Bioecological and Nutritional Control of Disease - Prebiotics, Probiotics

8/14/2019 Bioecological and Nutritional Control of Disease - Prebiotics, Probiotics

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CONTROL BIOECOLGICO Y NUTRICIONALDE LA ENFERMEDAD: PREBITICOS,

PROBITICOS Y SIMBITICOS

ResumenUn nmero creciente de pacientes en todo el mundo sufre de

enfermedades agudas y crnicas. Evidencias actuales apoyan la

asociacin de las enfermedades crnicas con los hbitos de vida

moderna y la disfuncin del sistema inmunolgico. La morbilidad y

mortalidad de los pacientes afectados de enfermedades crnicas

son inaceptablemente elevadas a pesar de los avances en los trata-

mientos mdicos y quirrgicos. Actualmente, existe un inters ele-

vado en el control bioecolgico y nutricional de las enfermedades.

El uso de prebiticos, probiticos y simbiticos tales como antioxi-

dantes, emulsiones lipdicas antiinflamatorias de cidos grasos

omega-3, fibras bioactivas, bacterias del cido lctico (LAB), etc.,

aparece como una nueva herramienta para el tratamiento de la

enfermedad. Los efectos de los antioxidantes y de las emulsioneslipdicas de cidos grasos omega-3 an estn ampliamente inexplo-

rados, pero se conocen sus efectos moduladores sobre los neutrfi-

los y la morbilidad. Es muy significativo que estos compuestos se

estn utilizando en el tratamiento de pacientes crticos, incluidos los

pacientes quirrgicos. Algunas fibras bioactivas y algunas bacte-

rias probiticas han demostrado una extraordinaria eficacia para

restaurar y mantener la inmunidad y prevenir las complicaciones.

Las LAB han demostrado su capacidad para reducir o eliminar

microorganismos potencialmente patognicos, as como varias

toxinas, mutgenos y carcingenos; tambin promueven la apopto-

sis, sintetizan y liberan numerosos nutrientes, antioxidantes, facto-

res de crecimiento, compuestos implicados en la coagulacin y

otros compuestos bioactivos, y modulan los mecanismos de defensa

inmunolgica innata y adaptativa. Estudios ms recientes sugierenque las LAB promueven y mantienen la motilidad gastrointestinal

(GI) y previenen la parlisis GI y el leo postoperativo, y tienen la

capacidad de inhibir la inflamacin. Se necesitan estudios ulterio-

res para determinar los mecanismos moleculares por los cuales los

prebiticos, probiticos y simbiticos influencian la recuperacin

de los pacientes en una amplia variedad de enfermedades agudas y

crnicas.

(Nutr Hosp 2006, 21:72-84)

Palabras clave: Prebiticos. Probiticos. Simbiticos. Bac-terias de cido lctico. Microbiota. Flora intestinal.

Artculo

Bioecological and nutritional control of disease: prebiotics, probiotics

and synbioticsS. Bengmark1 and A. Gil2

1Departments of Hepatology and Surgery, Institute of Hepatology. University College London Medical School, 69-75 Chenies Mews.London. WC1E 6HX. United Kingdom and2Department of Biochemistry and Molecular Biology II, School of Pharmacy. Universityof Granada. Spain.

Nutr. Hosp. (2006) 21 (Supl. 2) 72-84ISSN 0212-1611 CODEN NUHOEQ

S.V.R. 318

Correspondence: ngel GilDepartment of Biochemistry and Molecular BiologySchool of PharmacyCampus de Cartuja18071 Granada (Spain)E-mail: [email protected]

