J Nutr 130: 1344s-9s.
- Prasad AS, Halsted JA, Nadimi M (1961) Syndrome of iron deficiency anemia, hepatosplenomegaly, hypogonadism, dwarfism and geophagia. Am J Med 31: 532-546.
- Prasad AS, Miale Jr A, Farid Z, Sandstead HH, Schulert AR (1990) Zinc metabolism in patients with the syndrome of iron deficiency anemia, hepatosplenomegaly, dwarfism, and hypogonadism. J Lab Clin Med 116: 737-749.
- Lonnerdal B (2000) Dietary factors influencing zinc absorption. J Nutr 130: 1378s-83s.
- Roohani N, Hurrell R, Kelishadi R, Schulin R (2013) Zinc and its importance for human health: An integrative review. J Res Med Sci 18: 144.
- Warda Hussain AM, Yasmeen F, Khan SQ, Butt T (2014) Reference range of zinc in adult population (20-29 years) of Lahore, Pakistan. Pak J Med Sci 30: 545.
- National Nutrition Survey of Pakistan (2011) Government of Pakistan.
- Roohani N, Hurrell R, Wegmueller R, Schulin R (2012) Zinc and phytic acid in major foods consumed by a rural and a suburban population in central Iran. J Food Composit Analysis 28: 8-15.
- Lonnerdal B (2003) Genetically modified plants for improved trace element nutrition. J Nutr 133: 1490s-3s.
- Lopez HW, Krespine V, Guy C, Messager A, Demigne C, et al. (2001) Prolonged fermentation of whole wheat sourdough reduces phytate level and increases soluble magnesium. J Agric Food Chem 49: 2657-2662.
- Leenhardt F, Levrat-Verny MA, Chanliaud E, Rémésy C (2005) Moderate decrease of pH by sourdough fermentation is sufficient to reduce phytate content of whole wheat flour through endogenous phytase activity. J Agric Food Chem 53: 98-102.
- Urooj S, Memon HU, Memon Y, Ali BS (2017) Comparison of the effectiveness of zinc supplementation in tablets form with that of the suspension form in the treatment of acute diarrhoea. J Pak Med Assoc 67: 156.
- O'Hara AM, Shanahan F (2006) The gut flora as a forgotten organ. EMBO Rep 7: 688-693.
- Monira S, Nakamura S, Gotoh K, Izutsu K, Watanabe H, et al. (2011) Gut microbiota of healthy and malnourished children in Bangladesh. Front Microbiol 2: 228.
- Reed S, Neuman H, Moscovich S, Glahn RP, Koren O, et al. (2015) Chronic zinc deficiency alters chick gut microbiota composition and function. Nutrients 7: 9768-9784.
- Alam AN, Sarker SA, Wahed MA, Khatun M, Rahaman MM (1994) Enteric protein loss and intestinal permeability changes in children during acute shigellosis and after recovery: Effect of zinc supplementation. Gut 35: 1707-1711.
- Yin J, Li X, Li D, Yue T, Fang Q, et al. (2009) Dietary supplementation with zinc oxide stimulates ghrelin secretion from the stomach of young pigs. J Nutr Biochem 20: 783-790.
- Ou D, Li D, Cao Y, Li X, Yin J, et al. (2007) Dietary supplementation with zinc oxide decreases expression of the stem cell factor in the small intestine of weanling pigs. J Nutr Biochem 18: 820-826.
- Miyoshi Y, Tanabe S, Suzuki T (2016) Cellular zinc is required for intestinal epithelial barrier maintenance via the regulation of claudin-3 and occludin expression. Am J Physiol Gastrointest Liver Physiol 311: G105-116.
- Finamore A, Massimi M, Devirgiliis LC, Mengheri E (2008) Zinc deficiency induces membrane barrier damage and increases neutrophil transmigration in Caco-2 cells. J Nutr 138: 1664-1670.
- Roselli M, Finamore A, Garaguso I, Britti MS, Mengheri E (2003) Zinc oxide protects cultured enterocytes from the damage induced by Escherichia coli. J Nutr 133: 4077-4082.
- Gielda LM, DiRita VJ (2012) Zinc competition among the intestinal microbiota. MBio 3: e00171-12.
- Davis LM, Kakuda T, DiRita VJ (2009) A Campylobacter jejuni znuA orthologue is essential for growth in low-zinc environments and chick colonization. J Bacteriol 191: 1631-1640.
