Friday, April 29, 2011

XGP Antibiotica treatment LIEGE CIPRO full text - french original paper

A case of Xanthogranulomatous Pyelonephritis managed conservatively

  • Parthasarathy Shanmugasundaram, Wollongong Hospital, Australia
  • Dr Maureen Lonergan, Wollongong Hospital, Australia
  • Xanthogranulomatous Pyelonephritis (XPN) is a rare form of pyelonephritis characterised by massive destruction of the kidneys often requiring nephrectomy. An 80-year non-diabetic lady presented to the Emergency Department with severe obtundation, reduced oral intake and falling urine. In the past she had episodes of dysuria but no urolithiasis or obstructive uropathy. She was dehydrated, hypotensive BP and afebrile. Her initial results:- serum creatinine 690 umol/L, urea 47.6 mmol/L, potassium 5.4 mmol/L, blood sugar 4.3 mmol/L, albumin 20 g/L, bicarbonate 7 mmol/L and haemoglobin 68 g/L. The urine was grossly pyuric and grew Pseudomonas aeruginosa and Proteus mirabilis. A non-contrast CT of the abdomen demonstrated a small and irregular left kidney but the right kidney was replaced by a large, predominantly hypodense mass with extensive calcification and dilated pelvicalyceal system, features consistent with XPN. The ureter was dilated to the vesico-ureteric junction. Retrograde ureteric stenting was attempted but was unsuccessful. Debris was dislodged. The patient was managed with inotropes, fluids and antibiotics, vancomycin and timentin empirically then ciprofloxacin replacing the former. She also received blood transfusion and intravenous bicarbonate. Her general well-being and renal function improved. Her serum creatinine fell to 168 umol/L at 4 weeks without the need for dialysis. Eleven weeks later the right kidney measured 7.1cms and the left 8.0 cms in length on the ultrasound. Hydronephrosis had improved on the right. Presently she continues to maintain a stable although impaired renal function. Our case demonstrates successful conservative management of XPN, which almost inevitably necessitates nephrectomy.



    Pyélonéphrite xanthogranulomateuse pseudotumorale : diagnostic par la biopsie percutanée et succès du traitement conservateur

    REUL O, WALTREGNY D, BOVERIE J, LEVAL J, ANDRIANNE R
    Prog Urol, 2001, 11, 6, 1274-1276
    Cas clinique
    Résumé
    La pyélonéphrite xanthogranulomateuse est une forme inhabituelle d'infection rénale dont le diagnostic est souvent méconnu avant l'intervention chirurgicale. Nous rapportons le cas d'une jeune fille âgée de 19 ans qui présentait une masse rénale pseudotumorale. Le diagnostic de pyélonéphrite xanthogranulomateuse focale a été suspecté par les caractéristiques de la masse aux différents examens d'imagerie médicale et confirmé par l'analyse histologique d'un fragment prélevé par une biopsie percutanée échoguidée. La guérison a été obtenue avec un traitement antibiotique. Une exploration exhaustive comprenant une biopsie rénale devrait être réalisée afin de poser le diagnostic de pyélonéphrite xanthogranulomateuse avant tout geste chirurgical. Nous préconisons le traitement antibiotique comme traitement de première intention de la pyélonéphrite xanthogranulomateuse focale.

    Observation

    Une jeune fille âgée de 19 ans a été adressée à notre hôpital pour des douleurs lombaires droites importantes, permanentes, présentes depuis 3 semaines et en aggravation depuis 3 jours. Lors de son admission, la patiente était apyrétique et ne signalait aucun symptôme urinaire. Elle n'avait pas d'antécédents d'infection urinaire ou de lithiase. L'examen clinique était sans particularité hormis un point douloureux costo-musculaire droit. Il n'y avait pas d'organomégalie ni de contact lombaire au palper bimanuel. Sur le plan biologique, il n'y avait pas d'anomalie à l'exception d'une élévation de la CRP à 49 mg/l. La leucocytose était de 9780/mm3 dont 64% de neutrophiles et l'hémoglobine est de 12.3g/dl. La fonction rénale était conservée avec une urémie de 0.2 g/l et une créatinémie de 8 mg/l. La culture urinaire était stérile.

    L'échographie rénale a objectivé une masse hétérogène de 5 cm de diamètre au pôle inférieur du rein droit tandis que le rein gauche avait un aspect normal. La tomodensitométrie abdominale a confirmé la présence d'une lésion de 5 cm à zone centrale hétérogène et hypodense entourée d'une coque rehaussée par l'injection de produit de contraste (Figure 1).
    Figure 1 : Lors du diagnostic, présence à l'examen tomodensitométrique d'une masse hétérogène à centre hypodense et rehaussée en périphérie par le produit de contraste. Lésion similaire de petite taille au pôle inférieur du rein droit.
    Une seconde lésion de 1 x 1,2 cm de mêmes caractéristiques densitométriques était visible à la partie antérieure du pôle inférieur du rein droit. A l'artériographie rénale sélective, la lésion était hypovascularisée avec étirement des vaisseaux en périphérie sans caractéristique de vascularisation anarchique tumorale (Figure 4).
    Figure 4 : Masse hypovascularisée avec étirement des vaisseaux en périphérie à l'artériographie rénale sélective.
    L'urographie intraveineuse puis la pyélographie rétrograde, l'UIV étant insuffisante, ont révélé un syndrome de masse avec refoulement des tiges calicielles inférieures.

    Nous avons réalisé deux biopsies percutanées de la lésion la plus volumineuse sous guidage échographique. L'analyse anatomo-pathologique a révélé un envahissement du parenchyme rénal par un infiltrat inflammatoire chronique formé de macrophages d'aspect spumeux associés à des monocytes, lymphocytes et de la fibrose. Cet aspect était compatible avec le diagnostic de pyélonéphrite xanthogranulomateuse. La culture de la deuxième biopsie était positive pour des E. Coli, sensibles aux quinolones. La patiente a été traitée pendant cinq semaines par de la ciprofloxacine per os à raison de 250 mg 2 fois par jour. Une réduction considérable du volume de la masse a été observée à l'examen tomodensitométrique réalisé après un mois de traitement (Figure 2).
    Figure 2 : Après un mois de traitement, diminution importante de la taille des lésions en tomodensitométrie abdominale
    Trois mois plus tard, la tomodensitométrie a révélé des zones cicatricielles au niveau des sites des deux lésions initiales (Figure 3).
    Figure 3 : Aspect cicatriciel au contrôle tomodensitométrique après 4 mois.
    Durant les douze mois suivants, aucune récidive n'a été constatée. L'échographie, à un an, était normale

    Discussion

    La pyélonéphrite xanthogranulomateuse est une forme de suppuration rénale chronique survenant à tout âge, le plus souvent après 40 ans et touchant trois fois plus fréquemment les femmes que les hommes. La forme focale est de diagnostic difficile car elle est souvent confondue avec un processus néoplasique. L'étiopathogénie de la pyélonéphrite xanthogranulomateuse n'est pas connue avec certitude mais plusieurs facteurs étiologiques ont été incriminés dont l'obstruction de la voie excrétrice (lithiase, sténose, tumeur, ...), l'infection urinaire récidivante plus ou moins décapitée par les antibiothérapies et les déficits immunitaires [5] Aucun des ces facteurs n'est présent dans notre observation.

    Les patients souffrant de pyélonéphrite xanthogranulomateuse focale présentent classiquement une douleur intermittente du flanc, de la fièvre, des frissons ou une altération de l'état général avec perte de poids. La symptomatologie dure habituellement depuis plusieurs semaines avant que le diagnostic ne soit posé.

    Sur le plan biologique, on note des signes d'infection avec élévation des tests inflammatoires (C reactive protein, vitesse de sédimentation, fibrinogène) et hyperleucocytose. La culture urinaire est stérile dans 50 % des cas de pyélonéphrite xanthogranulomateuse mais la culture du tissu rénal est presque toujours positive, comme dans notre observation. Les bactéries les plus souvent en causes sont le Proteus Mirabilis et l'E.Coli.

    La pyélonéphrite xanthogranulomateuse focale doit être suspectée à l'examen tomodensitométrique qui révèle classiquement une masse hétérogène centrée sur une tige calicielle et faiblement rehaussée en périphérie par le produit de contraste [7]. L'absence de lymphonoeuds pathologiques, de thrombus veineux ou de métastases sont des signes importants pour orienter le diagnostic. L'échographie rénale, l'urographie intraveineuse et la pyélographie rétrograde révèlent un syndrome de masse aspécifique. Même si la tomodensitométrie abdominale et l'artériographie ont permis de suspecter fortement la nature inflammatoire et non tumorale des lésions rénales dans le cas présenté, ces deux examens ne peuvent pas exclure formellement le diagnostic de lésion néoplasique. Nous avons donc opté pour la biopsie percutanée de la masse rénale, ce qui a permis de confirmer le diagnostic de pyélonéphrite xanthogranulomateuse.

    Le traitement habituel de la pyélonéphrite xanthogranulomateuse focale est malheureusement souvent la néphrectomie totale ou partielle [3]. Cette approche thérapeutique est attribuable à un diagnostic préopératoire rarement correctement posé [4]. Le traitement conservateur de la pyélonéphrite xanthogranulomateuse pseudotumorale par une antibiothérapie seule est donc une exception, avec de rares cas décrits dans la littérature [1, 2, 6] Pour ces cas décrits comme dans le nôtre, le traitement médical s'est avéré efficace avec une résolution complète des lésions rénales.

