Dear Editor

Tamboli et al[1] have initiated the discussion about dysbiosis that is rather a forgotten term.

Most of the Medical Dictionaries have yet to define this term. Dysbiosis as described by Metchnikoff (1910),[2] a colleague of Louis Pasteur, can be explained as the process rendering abnormal condition of the native gut micro-biota. Circumstances suggest that dysbiosis preceding the rotavirus infection in infants and children determine the severity of disease.

Professor Stig Bengmark, Lund University, Sweden, regards the native gut microbiota as the non-somatic organ of the body (personal communication).[3] Could we use a term gut eco-organ for this? The non-pathogenic native (and autochthonous as explained by Dubos et al.[4] and not the transient/ allochthonous) gut micro-biota can safely be regarded as an eco-organ (or micro-biota organ). This organ is made up of diverse micro-biota that follows the rules of open ecosystem. It is not made up of body cells hence the prefix eco- is used. It produces metabolites useful for the body, participates in the metabolism of the body, and is a part of body’s immune system hence the suffix –organ is used. Similarly, introducing the terms vaginal eco-organ or skin eco-organ would simplify the discussion of pathogenesis of diseases associated with these.

In human species, the microbial population exceeds by at least 10- fold the population of human cells in the body. Hence the human animal can be regarded as the vessel that has evolved to permit the survival and propagation of microorganisms. Alternatively, the human can be regarded as a biological organism composed of both eukaryotic animal cells and eukaryotic and prokaryotic microbial cells.[5] The concept is supported by the lifetime work of the R. Dubos and R. W. Schaedler from Rockfeller University, New York, USA; B. Gustafsson and T. Midtvedt from Karolynska Institute, Stockholm, Sweden; T.Mitsuoka, from University of Tokyo, Japan and P. Raibaud and R. Ducluzeau from Institut National de Recherches Agronomiques, Jouy-en-Josas, France.[6]

The latter concept anticipated by Savage has been examined. In simpler words, human animal has genetic plus somatic plus micro-biotic cells or human is a macroorganism having micro-biotic cells.

Here is a model given by Bry et al.[7] to show how a bacterium behaves like an organ of the mammalian physiological system. Bacteroides thetaiotaomicron was the component of the normal gut microbiota of conventionally housed experimental NMRI mice. These mice produced fucosylated glycoconjugates and an alpha1, 2-fucosyltransferase messenger RNA in the epithelial cells of small intestine. The epithelial cells of small intestine of germ free NMRI mice lack this fucosylation program. The fucosylation program was restored in the gnotobiotes produced from the germ free animals using Bacteroides thetaiotaomicron. When the mice were modified by transgenesis (insertion of transposon) they lost their ability to use L-fucose as a carbon source. Gnotobiotes produced using such a modified mice did not restore the small intestine epithelium fucosylation program. This indicates that particular bacteria may be suitable for a particular host.

The intestinal niches are unique.[8] Hence the autochthonous microorganisms evolved in those niches are also unique. A microorganism native to one niche may be transient to another.[9] It is felt that isolation of autochthonous microorganisms from these niches and their cultivation in vitro is difficult by conventional methods and appropriate environment resembling the niche in the gut is yet to be created through the application of tissue engineering. The microorganisms isolated from the gut and propagated in vitro and used as probiotics, are most likely to be transient microorganisms present in the gut and does not seem to be true to most of the niches in the intestine.

The terms probiotic, symbiotic or antibiotic are used to denote the relationship between the life forms. The eco-organ has to be considered as the part of the body or macroorganism. The body is a single (although complex) life presentation. If the eco-organ concept is recognized then the relationship of eco-organ with the body as a whole is a self-dialogue. The emotional stress cause disturbance in the stable composition of gut microbiota i.e. gut eco-organ [10-12] and the physical exercise done by the individual may have impact on the health of the organs including eco-organ. Recognizing the concept of eco-organ makes the subject understandable as discussed below.