Abstract

A growing number of patients worlwide suffer acuteand chronic diseases. Evidence supports the associationof chronic diseases to modern lifestyle habits and mal-

function of the immune system. Morbidity and mortalityfor patients affected of chronic diseases is unacceptablyhigh despite advanced surgical and medical treatments.Nowadays there is an increasing interest in the bioecolo-gical and nutritional control of diseases. The use of pre-biotics, probiotics and synbiotics, e.g. antioxidants, anti-inflammatory -3 lipid emulsions, bioactive fibers, lacticacid bacteria (LAB), etc, appears as a new tool for the tre-atment of disease. The effects of antioxidants and -3lipid emulsions remain largely unexplored, but signifi-cant modulatory effects on neutrophils and morbidityhave been observed. It is burning that these compoundsare tried in patients including surgically and critically illpatients. Some bioactive fibers and some probiotic bacte-

ria have demonstrated extraordinary efficacy to restoreand maintain immunity and prevent complications. Lac-tic acid bacteria (LAB) have demonstrated ability toreduce or eliminate potential pathogen micro-organisms,as well as various toxins, mutagens and carcinogens; theyalso promote apoptosis, synthesize and release numerousnutrients, antioxidants, growth-factors, coagulation andother bioactive compounds, and modulate the innate andadaptive immune defence mechanisms. More recent stu-dies suggest that LAB promote and maintain gastrointes-tinal (GI) motility and prevent GI paralysis and postope-rative ileus and have the ability to inhibit inflammation.Further studies are needed to ascertain the molecularmechanisms by which pre-, pro- and synbiotics influencethe outcome in a variety of acute and chronic diseases.

(Nutr Hosp 2006, 21:72-84)

Key words: Prebiotics. Probiotics. Synbiotics. Lactic acidbacteria. Microbiota. Intestinal flora.


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Introduction

A Tsunami of chronic illness and a Katrina

of critical ilness

It is well known that the majority of individuals, whosuffer acute diseases, are elderly and are affected byone or several chronic illnesses, and have signs of a

malfunctional immune system resulting in reducedresistance to disease. The World Health Organizationestimates that 46% of global disease burden and 59%of global mortality is due to chronic diseases (ChDs);35 million individuals die each year from chronic dise-ases, and it is steadily increasing1. The increase, whichseems to have began at the time of the industrial revo-lution e.g. the middle of the 1850s, was during firsthundred years relatively slow, but has in recent deca-des obtained epidemic proportions.

Circumstantial evidence supports the association ofChDs to modern life style, stress, lack of exercise,abuse of tobacco and alcohol, and to the transition from

natural unprocessed foods to processed, calorie-con-densed and heat-treated foods. The association betwe-en reduced intake of plant fibers, plant antioxidants,increased consumption of dairy products, refinedsugars and starch products and increases in both ChDs,and CI, is obvious. The per capita consumption of refi-ned sugar has increased from about 0.5 kg per personand year in 1850 to about 50 kg/person/year in the year2000 and the per cow milk production from 2 to 50l/day. Dairy products, especially milk and cheese (80%of the milk is from pregnant cows) are rich in proin-flammatory molecules: hormones especially sex hor-mones and growth factors such as IGF-1. Heating up

makes it also rich in advanced glycation (AGEs) andlipoxidation (ALEs) products, which also are highlyproinflammatory 2, 3. This information is important asmany enteral nutrition solutions are based on milkpowders. Bread, especially from gluten-containinggrains, is also rich in molecules with documented pro-inflammatory effects4-6.

Advanced surgical and medical treatments, as wellas medical and surgical emergencies are, despite somebreath-taking advances in medico-pharmaceutical andsurgical treatment still affected by an unacceptablyhigh morbidity and mortality. And what is worse, bothmorbidity and mortality in critical illness is fast increa-sing and has done so for several decades. With a docu-mented 1.5% rate of increase per year it has the poten-tial to double within the coming 50 to 60 years. Sepsisis the most common medical and surgical complica-tion, estimated only in the US to annually affect asmany as 751,0007,8, and cause death of approximately215,000 patients (29%)7, which makes sepsis the tenthmost common cause of death in the country. And, mostworrying, the incidence seems to be rising with appro-ximately 1.5% per year, which most likely reflects adecreasing resistance to disease in the Society, but alsothe ineffectiveness of prophylactic and preventive

measures, including prophylactic antibiotics. Presentlyavailable treatment options: antibiotics and antago-nists/inhibitors of individual pro-inflammatory cytoki-nes have not met the early high expectations. Instead,these treatments have often instituted new complica-tions and new morbidities. Selective bowel decontami-nation e.g. parallel parenteral and topical application ofa handful of powerful antibiotics is no longer a treat-

ment option.The main goal of the present article is to review the

potential use of prebiotics, probiotics and synbiotics asan alternative to conventional treatments for both ChDs and critical diseases.