    Nous pensons donc qu'une exploration exhaustive suivie d'une biopsie percutanée pourrait être réalisée afin de poser le diagnostic de pyélonéphrite xanthogranulomateuse focale avant tout geste chirurgical. De plus, la culture des biopsies rénales permet d'identifier les micro-organismes en cause et d'adapter le traitement en fonction de l'antibiogramme. Nous suggérons l'utilisation du traitement antibiotique comme traitement de première intention de la pyélonéphrite xanthogranulomateuse focale à condition qu il n'y ait pas de pathologie obstructive sous-jacente telle qu'une lithiase ou une lésion des voies excrétrices.



    REFERENCES

    Références

    1. AIZAWA T., KURATA M., OHKUBO Y. A case of xanthogranulomatous pyelonephritis followed by computed tomographic scan. Hinyokika Kiyo, 1998, 44, 729-732.

    2. BROWN P.S. Jr, DODSON M., WEINTRUB P.S. Xanthogranulomatous pyelonephritis: report of nonsurgical management of a case and review of the literature. Clin. Infect. Dis., 1996, 22, 308-314.

    3. CHUANG C.K., LAI M.K., CHANG P.L.,HUANG M.H., CHU S.H., WU C.J., WU H.R. Xanthogranulomatous pyelonephritis: experience in 36 cases. J. Urol., 1992, 147, 333-336.

    4. EASTHAM J., AHLERING T., SKINNER E. Xanthogranulomatous pyelonephritis: clinical findings and surgical considerations. Urology, 1994, 43, 295-299.

    5. MALEK R.S., ELDER J.S. Xanthogranulomatous pyelonephritis: A critical analysis of 26 cases and of the literature. J. Urol., 1977, 119, 589-593.

    6. MOLLIER S., DESCOTES J.L., PASQUIER D., COQUILLAT P., MICHEL A., DALSOGLIO S., RAMBEAUD J.J. Pseudoneoplastic xanthogranulomatous pyelonephritis. A typical clinical presentation but unusual diagnosis and treatment. Eur. Urol., 1995, 27, 170-173.

    7. SHAH M., HAAGA J.R. Focal xanthogranulomatous pyelonephritis simulating a renal tumor: CT characteristics. J. Comput. Assist. Tomogr., 1989, 13, 712-713.

    Saturday, April 9, 2011

    XGP Which Antibiotics?

    WHICH ANTIBIOTICS?

    Intravenous
    * piperacillin/tazobactam
    * amikacin and metronidazole

    pyrizinamide, ethambutol


    The type of antibiotic depends on local practice, and may include
    fluoroquinolones (e.g. ciprofloxacin), beta-lactam antibiotics (e.g.
    amoxicillin or a cephalosporin), trimethoprim (alone or in combination
    with sulfamethoxazole). Aminoglycosides are generally avoided due to
    their toxicity, but may be added for a short duration
    ACUTE ... ciprofloxacin IV 400 mg every 12 hours is the first line
    treatment of choice. Alternatively, ampicillin IV 2g every 6 hours
    plus gentamicin IV 1 mg/kg every 8 hours also provide excellent
    coverage.

    ==================

    Drug makers including [[Pfizer]] and [[Sanofi-Aventis]] are interested
    in modern versions of Coley's
    Toxins<ref>[http://www.nytimes.com/2005/10/05/business/05toll.html?_r=1&scp=2&sq=william%20B%20coley&st=cse
    New York Times: article on Pfizer and Coley Pharmaceutical Group, 5
    October 2005]</ref>; Pfizer has acquired the Coley Pharmaceutical
    Group, set up in
    1997<ref>[http://www.news-medical.net/news/2007/11/19/32636.aspx
    news-medical.net
    : Pfizer to acquire Coley Pharmaceutical Group, 19
    November 2007]</ref>

    http://en.wikipedia.org/wiki/Pyelonephritis


    Xanthogranulomatous pyelonephritis (XGP) is a rare form of chronic
    pyelonephritis. With the review of the literature, we reported two
    cases of XPN with psoas muscle abscesses caused by Staphylococci
    aereus in one of the patient and Serratia mascerentes in the other.
    Both of the patients had renal calculus. We performed nephrectomy with
    psoas abscess drainage and started appropriate antibiotics, but one of
    the patients died of septic shock. Other patient is free of symptoms
    at the end of 5 years follow-up.

    Keywords Psoas abscess - Xanthogranulomatous pyelonephritis


    Case 1

    The 17 year old male patient was presented with complain of left side
    pain, difficulty in walking, high fever and general deterioration of
    health.
    The patient had been suffering from the left side pain for 1 month and
    clinicians other than urology tried to treat the patient. He had
    difficulty in walking for the last 1 week. He had severe left flank
    tenderness and his left leg was in flexion, from the hip.
    Pain became more severe when he extended his leg. Leukocyte count was
    23,000. Urine sediment showed leukocyturia but urine culture was
    sterile.
    Computerrized tomography (CT) showed that the left renal parenchyma
    thickness was severely reduced and no function was monitored on the
    left kidney (Figure 1). There were many calculi in the kidneyl the
    biggest at 1 cm diameter and thick walled collections at the dimension
    of 12 x 8 x 6 cm3 existed, extending from the posterior pararenal area
    along the psoas muscle (Figure 2). A culture was prepared from the
    liquid extracted percutaneously and empiric triple antibiotic
    treatment was commenced, using ceftriaxone, gentamisin and
    metranidazol. Hte culture reproduced Staphylococci aereus. The patient
    was explored and subjected to nephrectomy and the absess in the psaos
    was drained. The histopathological evaluation of the kidney revealed
    an appearance in compliance with XGP (Figure 3). Within the 48
    postoperative months, the patient developed no problem.

    ==========
    Xanthogranulomatous pyelonephritis mimicking malignant disease: is
    preservation of the kidney possible?

    A. Raziel, R. Steinberg, L. Kornreich, C. Mor and D. Golinsky, et al.

    Xanthogranulomatous pyelonephritis (XGP) is an uncommon form of
    pyelonephritis rarely seen in children. It is characterized by
    destruction of the renal parenchyma and invasion of adjacent tissues,
    mimicking renal tumors. Preoperative diagnosis is very difficult. Two
    children with XGP are presented. One underwent nephrectomy and the
    other drainage of a renal abscess with kidney preservation. Although
    surgery is considered the only effective treatment, a high index of
    suspicion and renal biopsy may prevent radical nephrectomy.

    http://www.springerlink.com/content/t42p3820q14n0325/

    ===================

    Medical treatment alone is inadequate to treat XGP; antibiotics are a
    temporary measure for patients requiring medical investigation prior
    to nephrectomy


    BMJ Case Reports 2011; doi:10.1136/bcr.09.2010.3356

    * Learning from errors

    Xanthogranulomatous pyelonephritis in a young postpartal female

    1. Vishal V Ramteke,
    2. Makardhwaj S Shrivastava,
    3. Brijesh A Agrawal,
    4. Ankit D Raiyani,
    5. Pramod A Darole,
    6. Namita J Padwal,
    7. Sandhya A Kamath

    + Author Affiliations

    1.
    Department of Medicine, Lokmanya Tilak Municipal Medical College
    and General Hospital, Mumbai, India

    1. Correspondence to Makardhwaj S Shrivastava, makar_in@rediffmail.com

    Summary

    Xanthogranulomatous pyelonephritis (XGP) is a rare chronic
    inflammatory disorder of the kidney characterised by an infectious
    phlegmon arising in the renal parenchyma. It is seen in patients who
    have urolithiasis, urinary tract infection and immunocompromised
    status. The clinical presentation is variable and renal neoplasm is
    considered as a differential due to its characteristic extrarenal
    visceral invasion. The treatment is almost universally extirpative and
    can pose a formidable challenge to the treating physician and surgeon.
    The authors report a rare case of XGP in a postpartal woman who
    presented with multiple visceral abscesses whose diagnosis was arrived
    on histopathological examination.


    http://casereports.bmj.com/content/2011/bcr.09.2010.3356.abstract

    preserve specimen formalin recipe preservation microscopy sample

    Here is what you should have ready at home, in case you shed a sample
    that the doctor should have investigated in the medical laboratory

    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2225110/pdf/31.pdf

    Consideration of the morphological and biochemical
    integrity of the fixed tissue suggests that 4 per cent formaldehyde, buffered at
    pH 7.2 with 0.067 M phosphate, and containing 7.5 per cent sucrose, is
    the most suitable
    of the fixatives for combined cytochemical staining and electron
    microscopical studies.

    Monday, April 4, 2011

    Anti Cancer Probiotics - Yoghurt for VRE Kidney Patients ...



    BACTERIA HELP KIDNEY DISEASE

    http://www.ncbi.nlm.nih.gov/pubmed/17484706

    Probiotic treatment of vancomycin-resistant enterococci: a randomised controlled trial.

    Manley KJ, Fraenkel MB, Mayall BC, Power DA.

    Austin Health, Melbourne, Victoria, Australia. karen.manley -at= austin.org.au

    Comment in:

       * Med J Aust. 2007 Sep 3;187(5):320.

    Abstract

    OBJECTIVE: To determine whether eating Lactobacillus rhamnosus GG (LGG) in the form of commercially available yoghurt improves clearance of vancomycin-resistant enterococci (VRE).

    DESIGN: Double-blind, randomised, placebo-controlled trial.

    SETTING: Renal ward of Austin Health, a tertiary hospital, Feb-Oct 2005.

    PARTICIPANTS: 27 VRE-positive patients, 14 receiving active treatment and 13 controls.