The body (inclusive of eco-organ) and probiotics can have a dialogue. These elements either have symbiotic relationship i.e. the probiotics exert symbiosis on the body by producing metabolites that can be called as symbiotic (e.g. short chain fatty acids, other fatty acids, amino acids, peptides, polyamines, carbohydrates, vitamins, numerous antioxidants and phytosterols, growth factors, coagulation factors, various signal molecules such as cytokine-like bacteriokines) and the results are beneficial for the body alone or the probiotic relationship where both the body and probiotics are benefited mutually by each other by probiosis. The term symbiotic was coined for the combined action (synergy) of prebiotics and probiotics and preferably spelled as synbiotics, however it is now used in the sense as described above.[13] The amino acid residues like glutamine that are heat labile may be produced in vivo by symbiotic supplement.

It appears most of the time that the benefits provided by the probiotics to the body outweigh the benefits provided by the body to the probiotics. Therefore, the probiotics are not likely to be permanent residents of the gut. After seeding of probiotics in the gut, they may adhere to mucus and may or may not proliferate to some extent and reach to plateau and then decline for the convenience of the autochthonous microbiota. It is quite possible that some bacteria are evolved for performing the role of probiotics however; work in this direction is still not carried out. The body (inclusive of eco-organ), the probiotics and the pathogenic microorganisms can have a trilogue. Both the body and the probiotics may exert antibiosis against the pathogenic microorganisms independently and/or through their interaction.

It would be interesting to observe whether microbiota of probiotics preparation mutates or adapts to become a member of the body. Bacteria influence other bacteria either by the release of signal molecules [14] or by the transfer of genetic material between bacteria.[15] It is known that antibiotic resistant bacterial species evolve in the gut.[16-18]

Food must nourish the native microbiota for prevention of disease:

Food contains several nutrients that nourish body including eco- organs. Malnutrition weakens immune system. However, food may also contain certain functional ingredients. Some of them are discussed.

Fresh fruits and vegetables are source of dietary nitrate. Some of the dietary nitrates are absorbed and re-secreted in the saliva. The bacterial enzymes produced in the mouth reduce some of the nitrate to nitrite. When saliva is swallowed the acidic gastric juice reduces nitrite to nitric oxide.[19] Human milk is a source of nitrate [20,21] and nitrate-reducing microorganisms.[22] A high Concentration of nitrite in the stomachs of breastfed neonates is suggested to enable a high production of Nitric Oxide (NO). It is proposed that breast milk is important in regulating the mucosal blood flow and gastric motility and in achieving bacteriostasis via induction of NO generation in the neonatal stomach.[21] The nitric oxide is antibacterial and antiviral.[23,24] Whether it has any role in controlling gastroenteritis due to rotavirus is not known. It appears that some of the weaning diets might be reducing supply of nitrate. The severity of acute infectious gastroenteritis could be related to this supply. Nitric Oxide is also an acute phase reactant. It is also thought to be mutagenic.[25]

The human milk contains array of protective substances. The anti- rotavirus effect of lactoferrin [26-28] and lactadherin [29-34] are known. Human milk may also contain antirotaviral antibodies.[35-44] In addition food is source of prebiotics and probiotics.

Understanding the dysbiosis with reference to the weaning:

We now understand that dysbiosis in our species could be due to the abnormal food (drifting away from diets having Palaeolithic pattern), or anti-metabolites produced by pathogenic microorganisms or by antibiotics taken as drugs. The dysbiosis is not a unique condition. The dysbiosis caused by eating high meat low fibre diet may be different than the one caused due to intake of antibiotics. Similarly, dysbiosis expressed by flatulence and bloating may be different than dysbiosis expressed by chronic diarrhoea or dysentery. The dysbiotic body has dysfunctional immune system.[45,46] Some of the dysbiotic condition in the gut promotes translocation of gut microorganisms that may have serious consequences like organ failure.[47,48]

We are living the modern life with a body that is genetically the same like body of a human in Palaeolithic era. As an adult we may be adapted to modern foods based mostly on cereal and milk products but the babies undergoing weaning may be facing such food as a strange one. How the Palaeolithic children were weaned is difficult to say but certainly cereal and milk based diets were not available to them. Rotavirus diarrhoea occurs in neonate animals but in humans it occurs mostly during weaning indicating the possibility that an animal virus had an opportunity created by typical dysbiotic condition due to modern weaning foods to evolve as a human pathogen.