Premorbid health determines outcome

The majority of patients suffering critical illness havebefore the acute critical illness occurs signs of a failingimmune system. About half of the patients affected bysepsis are in the age group of > 65 years, and 48% of the

patients are neutropenic9. Both microbiota and liningmucosal cells have endocrine functions and are producingand responding to hormones. The gastrointestinal (GI)tract contains 100 million neurons, which is equal to thenumber of neurons in the spinal cord, distributed throughall layers of the GI tract10, and exerting strong effects onboth immune cells and microbiota, hereby affectinghomeostasis of the immune system and resistance to dise-ase. A series of experiment have demonstrated an up to100,000 times (5 logs of order) increase in growth ofGram-negative bacteria exposed to noradrenaline11, whichexplains a relatively old observation of significantly hig-her blood levels of noradrenaline and adrenaline in

patients, who develop severe septic conditions comparedto patients with an uncomplicated postoperative course12.Luminal release of noradrenaline is a strong inducer ofincreased virulence of luminal bacteria13, and much sug-gest that potentially pathogenic micro-organisms (PPMs),normally indolent colonizers, under stress change theirphenotype and become life-threatening pathogens14.

Our knowledge about the innate immune system andits function and our understanding of resistance to dise-ase has increased significantly over the last 10-15years. Solid evidence suggests that outcome after lar-ger surgical operations as well as in medical emergen-cies is intimately associated with premorbid health andstrength of the immune system, and reflected by thespeed and depth of functional deterioration during theearly few hours after trauma.

Reducing and preventing immunoparesis

Highest priority should be given, to the extent possi-ble, to early efforts to avoid and minimize treatments,which will deepen the subsequent, to some extent una-voidable, immunoparesis such as use of drugs, inclu-ding antibiotics, parenteral nutrition, both glucose and

Bioecological and nutritional control ofdisease

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macromolecules, stored blood, drains and tubes andefforts to reduce mechanical manipulation of tissues,both surgical and mechanical ventilation see furt-her15,16.Enteral supply of nutrients must also be donewith care, and nutrition solutions which increasesblood glucose levels be avoided, as hyperglycemia isassociated with neutrophil dysfunction17 and signifi-cantly increase infection and mortality rates, as

demonstrated in trauma patients18. Also commercialenteral nutrition solutions rich in proinflammatorymolecules containing dairy-derived proinflammatorymolecules, should be avoided. Total parenteral solu-tions and some commercial enteral diets have in animalexperiments been shown to activate iNOS and disruptthe gut barrier function and the intestinal micromicro-biota and induce bacterial translocation, see further19.Hospital-produced nutrition formulas, made of freshfruits, vegetables, especially legumes, and fish/meat,and probably more suitable for enteral nutrition, havefor questionable hygienic and efficiency reasons beenabandoned at hospitals in the developed world. Contro-

lled clinical studies comparing the effects standardnutrition solutions and hospital-made nutrition solu-tions on immunity and outcome are most desirable. Arecent meta-analysis based on twenty peer-reviewedarticles and >13,000 patients reports an average 3.5times increase in postoperative infections in surgicalpatients receiving allogenic blood transfusion20.

Stress/acute and chronic phase response involvesnumerous molecules and pathways and affects multi-ple functions. Most pharmaceutical drugs designed toprevent inflammation are constructed to specificallyblock one molecule or pathway, which seem to explainwhy the success have been and will continue to be limi-

ted both in acute and chronic inflammatory conditions.The bodys acute phase response possesses numerouspathways, which effectively will by-pass pharmaceuti-cally inhibited functions. Bioecological control, e.g. touse of antioxidants, anti-inflammatory-3 lipid emul-sions, bioactive fibers and probiotic bacteria has theadvantage of modulating all pathways in parallel.