    INTERVENTIONS: Subjects were randomly assigned to either a treatment group (receiving 100 g daily of yoghurt containing LGG for 4 weeks) or a control group (receiving standard pasteurised yoghurt). Faecal samples were obtained three times at about weekly intervals. Treated patients were tested for VRE again at 8 weeks. Patients in the control group who had failed to clear VRE after 4 weeks were then given LGG-containing yoghurt for 4 weeks, as an open continuation.

    MAIN OUTCOME MEASURE: Number of faecal specimens clear of VRE.

    RESULTS: Of the 27 patients enrolled, 23 completed the study. Two patients were lost to follow-up, one died and one withdrew. All 11 patients in the treatment group who completed the study cleared VRE. Three subjects reverted to VRE positivity after using antibiotics to which LGG is sensitive, while all others remained negative for at least 4 weeks after trial completion. Twelve control subjects completed the study, of whom one cleared VRE and 11 remained VRE-positive. Eight of these 11 patients were subsequently crossed over to receive LGG yoghurt, and all cleared VRE within 4 weeks.

    CONCLUSION: To our knowledge, this is the first description of a probiotic therapy to successfully treat gastrointestinal carriage of VRE in renal patients. Further investigation of the use of LGG in VRE-positive patients is warranted.

    These guys in Denmark make LGG in 30,000 liter tank fermenters:
    http://www.chr-hansen.com/campaign_sites/probiotics_for_human_health/our_probiotic_products/strains/lggr.html

    http://www.asiakaslehti.com/foodsandfunctionals/sites/default/files/node68.jpg

    Anti-Carcinogenicity of Probiotics and Prebiotics

    A.J. Burns, and I.R Rowland

    Northern Ireland Centre for Diet and Health, School of Biomedical Sciences, University of Ulster, Coleraine BT52 1SA, Northern Ireland

    Yoghurt, and the lactic acid producing bacteria (LAB; probiotics) that it contains, have received much attention as potential cancer-preventing agents in the diet. It is usually considered that the mechanism of the action is by increasing the numbers of LAB in the colon, which modifies the ability of the microflora to produce carcinogens. Prebiotics such as non-digestible oligosaccharides (NDO) appear to have similar effects on the microflora by selectively stimulating the growth of LAB in the colon.

    Oligofructose is a CHEAP powder...21,00 € per Kg  google Oligofruct HT - german DIY people-owned-TV programme.

    Evidence for cancer-preventing properties of pro- and prebiotics is derived from studies on faecal enzyme activities in animals and humans, inhibition of genotoxicity of known carcinogens in vitro and in vivo, suppression of carcinogen-induced preneoplastic lesions and tumours in laboratory animals. Some of these studies indicate that combinations of pro and prebiotics ('synbiotics') are more effective. Epidemiological and intervention studies provide some, albeit limited, evidence for protective effects of products containing probiotics in humans.


    Review

    Probiotics Prebiotics and Synbiotics

    The original definition of a probiotic was 'a live microbial feed supplement which beneficially affects the host animal by improving its intestinal microbial balance' (Fuller, 1989). Recent definitions are more general, omitting the aspect of intestinal balance. For example Salminen et al (1998) define a probiotic as 'a live microbial food ingredient that is beneficial to health'. A probiotic organism should be non-pathogenic and non-toxic, and also resistant to low pH and to bile salts to improve its chances of survival in the gastrointestinal tract (Fuller, 1991). Most probiotics are members of two genera of lactic acid producing bacteria (LAB), Lactobacillus and Bifidobacterium, but Saccharomyces and Enterococcus are also used. Many of the bacteria used for probiotic preparations have been isolated from human faecal samples to maximise the likelihood of compatibility with the human gut microflora and hence enhance their chances of survival.

    The concept of probiotics evolved from a theory first proposed by Metchnikoff who suggested that the long, healthy life of Bulgarian peasants could be attributed to their consumption of fermented milk products. A variety of health benefits have been associated with LAB such as improvement of lactose intolerance, regulation of gastrointestinal stasis, resistance to infectious digestive diseases, especially rotavirus-associated diarrhoea in infants, and immunomodulation (Sanders, 1993).

    A prebiotic is 'a nondigestible food ingredient that beneficially affects the host by selectively stimulating the growth and/ or activity of one or a limited number of bacteria in the colon that have the potential to improve host health' (Gibson and Roberfroid, 1995). A number of poorly digested carbohydrates fall into the category of prebiotics including certain fibres and resistant starches (Silvi et al 1998), but the most widely described prebiotics are non-digestible oligosaccharides (NDOs). These are low molecular weight carbohydrates with 2-10 degrees of polymerisation, which are poorly digested in the small intestine thus reaching the colon largely unaltered and can act as a substrate for the colonic microflora. They appear to stimulate specifically the numbers of bifidobacteria and lactobacilli, often at the expense of other microflora components such as bacteroides, clostridia and Escherichia coli (Gibson et al 1995, Rowland and Tanaka 1993). Combinations of probiotics and prebiotics can result in additive or synergistic effects on gastrointestinal function. The term synbiotic has been proposed for such combinations. A synbiotic has been defined as 'a mixture of probiotics and prebiotics that beneficially affects the host by improving the survival and implantation of live microbial dietary supplements in the gastrointestinal tract, by selectively stimulating the growth and/or activating the metabolism of one or a limited number of health-promoting bacteria, and thus improving host welfare' (Gibson and Roberfroid, 1995)

    Role of the Gut Microflora in Cancer

    The enormous numbers and diversity of the human gut microflora is reflected in a large and varied metabolic capacity, particularly in relation to xenobiotic biotransformation, carcinogen synthesis and activation. The metabolic activities of the gut microflora can have wide-ranging implications for the health of the host, resulting in both beneficial and detrimental effects (Rowland et al,1999; Rowland and Gangolli 1999)

    Evidence from a wide range of sources supports the view that colonic microflora is involved in the aetiology of cancer. The main pieces of evidence are:

    1) Human faeces have been shown to be mutagenic, and genotoxic substances of bacterial origin have been isolated (Venturi et al, 1997)

    2) Intestinal bacteria can produce, from dietary components, substances with genotoxic, carcinogenic and tumour-promoting activity (Rowland et al, 1999)

    3) Gut bacteria can activate procarcinogens to DNA reactive agents

    4) Germ-free rats treated with the carcinogen 1,2-dimethylhydrazine have a lower incidence of colon tumours than similarly treated rats having a normal microflora (Reddy et al 1975)

    5) Germ-free rats fed human diets exhibit lower levels of DNA adducts in tissues than conventional rats (Rumney et al, 1993).

    It follows from the above, that modification of the gut microflora may interfere with the process of carcinogenesis and this opens up the possibility for dietary modification of colon cancer risk. Probiotics and prebiotics, which modify the microflora by increasing numbers of lactobacilli and/or bifidobacteria in the colon, have been a particular focus of attention in this regard. Evidence that probiotics and prebiotics can influence carcinogenesis is derived from a variety of sources:

    · Effects on bacterial enzyme activities.

    · Antigenotoxic effects in vitro and in vivo.

    · Effects on pre-cancerous lesions in laboratory animals.

    · Effects on tumour incidence in laboratory animals

    · Epidemiological and experimental studies in humans.

    Effects of Probiotics and Prebiotics on Bacterial Enzyme Activities

    The ability of the colonic microflora to generate a wide variety of mutagens, carcinogens and tumour promoters from dietary and endogenously-produced precursors is well documented (Rowland, 1995). For example, the enzyme ß-glucuronidase is involved in the release in the colon, from their conjugated form, of a number of dietary carcinogens, including polycyclic aromatic hydrocarbons. Similarly, bacterial ß-glycosidase hydrolyzes the plant glycoside cycasin to a carcinogen in the gut. It should be noted however that glycoside hydrolysis by intestinal microflora can result in the generation of potential anti-carcinogenic and anti-mutagenic substances in the form of flavonoids such as quercetin (Rowland, 1995). A major role for the intestinal microflora has been identified in the metabolism of the bile acids cholic and chenodeoxycholic acids to deoxycholic and lithocholic acids, which are thought to possess tumour-promoting activity. Other potential tumour-promoters, namely ammonia, phenols and cresols, are also generated by deamination of amino acids such as tyrosine by intestinal bacteria.

    The reaction of nitrite with secondary amines and amides can lead to the formation of N-nitroso compounds, many of which possess mutagenic and carcinogenic activity. There is evidence from germ-free rat studies that nitrosation can occur under neutral pH conditions by an enzymic process catalysed by intestinal bacteria (Massey et al 1988). Another bacterially-catalysed reaction yielding a reactive substance capable of causing DNA damage and mutation, is the conversion of the cooked food carcinogen 2-amino-3-methyl-3H-imidazo(4,5-f)quinoline (IQ) to its 7-hydroxy derivative. The latter, unlike its parent compound is a direct-acting mutagen (Carman et al, 1988).

    In general, species of Bifidobacterium and Lactobacillus, have low activities of these enzymes involved in carcinogen formation and metabolism by comparison to other major anaerobes in the gut such as bacteroides, eubacteria and clostridia (Saito et al 1992). This suggests that increasing the proportion of LAB in the gut could modify, beneficially, the levels of xenobiotic metabolising enzymes. Studies have been carried out in laboratory animals and humans in order to acquire a greater understanding of the way in which administration of specific probiotics and prebiotics affect gut microflora metabolism.

    Studies in Laboratory Animals

    The effects of probiotics and prebiotics on gut bacterial enzymes have been studied in conventional microflora animals and also germ free rats associated with a human faecal microflora, so called 'Human Flora Associated (HFA) rats. These studies are summarised in Table 1 and some examples are discussed in more detail below.