Piglets are used as an animal model for human rotavirus gastroenteritis. The piglets don’t show susceptibility to the human rotavirus unless they are derived in germ free state by caesarean operation and raised with restricted and known microbiota as gnotobiotes [49] a condition that can be called as induced dysbiosis.

Diarrhoea associated with rotavirus:

Breast-feeding helps in preventing the nosocomial rotavirus infection and prevention of diarrhoea in infected infants. Asymtomatic virus shedding was also seen in non-breast-fed infants.[50] It is recommended that breast-feeding should continue for the first two years [51] and that should be exclusive for the first 6 months of life.[52] The natural age of complete weaning for human children is thought to be between 2.3 and 7 years of age.[53] Ideally, child should guide the mother when to stop the breast-feeding completely and not the vice versa. Cooperstock and Zedd [54] divided the development of the intestinal microbiota in infants and children into 4 phases as follows:

Phase-1:
Acquisition of microbiota from transient one over the first 1–2 wk occurs during phase 1. This phase extends 2 weeks after the birth.

Phase-2:
Period of exclusive breast-feeding after the phase 1 till the start of food supplementation is phase 2.

Phase-3:
Period of supplementation after the phase 2 till weaning is phase 3

Phase-4:
From weaning till the growth of biota resembling adult is phase 4.

Nutrition of a child up to phase-2 i.e. exclusive breast-feeding is ultimate. The infection of rotavirus causing acute disease is uncommon during this period. Although the composition of breast milk of a mother of Palaeolithic era could be somewhat different than that of the modern mother by and large pattern of nutrients would be similar. The child receives a supplemental diet during phase 3 and a weaning diet during phase 4. These diets may range from Palaeolithic pattern to a complete non -Palaeolithic pattern/ modern pattern made up of highly processed foods. The extent of dysbiosis could depend upon the type of food pattern of these diets.

Bottle-feeding is common and may happen quite early in some infants. Lactic acid bacteria dominate the microbiota of breast-fed infant as evidenced by presence of lactic acid in the faeces. The lactic acid was absent in the faeces of formula-fed infants. The formula-fed infants also had higher faecal ammonia and other potentially harmful bacterial products.[55] The authors have asked 3 questions that could be answered as follows:

Should we retain a breast-fed style flora with limited ability to ferment complex carbohydrates?
The answer is probably "No" as it is difficult to maintain the breast-fed style flora. It is also impractical.

Can pro- and prebiotics achieve a flora with adult characteristics but with more lactic acid bacteria in weaned infants?
Supplementation of food and weaning food should have natural pre- and probiotics. It must be understood that the infant has a body similar to a Palaeolithic infant. Modern and processed food for supplementation and weaning is an artefact. The character of weaning diet having Palaeolithic- like human diet pattern should be worked out.

Are there any health risks associated with such manipulations of the flora?
Health risks are likely to be low if natural and hygienic food having high prebiotic value [56] is planned carefully for stabilization of flora. Fresh fruits and nuts may carry lesser health risks than animal milks.

In the infant or child the dysbiotic condition created due to faulty weaning as described above may prevail causing loss of resistance to rotavirus leading to severe acute diarrhoea on exposure to the virus. However, the infection of rotavirus itself may induce dysbiosis.[57] The dysbiotic conditions prevailing before and after infection are naturally different.

The products generated by dysbiosis could be toxic, carcinogenic, mutagenic or teratogenic and may affect the whole body. The abnormal digestive products present in the gut are known as Ama in Indian medicine.[58] These products may be called as dysbiotics (The term is not listed in the dictionary or medical texts) and could be the markers of dysbiosis. The diet having pattern of Palaeolithic human diet and/or predominantly raw vegan diet and life-style found on natural living could be the preventive measure against dysbiosis.

