geophagia, iron and mycobacteria
mycobacteria and iron
Three diseases at least are caused by mycobacteria : leprosy, tuberculosis and Buruli ulcer. Iron is a prerequisite for the growth of mycobacteria. It is a cofactor for numerous enzymes encoded in the mycobacterium genome. It is required for the cytochromes involved in electron transport. It has been estimated that 7 to 64 g Fe per kg of mycobacterial cell mass is required to support growth. Iron limitation in vitro to levels below these results in growth restriction in many species of mycobacteria, such as M. tuberculosis. Microorganisms have evolved many strategies for acquiring sufficient soluble iron for aerobic growth. An important component of the mammalian host defense involves restricting access of such organisms to iron. Mycobacterial acquisition of iron is mediated by siderophores. These substances are secreted by the bacteria to compete with other iron binding molecules in the human organism for the small amount of available iron. Siderophores are transient reservoirs of iron which bind to ferric iron during transport into the cell cytoplasm. Clinical studies in Africa have also established a strong correlation between dietary iron overload and enhanced risk of death from tuberculosis. Gordeuk VR, McLaren CE, MacPhail AP, Deichsel G, Bothwell TH. Associations ofiron overload in Africa with hepatocellular carcinoma and tuberculosis Blood 1996; 87: 3470–76. Moyo VM, Gangaidzo IT, Gordeuk VR, Kiire CF, Macphail AP. Tuberculosis and iron overload in Africa: a review, Cent Afr J Med. 1997 Nov; 43(11):334-9. Both pulmonary tuberculosis and dietary iron overload are common conditions in sub-Saharan Africa. The incidence of tuberculosis has increased markedly over the last decade. Dietary iron overload affects up to 10% of adults in rural populations and is characterized by heavy iron deposition both in parenchymal cells and in macrophages. Mycobacterium tuberculosis grows within macrophages and, at the same time, the antimicrobial function of macrophages is important in the body's defence against tuberculosis. In vitro, the loading of macrophages with iron reduces the response of these cells to activation by interferon-gamma and diminishes their toxicity against micro-organisms. In the clinical setting, dietary iron overload appears to increase the risk for death from tuberculosis even in the absence of the acquired immunodeficiency syndrome. It is possible that the prevention and treatment of dietary iron overload could contribute to the control of tuberculosis in African populations. In a tragic attempt to rectify what was perceived as a debilitating iron deficiency in patients in Somalia, iron supplementation was actually found to promote the development of active tuberculosis. Murray MJ, Murray AB, Murray MB, Murray CJ. The adverse effect of iron repletion on the course of certain infections. Br Med J. 1978 Oct 21;2(6145):1113-5. The incidence of infections was studied in 137 iron-deficient Somali nomads, 67 of whom were treated with placebo and 71 with iron. Seven episodes of infection occurred in the placebo group and 36 in the group treated with iron; these 36 episodes included activation of pre-existing malaria, brucellosis, and tuberculosis. This difference suggested that host defence against these infections was better during iron deficiency than during iron repletion. Iron deficiency among Somali nomads may be part of an ecological compromise, permitting optimum co-survival of host and infecting agent. This is deplorable as already in 1926 Strachan (MD thesis, Glasgow) had established that the odds of death from tuberculosis in South Africa were 16.9 times higher in people with a splenic iron overload. Strachan AS: Haemosiderosis and Haemochromatosis in South African Natives with a Comment on the Etiology of Haemochromatosis. MD Thesis, Glasgow, UK, University of Glasgow, 1929 There is no good explanation for the widespread persistence of iron deficiency in the world, irrespective of race, culture, or ethnic background. There is convincing evidence that this deficiency protects against many infectious diseases such as malaria, plague, and tuberculosis as shown by diverse medical, historical, and anthropologic studies. Epidemic infections exerted a selection pressure under which the iron deficiency phenotype survived better. Geophagia is the practice of eating earth or soil-like substrates such as clay or chalk. It occurs in non-human animals and also in humans, most often in rural or preindustrial societies among children and pregnant women. Geophagia is nearly universal around the world in tribal and traditional rural societies. In the ancient world, several writers noted the use of geophagia. Bloodletting, which was common until recently, might have had a similar purpose. Geophagia may be an evolutionary adaptation acquired over