    In a conventional rat study, supplementation of a high meat diet (72% beef) with Lactobacillus acidophilus (109 - 1010 organisms/day) significantly decreased by 40 - 50% the activity of faecal ß-glucuronidase and nitroreductase (Goldin and Gorbach 1976). Interestingly the modulating effect of the lactobacillus strain was dependent on the type of basal diet fed - no significant effects were seen when the rats were fed a grain based diet. In an analogous study in HFA rats, Cole et al (1989) demonstrated a significant reduction in ß-glucuronidase and ß-glucosidase activities when L. acidophilus was fed for 3 days, with the effect persisting for 7 days after dosing ceased.

    These changes in enzyme activities seen after consumption of LAB would in theory be expected to result in changes in rates of metabolism of their substrates in vivo, although only if the enzymes catalysed the rate limiting step in their metabolism. Goldin and Gorbach (1984) have confirmed this by showing that a reduction in activity of the bacterial enzymes nitroreductase, azoreductase and ß-glucuronidase in rats given oral lactobacilli, was matched by a decrease (of about 50% in comparison to controls) in the excretion in urine of the reaction products of the enzymes.

    Studies on the influence of NDOs on gut bacterial enzyme activities in laboratory animals have concentrated on fructo-oligosaccharides and galacto-oligosaccharides. In conventional microflora rats fed a purified diet containing tyrosine and tryptophan, incorporation of a fructo-oligosaccharide ('Neosugar') into the diet at 0.4 - 10% reduced the faecal concentration of the potential tumour promoter p-cresol (Hidaka et al 1986). The effect was related to dose of the NDO. Higher dietary concentrations of Neosugar (up to 20%) were found to increase short chain fatty acids and total daily excretion of neutral and acid sterols (Tokunaga et al 1986).

    The effect of ingestion of trans-galactosylated oligosaccharide (TOS; 5% w/w in diet for 4 weeks) with or without Bifidobacterium breve, was studied in HFA rats (Rowland and Tanaka 1993). In the TOS-fed animals, an increase in bifidobacteria and lactobacilli numbers in the caecum was seen, associated with significant decreases in ß-glucuronidase and nitrate reductase activities, pH and the conversion of IQ to its directly genotoxic derivative 7-OHIQ. Bacterial ß-glucosidase activity was increased presumably as a consequence of elevated numbers of LAB which have a high activity of this enzyme. No evidence for additive or synergistic effects of B. breve consumption on enzyme activities was detected. In contrast, in a recent study by Rowland et al (1998) in rats given B. longum, inulin or both, an increased effect of the synbiotic combination on enzyme activities and faecal bacterial metabolites was reported. For example, feeding of B. longum alone resulted in a 30% decrease in activity of ß-glucuronidase whereas a 55% decrease was seen in rats given diet supplemented with the probiotic/prebiotic combination.

    Studies in Human Subjects

    A number of studies have been carried out on the effects of pro-, pre-, and syn-biotics on human subjects which have included measurement of bacterial enzyme activities (Table 2). Goldin and Gorbach (1984) studied volunteers consuming milk supplemented with 109 viable lactobacilli per day. Prior to lactobacillus feeding, faecal ß-glucuronidase activity ranged between 1.7-2.1 units. This declined in all 21 subjects after consumption of lactobacilli to a mean value of 1.1 units. The activity returned to baseline values 10 days after consumption of LAB ceased. Lidbeck et al (1991) supplemented the diets of 14 colon cancer patients with L. acidophilus as a fermented milk product (approximately 3x1011 lactobacilli per day) for a period of six weeks and faecal microflora, faecal bile acids and ß-glucuronidase activity were measured. Coincident with changes in microflora (an increase of lactobacilli in faeces and a decrease in the numbers of E. coli) was a 14% decrease in ß-glucuronidase activity. A decrease in total bile acids and deoxycholic acid of 15% and 18%, respectively was also observed. Similar results were obtained by Spanhaak et al (1998) who reported a significant decrease in the activity of faecal ß-glucuronidase and ß-glucosidase activity in a group of twenty healthy male subjects given L. casei (approximately 1011 CFU/day for a four week test period).

    Marteau et al (1990) studied nine healthy volunteers before (period 1), during (period 2), and after (period 3) ingesting 100g/day of a fermented milk product ('Olifus') containing L. acidophilus (107CFU/g), Bifidobacterium bifidum (108CFU/g) and Streptococcus (Lactococcus) lactis (108CFU/g) and S. cremoris (Lactococcus lactis subsp. cremoris)(108CFU/g) for three weeks. Faecal azoreductase and ß-glucuronidase activities did not change throughout the three periods. Nitroreductase activities dropped significantly in period 2 and remained at a low level during period 3. There was no change in ß-galactosidase activity but ß-glucosidase activity significantly increased in period 2 and returned to baseline levels in period 3. In vitro the dairy product showed a high ß-glucosidase activity that was related to the presence of B. bifidum. The decrease in nitroreductase activity still persisted 3 weeks after cessation of ingestion of the fermented dairy product suggesting more prolonged modifications of the colonic microflora.

    Ayebo et al (1990) assessed the effect of consumption of non-fermented milk containing Lactobacillus acidophilus (2x106 CFU/ml) on faecal ß-glucuronidase and ß-glucosidase in a cross-over study in elderly human subjects. Low fat milk was given as a control and diets were consumed for a period of four weeks. Faecal counts of lactobacilli rose during the period of probiotic consumption by approximately one order of magnitude. ß-glucuronidase activity decreased slightly after four weeks of lactobacillus feeding. Inconsistencies in ß-glucosidase activity were evident as the activity decreased from 0.9 units to 0.45 units during one period of exposure whereas during another period there was no change in activity.

    In a study on young women with premenstrual syndrome, Bertazzoni-Minelli et al., (1996) found that consumption of lyophilised L. acidophilus and B. bifidum (1 x 109 of each type of bacterium / capsule) was associated with only minor changes in ß-glucosidase and no significant effects on ß-glucuronidase.

    Effects in human studies of prebiotics and synbiotics on toxic bacterial metabolites in faeces are few and generally have yielded inconsistent or negative results. Tanaka et al (1983) reported no effect of TOS (3 or 10g/day) on faecal ammonia, but did show that simultaneous ingestion of TOS and B. breve reduced ammonia concentration in 4 out of 5 subjects.

    A study in human volunteers given soy bean oligosaccharides (SOE); (10g/day) with or without simultaneous consumption of B. breve demonstrated no significant effects on faecal pH or amino acid breakdown products (p-cresol, phenol and indole), despite changes in faecal bifidobacteria numbers (Hayakawa et al 1990).

    Anti-Genotoxicity of Probiotics and Prebiotics in vitro and in vivo

    More direct evidence for protective properties of probiotics and prebiotics against cancer has been obtained by assessing the ability of cultures to prevent DNA damage and mutations (which is considered to be an early event in the process of carcinogenesis) in cell cultures or in animals (Table 3).

    The effect of LAB on the induction of mutations by a wide variety of model carcinogens in vitro has been studied using the Ames Salmonella assay. The carcinogens used include N-nitrosocompounds N-methyl-N-nitro-N-nitrosoguanidine (MNNG) and N-methylnitrosourea (MNU) heterocyclic amines (e.g. I Q and related compounds) and aflatoxin B1. Overall the results indicate that the various LAB can inhibit genotoxicity of dietary carcinogens in vitro. The degree of inhibition was strongly species dependent. For example Pool-Zobel et al (1993) demonstrated that Lactobacillus casei and L. lactis inhibited the mutagenic activity of nitrosated beef by over 85% whereas Lactobacillus confusus (Weisella confusa) and Lactobacillus sake had no effect.

    It seems likely that these results together with similar results by other workers, are a consequence of binding of the mutagens by the LAB (Zhang et al, 1991 Bolognani et al 1997). Whether such a mechanism operates in vivo is questionable, since binding appears to be highly pH dependent and easily reversed and does not appear to affect uptake of carcinogens from the gut, neither does it have any apparent in vivo effect on mutagenicity in the liver (Bolognani et al, 1997).

    Using the technique of single cell microgel electrophoresis (Comet assay), Pool-Zobel et al (1996) investigated the ability of range of species of LAB to inhibit DNA damage in the colon mucosa of rats treated with the carcinogens MNNG or 1,2-dimethylhydrazine (DMH). All the strains of lactobacilli and bifidobacteria tested - L. acidophilus (isolated from a yoghurt), Lactobacillus gasseri, L. confusus, B. breve and Bifidobacterium longum, prevented MNNG-induced DNA damage when given at a dose of 1010 cells/kg body weight, 8 hours before the carcinogen. In most cases the DNA damage was reduced to a level similar to that in untreated rats. Streptococcus thermophilus was not as effective as the other LAB strains.

    The protective effect was dose dependent: doses of L acidophilus representing 50 and 10% of the original dose were less effective in reducing MNNG-induced DNA damage. Importantly, heat-treatment of L. acidophilus abolished its antigenotoxic potential indicating the importance of viable cells. Similar results were obtained when the LAB strains were tested in rats given DMH as the DNA damaging agent. Again, all the lactobacilli and bifidobacteria strongly inhibited DNA damage in the colon mucosa, whereas S. thermophilus was much less effective. There was evidence of strain differences in antigenotoxic effects: Of three strains of S. thermophilus, two were ineffective and one exhibited protection against DNA damage.

    The Comet assay has also been used to evaluate the effect of a prebiotic, lactulose, on DNA damage in the colonic mucosa. Rats that were fed a diet containing 3% lactulose and given DMH, exhibited less DNA damage in colon cells than similarly treated animals fed a sucrose diet. In the latter animals, the percentage of cells with severe DNA damage comprised 33% of the total compared with only 12.6% in the lactulose-fed rats (Rowland et al., 1996).