Standardization of the assay of dysbiosis is required:

Nugent score is a simple and convenient method for quantitative estimation of vaginal dysbiosis.[59] It requires only smear of vagina and Gram staining. Unfortunately, a method for simple and quantitative estimation of gut dysbiosis giving appropriate index is yet to be developed and approved by the experts. It is the need of the day.

Methods to be devised for statistical bioassay of gut dysbiosis index could be molecular, biochemical, clinical or their combinations. The methods for field studies, particularly in developing countries, need to be simple and rapid.

Culture independent methods for stool analysis for the study of intestinal microbiota are preferred [60] for the simple reason that the outcome of culture depends on representative stool sample that is difficult to obtain. Cultural conditions promote growth of certain species of bacteria and may not support the growth of some fastidious autochthonous bacteria. Culture of mucosal microbiota is different than the stool microbiota as mentioned by Tamboli et al.[1]

However stool cultures have been tried and may be essential for identification of toxigenic Clostridium difficile.[61] Stool may not be uniform and a randomly picked up sample of a part of stool is not a desirable material particularly for a quantitative assay of metabolic markers of mucosal microbiota. A better sample of total bowel content for dysbiotic studies of a person appearing normal may be obtained by collection of complete morning stool followed by an enema by inert material, mixing thoroughly and then picking up the proportional sample.

Rectal swab samples have been used successfully for studying molecular epidemiology of antibiotic resistance Gram-negative bacilli in a neonatal intensive care unit during a non-outbreak period [62] and for isolation of Staphylococcus aureus strains from healthy infants.[63] Although these are convenient samples these have yet to be demonstrated as an acceptable for quantitative dysbiosis studies.

Blood and urine provide better samples for the quantitative assay of dysbiosis than stool or rectal swab. The metabolic activity of gut microbiota is determined by the amount of enzymes produced by them and their activity results in certain products that can be detected in faeces,[64], blood [65] or urine.[66]

Urease producing microorganisms hydrolyse urea and produce ammonia that raises the pH of the stool. This action is linked with the colon cancer.[67] The urease in the stool, stool ammonia and stool pH when raised are the markers of intestinal dysbiosis. Urease may be produced by several bacterial species and thus the amount of urease rather than the individual population of bacteria producing it carries significance. Moreover, it is easier to study stool urease than studying individual bacterial populations. The fresh stool samples give correct values for the stool urease assay. The values may decline during storage of stool sample.

Such procedures are usually used in controlled experiments and quantitative values for routine clinical application are yet to be defined. Another important thing in this regard is that quantitative rather than qualitative test carry significance.[68]

The bacterial tryptophanase degrades tryptophan to phenol, which is a nephrotoxin[69] and can be detected in the urine. Thus urinary phenol is a marker of gut dysbiosis.[70] It is interesting to see e.g. what would be the course of rotavirus in terms of pathogenesis that has crossed the intestinal barrier in the presence or absence of agents like phenol in the blood.

Similarly, degradation of amino acid residues by bacterial decarboxylase produces amines that are toxic. Metchnikoff recognized this toxicity almost a century ago.[2] The free primary amines particularly p-tyramine present in the faeces was more in the infants (1-18 months) with gastroenteritis than healthy ones. The amine concentration was significantly related to the diet and was low in breast fed infants than infants fed cow milk.[71] Since the amines are deaminated in the liver, stool sample rather than blood sample is preferred for the study of dysbiosis in this case.

Activities of gut bacterial azoreductase [72] and nitroreductase [73] are harmful to the body and the quantitative assay of these enzymes also provides information on gut dysbiosis.