The effects of antioxidants and -3 lipid emulsionsremain largely unexplored, but significant modulatoryeffects on neutrophils and morbidity have been obser-ved in the few studies this far reported in the literatu-re21,22. Most attempts with antioxidants have been donewith regular vitamins, or with glutamine and glutathio-ne. It is important to recognize that fruit and vegetable-derived polyphenols of various kinds, demonstratesometimes up to ten times stronger antioxidativeeffects. Among these are resveratrol from red wine andpeanuts, quercetin from apples and onions, and curcu-min from turmeric and many others. Curcumin is notonly a powerful antioxidant but also a natural, and mostpowerful and totally atoxic inhibitor of NF-B, COX-2,LOX and iNOS, and has in several experimental stu-dies shown strong preventive effects of induced disea-ses, both acute pancreas and liver injuries and chronicdiseases such as Alzheimer, cancer and diabetes23. It is

burning that these compounds are tried also in patientsincluding surgically and critically ill patients.

Some bioactive fibers and some probiotic bacteriahave demonstrated extraordinary efficacy to restore andmaintain immunity and prevent complications. Lacticacid bacteria (LAB) have demonstrated ability to:

reduce/eliminate PPM

reduce/eliminate various toxins, mutagens andcarcinogens

promote apoptosis synthesize/release numerous nutrient; antioxi-

dants, growth-, coagulation and other bioactivecompounds

modulate the innate and adaptive immune defencemechanismsFor further information see references24-27.More recent studies suggest that LAB

promote/maintain gastrointestinal (GI) motility andprevent GI paralysis and postoperative ileus28-30

and have the ability to:

inhibit NF-kB activation31,32

inhibit constitutive synthesis of IL-8 and synthesisand secretion of IL-8 induced by TNF-a33,34

inhibit Cox-2 expression and restore the Cox-1/Cox-2 ratio35.

Some of these effects are produced by both live anddead LAB. However, the inhibition of synthesis andsecretion of IL-8 is only induced by live LAB, and notby bacterial lysate, heat-killed or gamma-irradiatedLAB36. Immuno-modulatory effects are also induced

by microbial products, such as butyrate, propionate,pyruvate and sometimes also lactate and acetate. Buty-rate and proprionate for example decrease COX-2expression with 85% and 72% respectively and increa-se COX-1 expression with 37% and 23% respectively,effects, which cannot be obtained with lactate or aceta-te35. Of great interest in this connection are recentobservations by Fink, who observed that supplementedpyruvate is an effective scavenger of ROS and exhibitsstrong anti-inflammatory effects: suppresses NF-B

74 S. Bengmark et al.Nutr. Hosp. (2006) 21 (Supl. 2) 72-84

Fig. 1A.Histological sections of rat lungs 24 hours after cecalligation and puncture. A: After placebo treatment.


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activation, reduces secretion of NO and proinflamma-tory cytokines, prevents intestinal translocation, redu-ces cardiac ischemia and improves kidney function36.Cardioprotective effects has also been reported fromintravenous administration of lyophilised LAB37.

It was recently demonstrated in experimental ani-mals subjected to cecal ligation and puncture (CLP)

that stress-induced neutrophil infiltration of the lungand subsequent tissue destruction can be effectivelyprevented by oral supplementation of a synbiotic cock-tail. A synbiotic formulation, Synbiotic 2000 Forte (seefurther below), administered orally before the trauma38

or a subcutaneous injection39 of the four LAB in thecocktail prevented effectively both neutrophil accumu-lation and tissue destruction in the lungs (fig. 1 A-C).

Probiotics and synbiotics in clinical studies

The use of probiotics- and synbiotics to control

exaggerated inflammation and immunoparesis is thisfar a largely unexplored territory. The hope for identifi-cation of magic bug capable of controlling all typesof inflammation in all stages of disease, will mostlikely remain an illusion. The promising effects obser-ved in experimental studies have often not been possi-ble to repeat in patients, especially in those sufferingfrom ChDs. This might be explained on the basis thatspontaneously developed ChDs are more therapy-resistant than similar diseases when induced in ani-mals. Induced diseases will rarely remain chronic, andmore dramatic effects of probiotics are generally obtai-ned in acute conditions, both in animals and human.