    The above results provide evidence that both LAB and prebiotics may have protective effects against the early stages of colon cancer.

    Effect of Probiotics and Prebiotics on Pre-Cancerous Lesions in Laboratory Animals (Table 4)

    Aberrant crypts (AC) are putative pre-neoplastic lesions seen in the colon of carcinogen-treated rodents. In many cases a focus of two or more crypts is seen and is termed an aberrant crypt focus (ACF). Aberrant crypts are induced in colonic mucosa of rats and mice by treatment with various colon carcinogens such as azoxymethane (AOM), DMH and IQ. The findings of significantly more ACF with four or more crypts in rats with tumours compared with those without tumours suggests that large ACF may be a predictor of eventual tumour incidence (Pretlow et al, 1992). Studies have employed various treatment regimes with differences in the sequence of exposure to carcinogen and probiotic/prebiotic to allow conclusions to be drawn about the stage of carcinogenesis affected. In the majority of studies the protocol involved feeding the probiotic for about 1 week, followed by dosing with carcinogen and then continued probiotic administration until animals were killed prior to ACF assessment. Thus the probiotic treatment covered both initiation and early promotion stages. In the 'promotion' protocol, the rats were dosed with carcinogen prior to probiotic treatment.

    Effect of Probiotic Treatment Alone

    A variety of studies have been carried out using AOM or DMH to determine the effects of specific probiotics on ACF formation. Kulkarni and Reddy (1994) reported inhibition in ACF formation of about 50% when male F344 rats were fed B. longum in the diet (1.5% and 3% of a lyophilised culture containing 2x1010CFU/g) for 5 weeks and injected subcutaneously with AOM once weekly for 2 weeks. Since dietary treatments were started 5 weeks prior to administration of the carcinogen dose results do not allow deductions to be made about the stage of carcinogenesis affected. There were no differences between the animals fed the 1.5% and 3% B. longum diets.

    A similar study was carried out by Challa et al (1997) who observed a 23% reduction in total colonic ACF and a 28% reduction in total AC in rats given a diet containing 0.5% B. longum (1x108viable cells/g of feed). Animals were fed the experimental diet before treatment with AOM and throughout the experiment.

    Abdelali et al (1995) compared the effects of Bifidobacterium species administered in diet and also fed as a fermented milk product. The amounts of organisms consumed were similar (6x109 cells/day). DMH was given 4 weeks after the LAB and the latter treatments continued for a further 4 weeks before ACF assessment. The dietary bifidobacteria appeared to be slightly more effective in reducing ACF than the bifidobacteria - fermented milk (61% and 49% reduction respectively). Interestingly however, skim milk alone reduced ACF numbers by 51%.

    Rowland et al (1998) in a study of B. longum (6x109CFU/day) in AOM-treated Sprague Dawley rats, demonstrated a significant reduction of 26% in total ACF by comparison to control animals. The changes were seen only in small ACF (1-3 AC per focus). Since the probiotic treatment began 1 week after the carcinogen exposure, the results indicate an effect on the early promotional phase of carcinogenesis.

    Not all ACF studies with probiotics have yielded positive effects. Gallagher et al (1996), who used a 'promotion' protocol with B. longum and L. acidophilus, obtained inconsistent results, which they attributed to differences in ages of rats when DMH was administered.

    Prebiotic and Synbiotic Treatments on Colonic Aberrant Crypt Foci (ACF)

    Prebiotics alone appear to give inconsistent results on carcinogen-induced ACF induction which may be partly a consequence of differences in carcinogen and treatment regimes used. For example Rao et al (1998) reported that inulin (10% in diet) had no significant effect on total ACF in the colon, or their multiplicity, in F344 rats, although curiously a significant decrease in ACF/cm2 of colon was reported. The study by Gallaher et al (1996) on Bifidobacterium species and FOS (2% in diet) gave inconsistent results with only 1 out of 3 experiments showing a decrease in DMH-induced ACF. Differences in FOS dose and carcinogen treatment regimes may be responsible for the discrepancy between this study and those of Challa et al (1997) and Rowland et al (1998).

    Reddy et al (1997) compared short- (FOS) and long-chain (inulin) oligosaccharides incorporated at a level of 10% in the diet on AOM-induced ACF in rats. The NDOs were fed before carcinogen treatment and throughout the experiment and significant decreases of approximately 25% and 35% respectively in total ACF were reported. The decreases seen were almost entirely in the smaller ACF (< 3 AC per focus) and inhibition by inulin appeared to be more pronounced than that of FOS.

    Similar results were obtained by Rowland et al (1998) who reported a decrease of 41% in small ACF when inulin (5% in diet) was given 1 week after AOM dose. No effect of inulin on large ACF was observed.

    Challa et al (1997) demonstrated a small reduction (22%) in total ACF in AOM treated F344 rats when the synthetic, non-digestible disaccharide lactulose was incorporated in the diet at 2%. Both Challa et al (1997) and Rowland et al (1998) studied the effect of combined treatment of probiotic and prebiotic on ACF numbers. The combination of B. longum and lactulose resulted in a 48% inhibition of colonic ACF, which was significantly greater than that achieved by either B. longum or lactulose alone (Challa et al, 1997). Similarly Rowland et al reported a decrease in total ACF of 74% in rats given B. longum plus inulin (by comparison to a 29% and 21% reduction achieved by B. longum or inulin alone). Importantly, the combined administration of probiotic and prebiotic reduced large ACF by 59%, whereas the individual treatments had no effect (Rowland et al, 1998).

    Effect of Probiotics and Prebiotics on Tumour Incidence in Laboratory Animals (Table 5)

    Goldin and Gorbach (1980) investigated the effect of L. acidophilus on colon tumour incidence in rats treated with DMH. A reduction in colon cancer incidence (40% vs 77% in controls) was evident in animals receiving L. acidophilus after 20 weeks but no difference was discernible at 36 weeks suggesting that the lactobacilli had increased the latency period, or induction time, for tumours.

    Administration of dietary B. longum (0.5% lyophilised B. longum in diet, 1x1010 live bacterial cells/ day) significantly inhibited the formation of IQ-induced colon and liver tumours and multiplicity (tumours/animal) of tumours in colon, liver and small intestine in male rats (Reddy and Rivenson 1993). The percentage decrease in tumour incidence was 80% in liver and 100% in colon. In female rats, dietary supplementation with Bifidobacterium cultures also decreased the IQ induced mammary carcinogenesis to 50% and liver carcinogenesis to 27% of that on the control diet, but the differences were not significant. There were however significant changes in tumour multiplicity in the mammary gland.

    A mouse model has recently been developed (Min mice) in which the animals are heterozygous for a non-sense mutation of the Apc gene, the murine homologue of APC. These mice, which develop spontaneous adenomas throughout the small intestine and colon within a few weeks have been used for testing of chemopreventive agents targeted against cancerous lesions. In one such study Min mice were fed various diets containing wheat bran, resistant starch or FOS (5.8% in diet) for 6 weeks. Tumour numbers remained unchanged from the control (fibre free diet) in the mice fed either wheat bran or resistant starch, but a significant reduction in colon tumours was observed in rats receiving the diet supplemented with FOS. Furthermore 4 out of the 10 FOS fed animals were totally free of colon tumours (Pierre et al, 1997).

    Goldin et al (1996) investigated the effect of "Lactobacillus GG" (Lactobacillus rhamnosus GG) in DMH treated rats given either before, during and after DMH exposure (initiation + promotion protocol) or after (promotion protocol) the carcinogen treatment. Using the former protocol, a significant decrease was seen in the incidence of colon tumours (71% vs 100% in control rats), and the number of tumours per tumour-bearing animal (1.7 vs 3.7 in controls). However when Lactobacillus GG was administered after DMH, no decrease in tumour incidence was seen indicating that the effect of the LAB was on initiation stage rather than on promotion stage of tumorigenesis. In this study, the rats were fed basal diets either high or low in fat content. Although the decrease in colon tumour incidence induced by the probiotic was similar on the two diets, the effects on tumour multiplicity were more pronounced in the animals fed a high fat diet.

    Probiotics and Cancer in Human Epidemiological Studies (Table 6)

    A case-control study in the Netherlands showed that certain fermented dairy products may confer a protective effect against breast cancer. The results indicated that consumption of > 225 g per day of fermented dairy products (yoghurt, buttermilk, curds and kefir) reduced the odds ratio to 0.50 (van't Veer et al, 1989).

    Results from a case-control study by Boutron et al (1996) showed a significant (P=0.03) inverse relationship between risk of large colonic adenomas in both men and women and consumption of moderate amounts (0.5 - 1 pot per day) of yoghurt. The odds ratios (OR) were 0.6 and 0.5 respectively for the two levels of yoghurt consumption. There was no relationship between colorectal cancer risk and yoghurt consumption. Other population-based case control studies have provided evidence of inverse associations of colorectal cancer risk and consumption of fermented dairy products (Young and Wolf, 1988) and yoghurt (Peters et al, 1992) and Kampmann et al (1994a) reported a non-significant inverse relationship between yoghurt consumption and colonic adenomas. This finding, however, was not confirmed in a further case control study in the Netherlands of colorectal cancer risk and fermented dairy products which revealed a small significant positive association in men (OR 1.52) and a small, non-significant inverse association in women (OR 0.77) (Kampmann et al 1994b).