Oestrogen is conjugated in the liver and excreted in the bile. However its deconjugation occurs in the gut due to bacterial beta- glucuronidase releasing oestrogen that is reabsorbed raising the level of this hormone in the blood. This is implicated in the breast cancer. The same enzyme also deconjugates the bile releasing carcinogenic secondary bile products.[74,75]

Isolation of nucleic acid, Community finger printing by Denaturing Gradient Gel Electrophoresis (DGGE)/ Rapid Analysis of random amplified polymorphic DNA, Sequence analysis using rDNA database and preparation of phylogenic tree, Hybridisation in situ / whole cells/ Dot Blot- Southern blot /Quantitative Slot Blot is a protocol suggested by [76] and McCartney [77] for the study of gut microbial populations. Favier et al.[78] reported a method of molecular monitoring of succession of bacterial communities from neonate to infant using faecal samples. Recently, Vaughan et al. [79] and Tannock [80] have reviewed the Molecular methods for exploring the intestinal ecosystem.

These methods may be modified for detection and quantitation of dysbiosis. Having standardized these techniques to calculate a sort of Dysbiotic Index, a great asset for research would be developed. Predisposing conditions of not only rotavirus but also several other diseases may be seen clearer. At this juncture no technique may be called as the best but most of them are complementary to each other.

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74. Hill MJ, Melville DM, Lennard-Jones JE, Neale K, Ritchie JK. Faecal bile acids, dysplasia, and carcinoma in ulcerative colitis. Lancet. 1987 Jul 25;2(8552):185-6.

75. Bennet JD. Ulcerative colitis: the result of an altered bacterial metabolism of bile acids or cholesterol. Med Hypotheses. 1986 Jun;20 (2):125-32.

76. Mackie RI, Sghir A, Gaskins HR. Developmental microbial ecology of the neonatal gastrointestinal tract. Am J Clin Nutr. 1999 May;69(5):1035S- 1045S

77. McCartney AL, McCartney AL. Application of molecular biological methods for studying probiotics and the gut flora. Br J Nutr. 2002 Sep;88 Suppl 1:29-37.

78. Favier CF, Vaughan EE, De Vos WM, Akkermans AD. Molecular monitoring of succession of bacterial communities in human neonates. Appl Environ Microbiol. 2002 Jan;68(1):219-26.

79. Vaughan EE, Schut F, Heilig HG, Zoetendal EG, de Vos WM, Akkermans AD. A molecular view of the intestinal ecosystem. Curr Issues Intest Microbiol. 2000 Mar;1(1):1-12.)

80. Tannock GW. Molecular methods for exploring the intestinal ecosystem. Br J Nutr. 2002 May;87 Suppl 2:S199-201.

Dear Editor,

We read with interest the case report by Buchel et al., published on the July issue.[1] The authors report a patient with portal hypertension, nodular regenerative hyperplasia and portal thrombosis that presented an avascular hip necrosis after a liver transplantation (OLT). The authors suggest that the whole clinical picture might stem from hyperhomocysteinaemia (high Hcy) and 677C->T heterozigosity for the common gene of methylen-tetrahydrofolate reductase (MTHFR).

Although the history is suggestive of this hypothesis, high Hcy might also be a secondary phenomenon. It is not clear whether high Hcy was demonstrated in a sample obtained before – as suggested in Table – or after OLT – as suggested in the text. In both cases Hcy might be elevated as a consequence of either liver disease or drug treatment.

Liver disease per se raises Hcy, due to the multiple metabolic problems generated by a failing liver, including low folate levels, altered transsulphuration/transmethylation pathway and decreased renal function. High Hcy is present in 50% of liver disease patients, and values as high as 30 µmol/L are not uncommon in end-stage disease [2], independently of MTHFR polymorphism.