Another possible explanation might be that animalsusually receive much larger doses of probiotic, bothwhen related to mucosal surface and to body weight.Unfortunately, as yet no systematic dose/response stu-dies have been published. The most successful resultsthis far has been obtained with the use of cocktails ofLAB, with or without simultaneous supply of prebio-tics. However, these cocktails are commonly suppliedin significantly larger doses than is the case with theuse of single-strain probiotics or single strain/single-fiber synbiotics, which treatments most often are pro-vided with daily doses of 1 to 10 x 109 LAB per day.

Clearly, the trend of today is towards more complexcompositions and towards use of much larges doses ofLAB. Recent studies with the multi-strain probioticVSL#3 use doses varying between 1.8 and 3,600 x 1012

LAB per day, and the multi-strain/multi-fiber Synbio-

tic 2000 between 4 x 1010 and 1,200 1012 LAB seefurther below.

Commercially available prebioticsand probiotics

While some trials in the past have used LAB fromhealth stores, dairy products or a plethora of LAB avai-lable on the spot market most of the trials have beendone with less than ten different formulations:

Single-strain probiotics

Sacharomyces boulardi marketed by LaboratoiresBiocodex, Montrouge, France. It is commonly given indoses of 2 capsules containing 250 mg morning andevening, equivalent to app 1 x 1010 live organism/day.

The non-pathogenicE. coli (serotype O6:K5:H1)referred to as Nissle 1917 after early observations doneby Nissle already during the first world war. This strainis marketed as Mutaflor, by Ardeypharm GmbH, Her-decke, Germany. It is commonly given in doses of lessthan 1 x 1010LAB per day.

Lactobacillus GG (LGG) marketed by Valio, Hel-sinki, Finland. It is commonly given in doses between 1and 5 x 109 LAB per day.

Lactobacillus acidophilus LA1 (LA1): marketed byNestle, Vevey, Switzerland. It is commonly given indoses of less than 5x 109 LAB per day, sometimes evenless than 1 x 109.

Multi-strain probiotics

Theprobiotic cocktail called VSL#3 is the only multi-strain probiotic tried this far. It consists in four lactobaci-


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Fig. 1B.After treatment with only bioactive fibers. Fig. 1C.After treatment with both bioactive fibers and live lac-tic acid bacteria (Synbiotic 2000). With permission of Dr. OzerIlkgul Izmir, Turkey.


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llus strains (Lb acidophilus, Lb casei, Lb delbrueckisubsp bulgaricus, and lbplantarum) three bifidobacteriastrains (B longum, B infantis, B breve) plus Streptococ-cus salivarius ssp thermophilus (5 x 1011 cells/g). VSL#3has been tried in several studies, and yielded most inte-resting results, which have attracted interest of gastroen-terologists and patients around the world. VSL#3 con-tains 3 x 1012 live bacteria per gram. It is produced and

marketed by Sigma-Tau, Pomezia, Italy, and VSL Phar-maceuticals, Fort Lauderdale, USA. It is commonlygiven in high doses, usually 1.8 x 1012 LAB and morerecently up to 3.6 x 1012 LAB per day.

Single strain/single-fiber synbiotics

Lactobacillus plantarum 299 or 299V + oat fiber.When based on 299V it is called PRO VIVA. Thecomposition was constructed after extensive studies ofhuman lactobacillus strains40. It is produced and marke-ted by AB Probi, Lund, Sweden. The composition con-

tains 10 g of oat fiber and 109 e.g. oflactobacillus plan-tarum. A common dose is 1-2 x 109 LAB per day,occasionally 5 x 109 LAB per day has been tried. Mostof the experience with this synbiotic stems from studiesin critical care and in connection with extensive sur-gery.