    Probiotics and Cancer in Human Intervention Studies (Table 7)

    Intervention studies to evaluate the ability of probiotics to prevent cancer in humans have been based largely on the use of biomarkers for assessing cancer risk. Due their non-invasive nature, markers in faeces and urine have been mostly used. For example, the aqueous phase of human faeces (faecal water) is considered to be an important source of inducers and modulators of carcinogenesis in the colon and methods exist for assessing biological activities related to cancer risk in such samples.

    In order to determine whether the cytotoxicity and genotoxicity of faecal water were affected by a change in dairy product intake, 18 healthy males and females were shifted from their normal dairy product-rich diet to a dairy product-free diet in a cross-over design study (Glinghammar et al, 1997). Faecal water cytoxicity, analysed by the HT29 cytotoxicity assay, indicated a decrease in cell survival from 34% to 20% when dairy products were excluded from the subjects diet. This assay is considered to reflect potential tumour-promoting activity and suggests that dairy products may have beneficial effects. The comet assay (single cell gel electrophoresis) was used to analyse the genotoxicity of faecal water which indicated no differences due to dietary intervention.

    Hayatsu and Hayatsu (1993) examined the effect of 3 week oral administration of L casei in 6 healthy non-smokers on the urinary mutagenicity of dietary fried ground beef using the Ames assay (Salmonella typhimurium TA 98, with S9 mix). The 6 people were divided into two groups, one group for administration of the L. casei 3x1010cells/ day and another group for supplementation with L. casei 1.5x1011cells/ day for three weeks. Urine was collected before meat meals and 0-12 and 12-24 hour urines were collected after the meat meal. A suppressive effect of L. casei administration was observed (6-67% of the control group mutagenicity) when control urinary mutagenicity was compared to test sample results. The average decrease in activity (12 hour urine collection stage) was 47.5% and the decrease was statistically significant.

    Lidbeck et al (1992) carried out a study involving 11 subjects fed fried hamburgers as part of their diet (days 0-2) which are a source of pyrolysate mutagens detectable in urine. "Lactococcus milk" was given as a control (1010-1011/day) two days prior to dietary supplementation with fried hamburgers until 6 days after. The probiotic Lactobacillus acidophilus was given to the second group at a dose of 1-5x1011cells per day starting again two days before the hamburger addition and lasting for a further 6 days afterwards. Consumption of LAB decreased urinary excretion of mutagens by 50% to 70% and excretion of faecal mutagens was decreased by 30%.

    Increased cell proliferation in the mucosal crypts is considered to be a marker of elevated cancer risk. In a study of the effect of LAB on cell proliferation in the rectal mucosa, Biasco et al, (1991) administered six capsules containing 109 L. acidophilus and 109 B. bifidum daily for a period of 3 months to 20 patients with colonic adenomas. Four rectal biopsies were taken at baseline and after treatment, and cell proliferation in the upper part of the rectal mucosal crypts was assessed by tritiated thymidine incorporation. Overall, no significant differences were detected in crypt cell proliferation before and after treatment. Eight patients having elevated cell proliferation rates, however, showed a significant decrease in proliferation after LAB (0.21±0.03 vs 0.10±0.03, P<0.03.

    Aso et al (1995) investigated the administration of L. casei (Biolactis powder, 3g/day) on the recurrence of superficial transitional cell carcinoma of the bladder after trans-urethral resection in 125 patients. In patients with either primary multiple tumours or single recurrent tumours, the recurrence free rate increased from 54.9% in placebo group to 79.2% in the L. casei group. There was no significant effect however in patients with recurrent multiple tumours, who had very poor prognosis. The authors suggest that a stimulation of the immune system by the lactobacilli may be an important factor in its effect on the patients.

    Mechanisms of Anticarcinogenicity and Antigenotoxicity

    Binding of Carcinogens

    There are a large number of reports describing the adsorption or binding in vitro by LAB and other intestinal bacteria, of a variety of food-borne carcinogens including the heterocyclic amines formed during cooking of meat, the fungal toxin Aflatoxin B1, benzo(a)pyrene and the food contaminant AF2 (Morotomi and Mutai, 1986; Orrhage et al 1994; Zhang et al 1990; Zhang and Ohta 1991; Bolognani et al 1997). In several of these studies, a concomitant decrease in mutagenicity was reported. The extent of the binding was dependent on the mutagen and bacterial strain used, in general greatest binding was seen with the heterocyclic amines and least with Aflatoxin B1 and AF2. The adsorption appeared to be a physical phenomenon, mostly due to a cation exchange mechanism.

    However, although binding represents a plausible mechanism for the inhibition of genotoxicity and mutagenicity by LAB in vitro, it does not appear to have any influence in vivo. Bolognani et al (1997) demonstrated that simultaneous administration to mice of LAB with various carcinogens had no effect on absorption of the compounds from the gastrointestinal tract, nor did it affect the in vivo mutagenicity of the carcinogens in the liver. It should be noted that these results conflict with those of Zhang and Ohta (1993), who found that absorption from the rat small intestine of Trp-P-1 was significantly reduced by co-administration of freeze-dried LAB. However, the latter study was confounded by the use of rats that had been starved for 4 days, which would induce severe nutritional and physiological stresses on the animals.

    Effects on Bacterial Enzymes, Metabolite Production

    The studies listed in Tables 1 and 2 demonstrate that the increase in concentration of LAB as a consequence of consumption of LAB and/or prebiotics leads to decreases in certain bacterial enzymes purported to be involved in synthesis or activation of carcinogens, genotoxins and tumour promoters. This would appear to be due to the low specific activity of these enzymes in LAB (Saito et al 1992). Such changes in enzyme activity or metabolite concentration have been suggested to be responsible for the decreased level of preneoplastic lesions or tumours seen in carcinogen-treated rats given pro and pre biotics (Reddy and Rivenson 1993; Rowland et al 1998). Although a causal link has not been demonstrated, this remains a plausible hypothesis.

    Stimulation of Protective Enzymes

    Many of the food-borne carcinogens such as heterocyclic amines and polycyclic aromatic hydrocarbons, are known to be conjugated to glutathione, which appears to result in inactivation. The enzyme involved, glutathione transferase (GSH), is found in the liver and in other tissues including the gut. Challa et al (1997) in a study of the effect of B. longum and lactulose on AOM-induced ACF in the colon, showed that the activity of GSH in the colonic mucosa was inversely related to the ACF numbers. Such a mechanism of protection would be effective against a wide range of dietary carcinogens

    Increase in Immune Response

    Another mechanism suggested by Perdigon et al (1998) by which probiotics exert anti-tumour activity is by reducing the inflammatory immune response. In a study of tumour growth in DMH treated mice, yoghurt was found to suppress the inflammatory immune response with an increase in IgA secreting cells and in CD4+ T lymphocytes. In those animals, a marked reduction in tumours was seen. An immune mechanism was also proposed to explain the increase in time before tumour recurrence in bladder cancer patients given L. casei (Aso et al 1995) although no supporting evidence for the mechanism was presented.

    Such studies are consistent with the work of Schiffrin et al (1996) and Marteau et al (1997) who have provided evidence of modulation of the immune system in human subjects consuming probiotics. The changes seen were increased phagocytic activity of monocytes and granulocytes and increases in levels of antibody secreting cells. The significance of these changes in relation to tumour development has not been established.

    Conclusions

    Overall, studies in in vitro systems and in a wide range of animal models provide considerable evidence that probiotics, and to a lesser extent prebiotics, have the potential to reduce colon cancer risk. The evidence from humans is less compelling, but nevertheless is suggestive of a cancer-preventing effect of fermented foods. Clearly what is now needed, are carefully controlled intervention studies in human subjects using biomarkers of cancer risk. The data from animal studies would suggest that using a combination of pro- and prebiotics may be the most effective strategy to maximize any anticarcinogenic effects.

    Acknowledgements

    Anthony J. Burns acknowledges with thanks the support of St Ivel Ltd.


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    Hayakawa, K., Mizutani, J., Wada, K., Masai, T., Yoshihara, I., and Mitsuoka, T. 1990. Effects of soybean oligosaccharides on human faecal microflora. Microb. Ecol. Health Dis. 3: 293-303.

    Hayatsu, H., and Hayatsu, T. 1993. Suppressing effect of Lactobacillus casei administration on the urinary mutagenicity arising from ingestion of fried ground beef in the human. Cancer Lett. 73: 173-179.

    Hidaka, H., Eida, T., Takizawa, T., Tokunga, T., and Tashiro, Y. 1986. Effects of fructooligosaccharides on intestinal flora and human health. Bifidobacteria Microflora. 5: 37-50.

    Kampmann, E., Giovanucci, van't Veer, P., Rimm, E., Stampfer, M.J., Colditz, G.A., Kok, F.J., and Willett, W.C. 1994(a). Calcium, vitamin D, dairy foods, and the occurrence of colorectal adenomas among men and women in two prospective studies. Am. J. Epidem. 139: 16-29.

    Kampman, E., van't Veer, P., Hiddink, G.J., van Aken-Schneijder, P., Kok, F.J., and Hermus, R.J. 1994(b). Fermented dairy products, dietary calcium and colon cancer: a case-control study. Int. J. Cancer. 59: 170-176.

    Kulkarni, N., and Reddy, B.S. 1994. Inhibitory effect of Bifidobacterium longum cultures on the azoxymethane induced aberrant crypt foci formation and faecal bacterial ß-glucuronidase. Proc. Soc. Exp. Biol.Med. 207: 278-283.

    Lidbeck, A., Geltner Allinger, U., Orrhage, K.M., Ottova, L., Brismar, B., Gustafsson, J.A., Rafter, J.J., and Nord, C.E. 1991. Impact of Lactobacillus acidophilus supplements on the faecal microflora and soluble faecal bile acids in colon cancer patients. Microbial Ecol. Health Dis. 4: 81-88.