- Hood MI, Skaar EP (2012) Nutritional immunity: Transition metals at the pathogen-host interface. Nat Rev Microbiol 10: 525-537.
- Ashida H, Ogawa M, Kim M, Mimuro H, Sasakawa C (2012) Bacteria and host interactions in the gut epithelial barrier. Nat Chem Biol 8: 36-45.
- Janczyk P, Kreuzer S, Assmus J, Nöckler K, Brockmann GA (2013) No protective effects of high-dosage dietary zinc oxide on weaned pigs infected with Salmonella enterica serovar Typhimurium DT104. Applied Environ Microbiol 79: 2914-2921.
- Bolick DT, Kolling GL, Moore JH, de Oliveira LA, Tung K, et al. (2014) Zinc deficiency alters host response and pathogen virulence in a mouse model of enteroaggregative Escherichia coli-induced diarrhea. Gut Microbes 5: 618-627.
- Broom LJ, Miller HM, Kerr KG, Knapp JS (2006) Effects of zinc oxide and Enterococcus faecium SF68 dietary supplementation on the performance, intestinal microbiota and immune status of weaned piglets. Res Vet Sci 80: 45-54.
- Molist F, Hermes RG, de Segura AG, Martín-Orúe SM, Gasa J, et al. (2011) Effect and interaction between wheat bran and zinc oxide on productive performance and intestinal health in post-weaning piglets. Br J Nutr 105: 1592-1600.
- Vahjen W, Pietruszyńska D, Starke IC, Zentek J (2015) High dietary zinc supplementation increases the occurrence of tetracycline and sulfonamide resistance genes in the intestine of weaned pigs. Gut Pathog 7: 23.
- Herrero‐Fresno A, Larsen I, Olsen JE (2015) Genetic relatedness of commensal Escherichia coli from nursery pigs in intensive pig production in Denmark and molecular characterization of genetically different strains. J Appl Microbiol 119: 342-353.
- Yazdankhah S, Rudi K, Bernhoft A (2014) Zinc and copper in animal feed development of resistance and co-resistance to antimicrobial agents in bacteria of animal origin. Microb Ecol Health Dis 25: 25862.
- Roy SK, Tomkins AM, Akramuzzaman SM, Behrens RH, Haider R, et al. (1997) Randomised controlled trial of zinc supplementation in malnourished Bangladeshi children with acute diarrhoea. Arch Dis Child 77: 196-200.
- Qadri F, Svennerholm AM, Faruque AS, Sack RB (2005) Enterotoxigenic Escherichia coli in developing countries: epidemiology, microbiology, clinical features, treatment, and prevention. Clin Microbiol Rev 18: 465-483.
- Platts-Mills JA, Babji S, Bodhidatta L, Gratz J, Haque R, et al. (2015) Pathogen-specific burdens of community diarrhoea in developing countries: A multisite birth cohort study (MAL-ED). Lancet Glob Health 3: e564-e575.
- Kotloff KL, Nataro JP, Blackwelder WC, Nasrin D, Farag TH, et al. (2013) Burden and aetiology of diarrhoeal disease in infants and young children in developing countries (the Global Enteric Multicenter Study, GEMS): A prospective, case-control study. Lancet 382: 209-222.
- Faiz U, Butt T, Satti L, Hussain W, Hanif F (2011) Efficacy of zinc as an antibacterial agent against enteric bacterial pathogens. J Ayub Med Coll Abbottabad 23: 18-21.
- Sazawal S, Black RE, Bhan MK, Bhandari N, Sinha A, et al. (1995) Zinc supplementation in young children with acute diarrhea in India. N Engl J Med 333: 839-844.
- Sarker SA, Brüssow H (2016) From bench to bed and back again: Phage therapy of childhood Escherichia coli diarrhea. Ann N Y Acad Sci 1372: 42-52.
- Salvatore S, Hauser B, Devreker T, Vieira MC, Luini C, et al. (2007) Probiotics and zinc in acute infectious gastroenteritis in children: Are they effective? Nutrition 23: 498-506.
Citation: Usama U, Khan MJ, Fatima S (2018) Role of Zinc in Shaping the Gut Microbiome; Proposed Mechanisms and Evidence from the Literature. J Gastrointest Dig Syst 8: 548. DOI: 10.4172/2161-069X.1000548
Copyright: © 2018 Usama U, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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