millenia of interaction with bacteria. It was conventionally assumed that clays which are rich in minerals, particularly iron, might help supplement these nutrients. This assumption was also based on the fact that these were potentially available for absorption in the body. An English team P.S. Hooda. C.J.K. Henry T.A. SeyoumL. D.M. Armstrong M.B. Fowler. The Potential Impact of Geophagia on the Bioavailability of Iron, Zinc and Calcium in Human Nutrition. Environmental Geochemistry and Health December 2002, Volume 24, Issue 4, pp 305–319 has tested this assumption with five geophasic materials collected from Uganda, Tanzania, Turkey and India. The results showed that all five materials, regardless of their composition, absorbed large amounts of Fe and Zn across a range of dietary intake scenarios. However significant amounts od Ca were rendered bioavailable from calcareous soil samples. Clays are known for their rapid uptake of iron impairing bacterial metabolism. Zeolites are known for their immobilisation of metals. Bentonite clay is available worldwide as a digestive aid; kaolin is also widely used as as the base for some medicines. Beringite, is an artificial zeolite which is formed by the reaction of fly ash in NaOH solutions at 100 °C for several hours or days. The cation exchange capacity is increased from 100 to 3000 mmolc/kg. French green clay is well known for its wound healing properties. This property is used in Africa for treating and healing the Buruli ulcer, in the Centre Anti-Ulcère de Buruli, Côte-d’Ivoire, for example. Amin N, Andi Y, Mineralogie et physicochimie des argiles de traitement de l’ulcère de Buruli en Côte-d’Ivoire J. sci. pharm. biol., Vol.10, n°1 - 2009, pp. 21-30 Lynda B. Williams, Rossman F. Giese, Jr., and Dennis D. Eberl. Shelley E. Haydel, Chemical and mineralogical caracteristics of French green clays used for healing. Clays Clay Miner. 2008 Aug; 56(4): 437–452. Thus, although geophagic earths and mineral clays are high in total Fe, very little of this Fe is bioavailable. Further, some geophagic earth and clay mineral samples inhibit Fe absorption from foods. In vivo research is warranted to confirm these observations and to determine if geophagic earth samples can be a source of Fe and/or inhibit Fe absorption Gretchen L. Seim, Cedric I. Ahn, Mary S. Bodis,c Flavia Luwedde, Dennis D. Miller, Stephen Hillier, Elad Tako, Raymond P. Glahn, and Sera L. Younga. Bioavailability of iron in geophagic earths and clay minerals, and their effect on dietary iron absorption using an in vitro digestion/Caco-2 cell model. Food Funct. 2013 Aug; 4(8): 1263–1270. doi: 10.1039/c3fo30380b The expanding bacterial resistance to antibiotics has become a growing concern worldwide. Mycobacterium tuberculosis which infects one third of the world population has seen the emergence of multidrug resistant strains that have made most of the front line drugs ineffective. This bacterial resistance is prompting the resurgence in research on herbs against resistant strains. A study from India finds that among some 10 medicinal herbs there are only two with antimycobacterial effect, Artemisia nilagirica-vulgaris and Murraya koeningii. Others like Azadirachta indica, Moringa oleifera have no effect. The ethanolic extract of A nilagirica was found to kill intracellular mycobacteria. In the artemisia family the anti-TB properties of Artemisia afra are described in several papers. Sumanta Kumar Naik, Soumitra Mohanty,Avinash Padhi, Rashmirekha Pati, and Avinash Sonawane. Evaluation of antibacterial and cytotoxic activity of Artemisia nilagirica and Murraya koenigii leaf extracts against mycobacteria and macrophages. BMC Complement Altern Med. 2014; 14: 87 Ntutela S, Smith P, Matika L, Mukinda J, Arendse H, Allie N, Estes DM, Mabusela W, Folb P, Steyn L, Johnson Q, Folk WR, Syce J, Jacobs M. Efficacy of Artemisia afra phytotherapy in experimental tuberculosis. Tuberculosis 2009; 89: 33-40. M van de Venter , M Pruissen, In vitro anti-HIV and -TB activities of Annona muricata and Artemisia afra extracts. Planta Med 2014; 80 - P1L29 Artemisia abyssinica showed in vitro anti-mycobacterial activity against Mycobacterium tuberculosis and Mycobacterium bovis strains. Gemechu A, Giday M, Worku A, Ameni G. In vitro anti-mycobacterial activity of selected medicinal plants against Mycobacterium tuberculosis and Mycobacterium bovis strains. BMC Complement Altern Med. 2013 Oct 29;13:291. doi: 10.1186/1472-6882-13-291. There are so far no papers on similar properties documented for Artemisia annua. The antimalarial agent, artemisinin itself is not active against tuberculosis. Antagonism between antimalarial drugs and tuberculosis treatment has been documented. Lamorde M, Byakika-Kibwika P, Mayito J, Nabukeera L, Ryan M, Hanpithakpong W, Lefèvre G, Back DJ, Khoo SH, Merry C. Lower artemether, dihydroartemisinin and