After OLT a specific effect of tacrolimus on Hcy metabolism and concentration is well documented. Both calcineurin inhibitors (cyclosporine and tacrolimus) are known to interfere with the folate- dependent remethylation of Hcy, thus raising plasma levels to values in the pathological range. The problem is well documented in patients following with renal [3], cardiac [4] and liver transplant [2]. In a recent analysis of 230 patients submitted to OLT we found 26 cases with fasting Hcy >= 30 µmol/L in the late post-transplant phase, independently of MTHFR polymorphism.[5]

Also the relationship between high Hcy and MTHFR polymorphism deserves a comment. The MTHFR gene independently and unfavourably influences homocysteine metabolism, but high Hcy levels are mainly observed in subjects with low folate levels [6], indicating a low phenotypic expression. Therefore, the presence of the genetic variant, mainly in its heterozygous form, might be an occasional phenomenon without any clinical significance. In conclusion, although the clinical history of the patients raises the suggested pathogenic role of Hcy and genetic predisposition, no clues can be made on the “egg-chicken” sequence, particularly in a patient with positive markers for hepatitis B infection.

For sure, an adequate folate intake or pharmacological supplementation may overcome the genetic predisposition to high Hcy, but may also decrease Hcy independently of any gene defect, and remains a suitable therapeutic option to prevent additional vascular problems.

References

1. Buchel O, Roskams T, Van Damme B, et al. Nodular regenerative hyperplasia, portal vein thrombosis, and avascular hip necrosis due to hyperhomocysteinaemia. Gut 2005;54:1021-3.

2. Bosy-Westphal A, Ruschmeyer M, Czech N, et al. Determinants of hyperhomocysteinemia in patients with chronic liver disease and after orthotopic liver transplantation. Am J Clin Nutr 2003;77:1269-77.

3. Fernandez-Miranda C, Gomez P, Diaz-Rubio P, et al. Plasma homocysteine levels in renal transplanted patients on cyclosporine or tacrolimus therapy: effect of treatment with folic acid. Clin Transplant 2000;14:110-4.

4. Cole DE, Ross HJ, Evrovski J, et al. Correlation between total homocysteine and cyclosporine concentrations in cardiac transplant recipients. Clin Chem 1998;44:2307-12.

5. Bianchi G, Nicolino F, Passerini G, et al. Plasma total homocysteine and cardiovascular risk in patients submitted to liver transplantation. Liver Transplant (in press).

6. Potena L, Grigioni F, Viggiani M, et al. Interplay between methylenetetrahydrofolate reductase gene polymorphism 677C-->T and serum folate levels in determining hyperhomocysteinemia in heart transplant recipients. J Heart Lung Transplant 2001;20:1245-51.

Dear Editor,

We read with interest the findings of Forrest et al ; Gut 2005; 54: 1174-1179, regarding their prognostic algorithm for alcoholic hepatitis; Glasgow alcoholic hepatitis score (GAHS). The study uses robust clinical end-points to develop an algorithm that has diagnostic advantages over the modified discriminant function score (DFS). We would like to discuss some of the future implications of this important study.

The overall death rate in the study was 23% at 28 days and the death rate of patients with a DFS >32 was 29% at 28 days in the derivation population. The latter figure is lower than the placebo arms of many of the RCTs of alcoholic hepatitis that range between 35 to 50%.[1-3] This difference compared to the published literature may be attributable to case definition. It is possible that there were a fewer number of patients in the derivation cohort for GAHS with true alcoholic hepatitis. Some of the previous studies of alcoholic hepatitis have required liver biopsy evidence of alcoholic hepatitis as part of the case definition. This was not the case for entry into the derivation cohort for the GAHS study and the case definition was based solely on clinical and biochemical evidence of liver dysfunction in patients with heavy alcohol consumption. In the validation population there was biopsy evidence of alcoholic hepatitis in only 33%.