Multi-strain/multi-fiber synbiotics

Synbiotic 2000. It consists in a mixture of fourLAB, one from each of the four main genera of lactoba-cillus; 1010 ofPediacoccus pentosaceus 5-33:3, 1010 of

Leuconostoc mesenteroides 32-77:1,1010

ofLactobaci-llus paracasei subspparacasei 19 and 1010ofLactobaci-llus plantarum 2,362, e.g. 4 x 1010 LAB per dose, plus amixture of four well studied bioactive plant fibers: 2.5 gbetaglucan, 2.5 g inulin, 2.5 g pectin and 2.5 g resistantstarch, totally 10 g plant fibers. The composition isconstructed after extensive studies of > 350 human and> 180 plant strains by Lund university microbiologistssa Ljungh and Torkel Wadstrm41,42. They choose theLAB to be used in the composition based on the abilityof the various LAB to produce bioactive proteins,transcribe NF-?B, produce pro- and anti-inflammatorycytokines, produce antioxidants, and to functionallycomplement each other. The four LAB function indivi-dually differently, but show synergistic effects whensupplemented together. Synbiotic 2000 is producedand marketed by Medipharm, Kgerd Sweden andDes Moines, Iowa, USA. Since a few months there alsoexists a Synbiotic 2000 FORTE and a Probiotic 2000FORTE (no fiber added), based on 1011 of each of thefour LAB, e.g. 4 x 1011 LAB per dose or if supplemen-ted twice or three times daily 0.8-1.2 x 10 12 LAB perday.

A few studies are also reported in the literature fromattempts to:

Total flora replacement (TFR)

TFR was introduced some 50 years ago as a treatmentalternative in severe Clostridium difficile infections. It isbased on transfer of fecal microbiota from an healthyindividual, often close relative, to a severely sick indivi-dual prepared for the supply by oral polyethylene glycollavage and broad spectrum antibiotic treatment. It has

during the last approximately fifty years been occasio-nally used in severe Clostridium difficile cases, but alsoon indications such as severe constipation, irritablebowel syndrome (IBS) and IBD. The patients do usuallyreceive, after preceding washout, about 200-300 ml freshfeces dissolved in an equal amount of saline solution. Theprocess is repeated for about five to seven days43,44.

Pro- and synbiotics in gastrointestinal disease

Infectious diarrhea

Diarrhea is one of the most common expressions ofdisease. In the developed world mainly elderly andimmuno-compromised individuals are targeted by thecondition. In the developing world t is said to affectchildren with no less than six to twelve episodes peryear compared to about at the worst twice annually inthe developed world. It is estimated that more than 3million children die globally each year in severe diarr-hea. Reversing dehydration is most effective treatmentbut there is a strong need for complementary treatment.Pre- pro- and synbiotics has the potential to be thatcomplement as it in addition of being relatively inex-pensive and without serious side effects also has the

potential to control infection and modulate motility45

.A recent meta-analysis based on twenty-three contro-lled studies totally involving 1,917 patients concludesthat the risk of diarrhea is reduced by 3 days (relativerisk 0.66) and the mean duration of diarrhea with 30.5hours46. The effects are seemingly especially pronoun-ced in rotavirus diarrhea where a mean duration ofdiarrhea was reduced by 38.1 hours. The study identi-fied great variations in results with the use of differentprobiotics. A combination ofL acidophilus andL bifi-dus appeared to be the most effective. In contrast tomost other regiments tried, S thermophilus andL bul-garicus appeared to have no effect on diarrhea, whichis in line with observations also in other conditions.

Antibiotic-associated diarrhea/

Clostridium difficile colitis

Approximately one fourth of all antibiotic-associa-ted diarrhea episodes involve Clostridium difficile(Cdiff). When 109 viable Sacharomyces boulardi orga-nisms was supplied to fifty Cdiff patients recurrencewas observed in 33/50 patients47. Prophylactic supplyto antibiotic-treated patients of 20x106 cfu/day ofLac-



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tobacillus GG (LGG) was tried in a randomized trialinvolving 267 patients but no difference observed;diarrhea developed in 39 (29%) of LGG-treatedpatients and in 40 (30%) of controls 48. Twenty-ninepatients with verified more than one episode of C.diff-associated diarrhea were in addition to metronidazolesupplemented with either 5 x 10 9L plantarum 299V(LP299V) or placebo49. No significant difference in

outcome was observed as 4/11 LP299V-treated and 6/9controls showed signs of recurrence. No study is yetreported with the use of more complex compositionssuch as VSL#3 or Synbiotic 2000. TFR has been usedin 84 patients: 36 patients with C diff-associated diarr-hea, 22 with C diffcolitis and 26 with pseudo-membra-nous colitis44,46. 72/84 patients (86%) showed immedia-te resolution of the problems. None of the patients asreported had signs of relapse during follow-up up tofive years. Cure is reported to have been achieved witha single-shot treatment in 33/36 patients (92%).