    Lidbeck, A., Nord, C.E., Gustafsson, J.A., and Rafter, J. 1992. Lactobacilli, anticarcinogenic activities and human intestinal microflora. Eur. J. Cancer Prevention. 1: 341-353.

    Marteau, P., Pochart, P., Flourie, B., Pellier, P., Santos, L., Desjeux, J-H., and Rambaud, J-C. 1990. Effect of chronic ingestion of a fermented dairy product containing Lactobacillus acidophilus and Bifidobacterium bifidum on metabolic activities of the colonic flora in humans. Am. J. Clin. Nutr. 52: 685-688.

    Marteau P, Vaerman JP, Dehennin JP, Bord S, Brassart D, Pochart P, Desjeux JF, and Rambeau JC 1997. Effects of intrajejunal perfusion and chronic ingestion of Lactobacillus johnsonii strain La1 on serum concentrations and jejunal secretions of immunoglobulins and serum proteins in healthy humans. Gastroenterol. Clin. Biol. 21: 293-298

    Massey, R.C., Key, P.E., Mallett, A.K., and Rowland, I.R. 1988. An investigation of the endogenous formation of apparent total N-nitroso compounds in conventional microflora and germ-free rats. Fd Chem. Toxicol. 26: 595-600.

    Morotomi, M., and Mutai, M. 1986. In vitro binding of potent mutagenic pyrolyzates to intestinal bacteria. J.Natl.Cancer. Inst. 77: 195-201.

    Orrhage, K., Sillerstrom, E., Gustafsson, J.-Å., Nord, C.E., and Rafter, J. 1994. Binding of mutagenic heterocyclic amines by intestinal and lactic acid bacteria. Mutat. Research. 311: 239-248.

    Perdigon, G., Valdez, J.C., and Rachid, M. 1998 Antitumour activity of yoghurt: study of possible immune mechanisms. J. Dairy Res. 65: 129-138.

    Peters, R.K., Pike, M.C., Garabrant, D., and Mack, T.M. 1992. Diet and colon cancer in Los Angeles County, California. Cancer Causes and Control. 3: 457-473.

    Pierre, F., Perrin, P., Champ, M., Bornet, F., Meflah, K., and Menanteau, J. 1997. Short-chain fructo-oligosaccharides reduce the occurrence of colon tumours and develop gut associated lymphoid tissue in Min mice. Cancer Research. 57: 225-228.

    Pool-Zobel, B.L., Munzner, R., and Holzaapfel, H. 1993. Antigenotoxic properties of lactic acid bacteria in the S. typhimurium Mutagenicity assay. Nutr Cancer. 20: 261-270.

    Pool-Zobel, B.L., Neudecker, C., Domizlaff, I., Ji, S., Schillinger, U., Rumney, C., Moretti, M., Vilarini, I., Scasellati-Sforzolini, R., and Rowland, I.R. 1996. Lactobacillus and Bifidobacterium mediated antigenotoxicity in the colon of rats. Nutr Cancer. 26: 365-380.

    Pretlow, T.P., O'Riordan, M.A., Somitch, G.A., Amini, S.B., and Pretlow, T.G. 1992. Aberrant crypts correlate with tumour incidence in F344 rats treated with azoxymethane and phytate. Carcinogenesis. 13: 1509-1512.

    Rao, C.V., Chou, D., Simi, B., Ku, H., and Reddy, B.S. 1998. Prevention of colonic aberrant crypt foci and modulation of large bowel microbial activity by dietary coffee fiber, inulin and pectin. Carcinogenesis. 19: 1815-1819.

    Reddy, B.S., Weisburger, J.H., Narisawa, T., and Wynder, E.L. 1975. Colon carcinogenesis in germfree rats with 1,2-dimethylhydrazine and N-methyl-N-nitro-N-nitrosoguanidine. Cancer Research. 74: 2368-2372.

    Reddy, B.S., and Rivenson, A. 1993. Inhibitory effect of Bifidobacterium longum on colon, mammary, and liver carcinogenesis induced by 2-amino-3-methylimidazo[4,5,-f]quinoline, a food mutagen. Cancer Research. 53: 3914-3918.

    Reddy, B.S., Hamid, R., and Rao, C.V. 1997. Effect of dietary oligofructose and inulin on colonic preneoplastic aberrant crypt foci inhibition. Carcinogenesis. 18: 1371-1374.

    Rowland, I.R., and Tanaka, R. 1993. The effects of transgalactosylated oligosaccharides on gut flora metabolism in rats associated with a human faecal microflora. J. Appl. Bact.. 74: 667-674.

    Rowland. I. R. 1995.Toxicology of the colon - role of the intestinal microflora. In: Human Colonic Bacteria, Role in Nutrition, Physiology and Pathology. Macfarlane, G T and Gibson, G (Ed) CRC Press Boca Raton, FL. pp 155-174.

    Rowland, I.R., Rumney, C.J., Coutts, J.T., and Lievense, L.C. 1998. Effect of Bifidobacterium longum and inulin on gut bacterial metabolism and carcinogen-induced aberrant crypt foci in rats. Carcinogenesis. 19: 281-285.

    Rowland, I.R., and Gangolli, S.D. 1999. Role of gastrointestinal flora in the metabolic and toxicological activities of xenobiotics. In: General and Applied Toxicology, 2nd Edition, Ballantyne B, Marrs TC and Syverson T (eds) Macmillan Publishers Ltd, London, p. 561-576.

    Rumney, C.J., Rowland, I.R., Coutts, T.M., Randerath, K., Reddy, R., Shah, A.B., Ellul, A., and O'Neill, I.K. 1993. Effects of risk-associated human dietary macrocomponents on processes related to carcinogenesis in human-flora-associated (HFA) rats. Carcinogenesis. 14: 79-84.

    Saito, Y., Takano, T., and Rowland, I.R. 1992. Effects of soybean oligosaccharides on the human gut microflora in in vitro culture. Microb. Ecol. Health Dis. 5: 105-110.

    Sanders, M.E. 1993. Effect of consumption of lactic cultures on human health. Adv. Fd Nutr. Research. 37: 67-130.

    Schiffrin, E., Rochat, F., Link-Amster, H., Aeschlimann, J., and Donnet-Hughes, A. 1996. Immunomodulation of blood cells following ingestion of lactic acid bacteria. J Dairy Sci. 78: 491-497

    Silvi, S., Rumney, C.J., Cresci, A., and Rowland, I.R. 1990. Resistant starch modifies gut microflora and microbial metabolism in human flora-associated rats inoculated with faeces from Italian and UK donors. J. Appl. Microbiol. 86: 521-530.

    Spanhaak, S., Havenaar, R., and Schaafsma, G. 1998. The effect of consumption of milk fermented by Lactobacillus casei strain Shirota on the intestinal microflora and immune parameters in humans. Eur. J. Clin. Nutr. 52: 899-907.

    Tanaka, R., Takayama, H., Morotomi, M., Kuroshima, T., Ueyama, S., Matsumoto, K., Kuroda, A., and Mutai, M. 1983. Effects of administration of TOS and Bifidobacterium breve 4006 on the human faecal flora. Bifidobacteria Microflora. 2: 17-24.

    Tokunga, T., Oku, T., and Hoysoya, N. 1986. Influence of chronic intake of new sweetener fructooligosaccharide (Neosugar) on growth and gastrointestinal function of the rat. J. Nutr. Sci. Vitaminol. 32: 111-121.

    Venturi, M., Hambly, R.J., Glinghammar, B., Rafter, J.J., and Rowland, I.R. 1997. Genotoxic activity in human faecal water and the role of bile acids: a study using the alkaline comet assay. Carcinogenesis. 18: 2353-2359.

    Van't Veer, P., Dekker, J.M., Lamers, J.W.J., Kok, F.J., Shouton, E.G., Brants, H.A.M., Sturmans, F., and Hermus, R.J.J. 1989. Consumption of fermented milk products and breast cancer: A case-control study in the Netherlands. Cancer Research. 49: 4020-4023.

    Young, T.B., and Wolf, D.A. 1988. Case-control study of proximal and distal colon cancer and diet in Wisconsin. Int. J. Cancer. 42: 167-175.

    Zhang, X.B., Ohta, Y., and Hosono, A. 1990. Antimutagenicity and binding of lactic acid bacteria from a Chinese cheese to mutagenic pyrolyzates. J. Dairy. Sci. 73: 2702-2710.

    Zhang, X.B., and Ohta, Y. 1991. In vitro binding of mutagenic pyrolyzates to lactic acid bacterial cells in human gastric juice. J. Dairy. Sci. 74: 752-757.

    Zhang, X.B., and Ohta, Y. 1993. Microorganisms in the gastrointestinal tract of the rat prevent absorption of the mutagen-carcinogen 3-amino-1,4-dimethyl-5H-pyrido(4,3-b)indole. Can. J. Microbiol. 39: 841-845.

    http://www.floridral.dk/images/image_bacteria_1.jpg


    THIS IS SPECIFIC TO A CERTAINS STRAIN OF LACTOBACILLUS

    Lactobacillus rhamnosus GG (ATCC 53103)


    It is important to have the RIGHT KIND of bacteria, not simply "eat more yoghurt"
    http://www.probiotic.org/ has a list.
    The effect of Lactobacillus THAMNOSUS for example, here in a PubMed search:
    http://www.ncbi.nlm.nih.gov/pubmed?term=rhamnosus%20carcinogens


    The influence of Lactobacillus rhamnosus LC705 together with Propionibacterium freudenreichii ssp. shermanii JS on potentially carcinogenic bacterial activity in human colon.