While this may invalidate the GAHS as a means for identifying cases of alcoholic hepatitis it does not invalidate its use in identifying patients at risk of death when admitted to hospital with liver dysfunction on a background of heavy alcohol use. This makes it far more pragmatic than tests based on biopsies as many hospitals do not have access to specialised services to perform transjugular liver biopsies in the acute setting. Furthermore, there are published RCTs which have not required histological evidence of alcoholic hepatitis before allocating treatment.[1,4] The corollary to this is that although alcoholic hepatitis often presents with clinical features of fever, leucocytosis and hyperbilirubinaemia, there remains a differential diagnosis which may require a biopsy to resolve.[5]

It is important to differentiate between true alcoholic hepatitis and severe liver dysfunction in patients with heavy alcohol consumption because it will influence the choice of intervention. Randomised controlled trials that use GAHS to identify patients with alcoholic hepatitis might be greatly underpowered if the therapy, e.g. steroids, is effective in alcoholic hepatitis but ineffective or harmful in other clinical conditions where abnormal clinical parameters might be associated with heavy alcohol consumption. The selection of risk stratification models should be determined by the severity of the adverse effects of the therapy under trial. Those with more severe adverse effects will warrant models with high specificity whereas drugs with minimal side effects will benefit from a model with a high sensitivity. Compared to the DFS, the GAHS has an increased specificity, decreased sensitivity and improved accuracy making it suited to the selection of subjects in studies using more toxic therapies.

The utility of the GAHS will depend upon the effect of its use in the care of patients. We suggest that the next step in the evaluation of GAHS should be a clinical trial to see if patients randomised to risk stratification with GAHS followed by appropriate interventions have a better outcome than those managed conventionally.

We think this is an excellent study using robust clinical end points. It is a practical model which can be used easily at the bed side, to give valuable prognostic information. Success of future therapeutic trials in alcoholic hepatitis will not only depend on the efficacy of the drug but also the appropriate selection of patients by models and their respective cut-off points.

Yours sincerely,

I N Guha
WM Rosenberg

University of Southampton Liver Unit
Mail point 811
Level D
Southampton General Hospital
Trenoma Road
S016 6YD

References

1. Carithers RL, Jr., Herlong HF, Diehl AM, Shaw EW, Combes B, Fallon HJ, Maddrey WC. Methylprednisolone therapy in patients with severe alcoholic hepatitis. A randomized multicenter trial. Ann Intern Med 1989;110:685-690.

2. Mathurin P, Mendenhall CL, Carithers RL, Jr., Ramond MJ, Maddrey WC, Garstide P, Rueff B, Naveau S, Chaput JC, Poynard T. Corticosteroids improve short-term survival in patients with severe alcoholic hepatitis (AH): individual data analysis of the last three randomized placebo controlled double blind trials of corticosteroids in severe AH. J Hepatol 2002;36:480-487.

3. Ramond MJ, Poynard T, Rueff B, Mathurin P, Theodore C, Chaput JC, Benhamou JP. A randomized trial of prednisolone in patients with severe alcoholic hepatitis. N Engl J Med 1992;326:507-512.

4. Mendenhall CL, Anderson S, Garcia-Pont P, Goldberg S, Kiernan T, Seeff LB, Sorrell M, Tamburro C, Weesner R, Zetterman R. Short-term and long-term survival in patients with alcoholic hepatitis treated with oxandrolone and prednisolone. N Engl J Med 1984;311:1464-1470.

5. Oxford Textbook of Clinical Hepatology 2nd Edition. Edited by Bircher J, Benhamou J, Mcintyre N, Rizetto M and Rodes J. Volume 2, Chapter 15.3; 1185-1238.

Dear Editor,

We read with considerable interest the article by Jarvela et al. (Gut 2005;54:643-647), who investigate the relationship between the genotype of adult-type hypolactasia and the risk of colorectal cancer in the Finnish, British, and Spanish populations. In this study, the C/C–13910 genotype, a robust molecular marker of lactase non-persistence[1], was found to significantly associate with the risk of colorectal cancer in the Finnish population; no significant risk was detected in the British or Spanish populations.

Despite the presence of a hereditary component, colorectal cancer is closely associated with environmental factors, such as diet.[2] High consumption of dietary fat, refined carbohydrates and red meat, are associated with high risk of colon cancer. By contrast, fruits, vegetables, whole grain cereals, fish and calcium has been associated with reduced risk.