lumefantrine concentrations during rifampicin-based tuberculosis treatment. AIDS. 2013 Mar 27;27(6):961-5. doi: 10.1097/QAD.0b013e32835cae3b. Rifampicin intake simultaneously with Coartem lowers the AUC of artemether by 83% and lumefantrine by 84%. Similar antagonisms have been noticed for Efavirenz and Neviparine which are often used indiscriminitaly agains HIV and tuberculosis. The Makerere University found that co-administration of Coartem (AL) with Efavirenz resulted in reduction in artemether, DHA, lumefantrine exposure. Pauline Byakika-Kibwika, Mohammed Lamorde, Jonathan Mayito, Significant pharmacokinetic interactions between artemether/lumefantrine and efavirenz or nevirapine in HIV-infected Ugandan adults. J. Antimicrob. Chemother. (2012) 67 (9): 2213-2221. doi: 10.1093/jac/dks207 The mechanism for the action of Artemisia against mycobacterium is not fully understood. It is likely that the flavone luteolin plays a key role in the case of Artemisia afra. Rafaele CP Araujo, Francisco AR Neves, Anelise SN Formagio, Candida AL Kassuya, Maria EA Stefanello, Vanessa V Souza, Fernando R Pavan and Julio Croda. Evaluation of the anti-mycobacterium tuberculosis activity and in vivo acute toxicity of Annona sylvatic. BMC Complementary and Alternative MedicineThe official journal of the International Society for Complementary Medicine Research (ISCMR) 2014 14:209 DOI: 10.1186/1472-6882-14-2 The effect of thymol and scopoletin has been studied. Brooks C. Chemotherapy of tuberculosis; thymol in experimental tuberculosis in the guinea pig. Fed Proc. 1946;5(1 Pt 2):168. Samuel E. Okhale, Peters Oladosu, Abayomi T. Orishadipe. Identification of Thymol as an Antitubercular Agent from Ocimum gratissimum Leaf Essential Oil. American Chemical Science Journal 9(2): 1-6, 2015, Article no.ACSj.19141. ISSN: 2249-0205 Disappearance of the irritating feeling on the face as well as the shooting pains in the muscles after a few injections. Drying up of the secretions of the ulcers after a few injections followed by complete healing of the ulcers. Flattening and general disappearance of the leprotic nodules which in the beginning were erythematous. In a few patients marked pigment spots took the places of the scars, but these were slowly resorbed and the skin regained its normal colour. A Thesis at the University of Fès on the bactericidal action of essential oils of Thyme, Rosemary and Artemisia and found that all three were active against Mycobacteria. The monoterpenes thymol, carvacrol and eugenol were the strongest. Eugenol is well present in Syzygium aromaticum (clove). Khadija Rhayour Etude du mécanisme de l’action bactéricide des huiles essentielles sur Escherichia coli, Bacillus subtilis et sur Mycobacterium phlei et Mycobacterium fortuitum 2002 Faculté des Sciences Dhar Mehraz -Fès A Pakistanese team studied two Origanum species and found that Origanum vulgaris had the best antibacterial properties. It contained thymol and carvacrol absent in Origanum majorana. Abdullah I. Hussain, Farooq Anwar, Shazia Rasheed, Poonam. S. Nigam, Omar Janneh, Satyajit D. Sarker. Composition, antioxidant and 21(6): 943-952, Nov./Dec. 2011 chemotherapeutic properties of the essential oils from two Origanum species growing in Pakistan Revista Brasileira de Pharmacognosis, 2011, 21, 943-952). The Gauhaty University of India also made a survey of medicinal plants used against leprosy SJ Deka and SP Deka. Survey of medicinal plants used against leprosy disease by the tribal (Lalung) people of Myong area in Assam India. Plant Archives, 7 2007, 635-655. ISN 0972-5210. A research team in Nigeria O.I Faleyimu, O Akinyemi, O.R Adejoba. Herbal solution to the treatment of tuberculosis infection in Kaduna south local government, Kaduna, Nigeria. AJOL, 8, 2009 examined the use of medicinal plants in the treatment of tuberculosis. Eighty randomly selected questionnaires were administered to traditional healers, herbs traders, farmers and civil servants in the Local Government and were interviewed on the use of forest plants in the treatment of tuberculosis. This study has proved that local people have a wealth of knowledge that needs to be the focal point in pharmaceutical research. It is very encouraging to find on internet the following project in Ghana In-vitro susceptibility of Mycobacterium ulcerans to herbal preparations. www.who.int/buruli/events/16.Addo_ENG.pdf For several of the herbs involved in this project the inhibition of mycobacteria is equivalent or better than for Pefloxacin and/or Miconazole. But the most encouraging are the conclusions of this WHO sponsored project : A single herb is never a single compound but a group of compounds which potentiate each other or create synergy. The use of an herb or herbal cocktail would simulate combination therapy, which may prevent, or at least delay the development of microbial resistance.