Crohns disease (CD)

CD is without doubt one of the diseases, which isproven to be most refractory to treatment. With increa-sing knowledge about the inflammatory cascade seve-ral possible treatment options have been suggested.This far antagonism of TNF- with the monoclonalantibody infliximab has proven to be the most success-ful. Future treatments will either be compared to infli-ximab as the golden standard or suggested as a supple-ment to infliximab treatment. Single-strain probioticslike Sacharomyces boulardi (SB)50,51, E coli Nissle(ECN)52 and Lactobacillus GG (LGG)53,54 have been

tried with no or minimal success. An abstract publishedin 2000 claimed effect with VSL#3, but the expectedfull paper was never presented55. Synbiotic 2000 hasbeen tried in two controlled trials After an initial treat-ment with infliximab were 63 patients randomized toreceive daily either Synbiotic 2000 or placebo 56.Median time to relapse was 9.8 and 10.1 months resp.In the other study were 20 patients supplied Synbiotic2000 and 9 patients placebo and no difference observedin disease activity scores after 3 months (R Eliakimpersonal communication). Clearly bio-ecological treat-ment has this not been able contribute to improved out-come in this group of patients. However, one cannotexclude that supply of significantly larger doses of pro-and synbiotic compositions could prove effective.

Ulcerative colitis (UC)

Of single-strain probiotics is it mainly Sacharomycesboulardi (SB)57 andE coli Nissle (ECN)58-60, which havebeen tried, both with some, but far from satisfactory,improvements. In one of the ECN studies involving 114patients did 44/59 ECN-treated (75%) and 39/57 mesa-lazine-treated patients reach remission. Relapses during

the study period was shown in 26/57 (67%) of ECN-tre-ated and 32/59 (73%) mesalazine-treated59. Subsequentreviewers have pointed out that the relapse rate is themesalazine group is significantly higher than expectedfrom the literature61. It has also been suggested that thestudy groups are heterogeneous with respect to severityof disease, and that the dose of mesalazine used in thestudy is lower than usually used. In the last study with

ECN as many As 327 patients with quiescent UC weretreated during one year with either ECN or mesalazine60.The relapse rate was 45% with ECN and 36 % withmesalazine. A study using VSL#3 provided much moreedge-cutting results62. Twenty patients with UC inremission and intolerant to 5-ASA treatment receiveddaily during one year morning and evening 3 g of pureVSL#3 bacteria, equivalent to the at that time almostastronomical amounts of 1.2 109 LAB. Four of thepatients showed significant relapse after 3, 5, 5 andseven months, one was lost to follow up, the remaining15 were still in remission after 12 months. Rectal insti-llations with Synbiotic 2000 reconstituted in saline were

during 2 weeks given to ten patients. One patient with-draw after one week, the remaining patients showedduring the 3 weeks of observation dramatic improve-ments in diarrhea scores, visible blood in stool, noctur-nal diarrhea, urgency and consistency of stool63. Twopatients reported significant bloating and wind but noother adverse or side effects were reported. Only tenIBD patients, 9 UC and one CD, are reported as treatedwith TFR in the literature43,44. All TFR-treated IBDpatients are reported to have suffered IBD for more thanfive years and to have been refractory to conventionaltreatments. They are claimed to all have experienced acomplete reversal of disease, and to have all anti-inflam-

matory treatments concluded after up to six weeks and,most important, to remain remission-free after periods ofobservation between one and 13 years. It is also claimedthat on follow-up endoscopy and histology the mucosahad shown a normal appearance. Clearly, this small butsignificant improvement with TFR is unprecedented.There is nothing to assume that even TFR will lead tomore than a temporary colonisation. Most likely theguest microbiota will disappear within two to fourweeks. With our present knowledge permanent neo-colonization will not occur in adults. The most likelyexplanation seems at this stage to be that the guestmicrobiota has managed to totally eliminate an unk-nown uncultivable pathogen, underlying the disease.