The effect of diet on the carcinogenic process could be mediated by changes in metabolic activity and composition of the colonic microflora. Bacteria such as bacteroides, eubacteria and clostridia could play a part in initiation of colon cancer through production of carcinogens, cocarcinogens, or procarcinogens, while lactic acid producing bacteria (LAB), such as lactobacillus and bifidobacteria, prevent tumorigenesis.[3]

In this regard, probiotics and prebiotics have received peculiar attention. In particular, a prebiotic is a non-digestible food ingredient able to indirectly stimulate growth and/or activity of LAB in the colon.[4] A number of poorly digested carbohydrates fall into this category. Lactose could be included in this group when consumed by subjects with lactase non-persistence.[5] In these patients, lactose present in dairy products cannot be digested in the small intestine, and instead is fermented by bacteria in the colon, acting as a prebiotic.[6] In addition, a not negligible percentage of lactase non-persistence patients are asymptomatic.[7]

Lactose is the predominant carbohydrate in milk. Consumption of milk is suggested to be inversely related to colorectal cancer incidence, and some of its component (calcium, vitamin D, lactose) could play a protecting role.[8]

Jarvela found that among the Finns, considered to have the highest consumption of milk in the world, people with lactase non-persistence have a higher risk to develop colorectal cancer. This is in contrast with the theory, that non absorbed lactose, acting as a prebiotic, prevents from colorectal cancer. He tried to explain this findings in two ways. First of all, he considered down-regulation of lactase activity after weaning as a normal phenomenon; persistence of elevated lactase activity is thought to be a relatively recent human evolutionary mechanism regulated at the transcription level: so, in terms of evolution, he suggested that milk may not be a nutritional need in adulthood and it may have some dangerous effects. According to this hypothesis, since milk is one of the staple foods of the Finnish diet, this population is submitted to the dangerous effects of milk, and it is more exposed to risk for colorectal cancer. Otherwise, milk could be protective for colorectal cancer, but it is possible that same malabsorber finnish people exclude from the diet milk because intolerant. Consequently, this group of Finns can not beneficiate of protective effects of milk.

Nevertheless, the role of dairy products in colorectal cancer remain controversial. We can suggest that the prebiotic activity of lactose can principally realise in asymptomatic subjects who do not eliminate dairy products from their diet despite lactose malabsorption. To evaluate this hypothesis it could be useful to stratificate the population with lactase non-persistence into two groups: symptomatic patients and asymptomatic subjects. In the latter, it is possible that milk has a supplementary protective effect due to the presence of lactose as prebiotic in addition to the other nutrients provided by milk. On the other hand, what is the risk of colorectal cancer in subjects consuming low lactose milk?

References

1) Rasinpera H, Savilahti E, Enattah NS, et al. A genetic test which can be used to diagnose adult-type hypolactasia in children. Gut 2004;53(11):1571-6

2) Guarner F, Malagelada JR. Gut flora in health and disease. Lancet 2003;360:512-519

3) Rowland IR, Gangolli SD. Role of gastrointestinal flora in the metabolic and toxicological activities of xenobiotics, in: B Ballantyne, TC Mars, Syverson (Eds.), General and Applied Toxicology, Second ed., Macmillan Publishers Ltd., London, pp.561-576

4) Burns AJ, Rowland IR. Antigenotoxicity of probiotics and prebiotics on faecal water-induced DNA damage in human colon adenocarcinoma cells. Mutation Research 2004;551:233-243

5) Montalto M, Nucera G, Santoro L, et al. Effect of exogenous â-galactosidase in patients with lactose malabsorption and intolerance: a crossover double-blind placebo-controlled study. Eur J Clin Nutr 2005;59(4):489-93

6) Szilagyi A. Review artiche: lactose – a potential prebiotic. Aliment Pharmacol Ther 2002;16:1591-1602

7) Montalto M, Curigliano V, Santoro L, et al. Management and treatment of lactose malabsorption. World J Gastroenterol in press

8) Norat T, Riboli E. Dairy products and colorectal cancer. A review of possible mechanisms and epidemiological evidence. Eur J Clin Nutr 2003;57:1-17