    Hatakka K, Holma R, El-Nezami H, Suomalainen T, Kuisma M, Saxelin M, Poussa T, Mykkänen H, Korpela R.

    Int J Food Microbiol. 2008 Dec 10;128(2):406-10. Epub 2008 Sep 27.

    PMID:
        18945506
        [PubMed - indexed for MEDLINE]

    2.

    Specific strains of probiotic bacteria are efficient in removal of several different cyanobacterial toxins from solution.

    Nybom SM, Salminen SJ, Meriluoto JA.

    Toxicon. 2008 Aug 1;52(2):214-20. Epub 2008 May 29.

    PMID:
        18639912
        [PubMed - indexed for MEDLINE]


    3.

    Effect of glucose in removal of microcystin-LR by viable commercial probiotic strains and strains isolated from dadih fermented milk.

    Nybom SM, Collado MC, Surono IS, Salminen SJ, Meriluoto JA.

    J Agric Food Chem. 2008 May 28;56(10):3714-20. Epub 2008 May 7.

    PMID:
        18459790
        [PubMed - indexed for MEDLINE]


    4.

    Evidence for in vitro anti-genotoxicity of cheese non-starter lactobacilli.

    Caldini G, Trotta F, Corsetti A, Cenci G.

    Antonie Van Leeuwenhoek. 2008 Jan-Feb;93(1-2):51-9. Epub 2007 Jun 21.

    PMID:
        17588126
        [PubMed - indexed for MEDLINE]

    Related citations
    5.

    Removal of microcystin-LR by strains of metabolically active probiotic bacteria.

    Nybom SM, Salminen SJ, Meriluoto JA.

    FEMS Microbiol Lett. 2007 May;270(1):27-33. Epub 2007 Jan 30.

    PMID:    17263839
        [PubMed - indexed for MEDLINE]

    Related citations
    6.

    Probiotic supplementation reduces a biomarker for increased risk of liver cancer in young men from Southern China.

    El-Nezami HS, Polychronaki NN, Ma J, Zhu H, Ling W, Salminen EK, Juvonen RO, Salminen SJ, Poussa T, Mykkänen HM.

    Am J Clin Nutr. 2006 May;83(5):1199-203.

    PMID:    16685066
        [PubMed - indexed for MEDLINE]

    Free Article


    7.

    The elimination of ochratoxin A by lactic acid bacteria strains.

    Piotrowska M, Zakowska Z.

    Pol J Microbiol. 2005;54(4):279-86.

    PMID:     16599298
        [PubMed - indexed for MEDLINE]

      8.

    Screening of potential lactobacilli antigenotoxicity by microbial and mammalian cell-based tests.

    Caldini G, Trotta F, Villarini M, Moretti M, Pasquini R, Scassellati-Sforzolini G, Cenci G.

    Int J Food Microbiol. 2005 Jun 25;102(1):37-47.

    PMID:    15925000
        [PubMed - indexed for MEDLINE]

    9.

    Removal of the cyanobacterial toxin microcystin-LR by human probiotics.

    Meriluoto J, Gueimonde M, Haskard CA, Spoof L, Sjövall O, Salminen S.

    Toxicon. 2005 Jul;46(1):111-4.

    PMID:    15922388
        [PubMed - indexed for MEDLINE]

    Related citations 10.

    Intestinal immunity of rats with colon cancer is modulated by oligofructose-enriched inulin combined with Lactobacillus rhamnosus and Bifidobacterium lactis.

    Roller M, Pietro Femia A, Caderni G, Rechkemmer G, Watzl B.

    Br J Nutr. 2004 Dec;92(6):931-8.

    PMID:     15613255
        [PubMed - indexed for MEDLINE]

    11.

    Fecal water genotoxicity is predictive of tumor-preventive activities by inulin-like oligofructoses, probiotics (Lactobacillus rhamnosus and Bifidobacterium lactis), and their synbiotic combination.

    Klinder A, Förster A, Caderni G, Femia AP, Pool-Zobel BL.

    Nutr Cancer. 2004;49(2):144-55.

    PMID:    15489207
        [PubMed - indexed for MEDLINE]

    Related citations 12.

    Chemical moieties and interactions involved in the binding of zearalenone to the surface of Lactobacillus rhamnosus strains GG.

    El-Nezami H, Polychronaki N, Lee YK, Haskard C, Juvonen R, Salminen S, Mykkänen H.

    J Agric Food Chem. 2004 Jul 14;52(14):4577-81.

    PMID:     15237970
        [PubMed - indexed for MEDLINE]

    13.

    Lactic acid bacteria isolated from dairy products inhibit genotoxic effect of 4-nitroquinoline-1-oxide in SOS-chromotest.

    Cenci G, Rossi J, Trotta F, Caldini G.

    Syst Appl Microbiol. 2002 Dec;25(4):483-90.

    PMID:
        12583707
        [PubMed - indexed for MEDLINE]

    14.

    Antitumorigenic activity of the prebiotic inulin enriched with oligofructose in combination with the probiotics Lactobacillus rhamnosus and Bifidobacterium lactis on azoxymethane-induced colon carcinogenesis in rats.

    Femia AP, Luceri C, Dolara P, Giannini A, Biggeri A, Salvadori M, Clune Y, Collins KJ, Paglierani M, Caderni G.

    Carcinogenesis. 2002 Nov;23(11):1953-60.

    PMID:     12419846
        [PubMed - indexed for MEDLINE]

    Free Article

    15.

    A probiotic strain of L. acidophilus reduces DMH-induced large intestinal tumors in male Sprague-Dawley rats.

    McIntosh GH, Royle PJ, Playne MJ.

    Nutr Cancer. 1999;35(2):153-9.

    PMID:    10693169
        [PubMed - indexed for MEDLINE]

    16.

    Ability of dairy strains of lactic acid bacteria to bind a common food carcinogen, aflatoxin B1.

    El-Nezami H, Kankaanpaa P, Salminen S, Ahokas J.

    Food Chem Toxicol. 1998 Apr;36(4):321-6.

    PMID: 9651049
        [PubMed - indexed for MEDLINE]

    17.

    The effect of Lactobacillus GG on the initiation and promotion of DMH-induced intestinal tumors in the rat.

    Goldin BR, Gualtieri LJ, Moore RP.

    Nutr Cancer. 1996;25(2):197-204.

    PMID: 8710689
        [PubMed - indexed for MEDLINE]


    http://www.healthchemist.co.nz/mm5/graphics/00000001/large_918446.jpg

    This product may have a lot of ingredients, but do the bacteria come back to live? 
    Why this weird mix?

    Natures Sunshine Sunshine Heroes Probiotic Powder Chews 90

    Benefits:

    • Aids digestion and intestinal function.

    • Strengthens immune response.

    Sunshine Heroes Probiotic Power [Digestive, Intestinal]. The human body relies on a healthy level of probiotics for numerous functions, including metabolizing foods, absorbing nutrients, and maintaining a proper balance of intestinal flora. Probiotic microbes have a symbiotic relationship with their human hosts—both the probiotics and the humans benefit from their relationship.

    It is estimated that over 400 different types of normal flora inhabit the human gastrointestinal and genitourinary tracts. Studies have shown that children age 1 to 6 years old who attended day care centers and were given milk containing Lactobacillus rhamnosus missed fewer days of day care than children not receiving the probiotic. Studies have also shown that a healthy intestinal bacterial colonization may reduce the risk of food allergies in infants. Researchers have also found that probiotics aid digestion.

    Probiotic Power contains 1 billion friendly cultures from 11 strains of probiotics, including Lactobacillus rhamnosus, Bifidobacterium bifidus, L. acidophilus, L. brevis, L. bulcaricus, L. plantarum, Streptococcus thermophilus, B. infantis, B. longum, L. casei and L. salivarius.
    What else should I know?
    Classification:
    General Sale

    Active Ingredients:

    %Daily Value %Daily Value

    Amount Per 1 Chewable Tablet Kids 2-3 Kids 4 & over

    Proprietary Probiotic Blend 1 Billion CFU

    Bifidobacterium bifidum, Bifidobacterium infantis, Bifidobacterium longum, Lactobacillus rhamnosus, Lactobacillus acidophilus, Lactobacillus bulgaricus, Lactobacillus brevis, Lactobacillus plantarum, Lactobacillus salivarius, Lactobacillus casei, Streptococcus thermophilus.

    Protector Shield Proprietary Blend 100 mg

    Whole Food Complex: Mangosteen fruit (Garcinia mangostana), Cranberry fruit (Vaccinium macrocarpon), Broccoli flower (Brassica oleracea), Spinach leaves and stems (Spinacia oleracea), Asparagus stems (Asparagus officinalis), Carrot root (Daucus carota), Tomato fruit (Solanumly copersicum), Acai fruit (Euterpe oleracea), Pomegranate fruit extract (Punica granatum).

    Fruit Juice Concentrates: White Grape, Apple, Pear, Orange, Pineapple, Cherry, Strawberry, Blueberry.

    MicroNutrients: L-leucine, L-lysine, L-valine, Choline bitartate, Inositol, L-isoleucine, L-threonine, L-phenylalanine, L-arginine, L-cysteine, L-methionine, L-tyrosine.

    Other Ingredients: Sorbitol, Mannitol, Xylitol, Fructose, FOS (short and long chain), Stearic acid, Beet root extract (Beta vulgaris), natural flavors combinations (including Orange, Blueberry, Raspberry, and Strawberry), Magnesium stearate.

    Dosage:
    Chew 1 to 2 tablets daily as a dietary supplement. Chew carefully and thoroughly before swallowing.