Pouchitis

Lactobacillus GG (LGG) was tried in two studies64,65.Twenty patients with a previous history of pouchitisand endoscopic signs of inflammation were randomi-zed to either 1 x 109 LGG or placebo. No differenceswere observed in disease activity, total anaerobes andaerobes in mucosal biopsies or in feces after threemonths of treatment64. Prophylactic supply of LGG,


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immediately after surgery with construction of ileo-anal anastomoses was tried in a recently publishedstudy65. Comparison was made to historical controls;2/39 vs 8/78 developed single episode pouchitis, 1 vs12 suffered recurrent episodes of pouchitis and 0 vs 7suffered chronic pouchitis. Edge-cutting improve-ments are reported from a controlled study with supplyof 1.2 109 VSL#3 for a period of nine months. Only

3/20 VSL#3-treated in contrast to 20/20 controlpatients suffered remission of pouchitis66. Similarresults were obtained in a second study in collaborationwith British gastroenterologists; 17/20 (85%) ofVSL#3-treated and 1/16 controls remained in remis-sion after one year of treatment67. In a third study didsupply of VSL#3 start immediately after the surgicalconstruction of ileo-anal anastomosis with the hope toprevent pouchitis to develop. Only 2/20 (10%) in theVSL#3-treated group compared to 8/20 (40%)in thecontrol group (p < 0.01) developed pouchitis68.

Irritable bowel syndrome (IBS)

IBS is most likely the most common gastrointestinaldisorder in the Western world. It is characterized by alte-red bowel habits, dysmotility, abdominal pain and/or dis-comfort. Its pathogenesis is obscure, but a recent a studysuggests that the majority of patients34-44 have a comparedto controls significant (p < 0.001) infiltration with mastcells in the mucosa69. Especially are the number of mastcells located close to (within 5 microns) nerve fibers sig-nificantly increased in IBS patients, and also signifi-cantly related to degree of abdominal pain and dis-comfort. Probiotics have been shown to modulate

entero-endocrine cell population in the rat intestine70

.Several attempts to affect the disease with probioticsupply are reported in the literature. Twenty-four patientswere randomized to either receive 5 x 109 LGG or place-bo twice daily during ten weeks, but no difference betwe-en the two groups was observed in bloating, pain scoresor bowel movements71. A recent well controlled study intotally seventy-eight patients supplied 1 x 1010 of eitherLsalivariusUCC4331,B infantis 35624 or placebo72.

Two different composite scores based on the threecardinal symptoms; pain/discomfort, bloating/disten-sion and bowel movement difficulty were calculated,both demonstrating statistically significant improve-ment with probiotic supply, the most pronouncedeffect seen with supply ofB infantis. The abnormalratio of the cytokines IL10:IL12 was reported normali-zed in theB infantis-treated group. Dual-strain probio-tics were tried in a study, where fifty patients were ran-domized to receive a combination of 5 x 109 ofL

plantarum Lp01 and 5 x 109 ofBifidobacterium breveBr0 during one month. The reduction in pain and ove-rall symptom scores were reported as 50% and 25%, nostatistical analysis was regarded possible73.

VSL#3 in a dose of 4.5 x 1011 LAB/day was tried in acontrolled study in twenty-five patients at Mayo Clinic74.

After eight weeks no differences were observed betweenVSL#3 treated and controls in mean gastro-intestinaltransit time, abdominal pain, gas and urgency. The sin-gle-strain/single-fiber synbiotics based onLactobacillus

plantarum 299V (L299V) and oat fiber has been tried inthree studies75-77. 20/20 in the L299V-treated and 11/20 inthe placebo group reported resolution of their abdominalpain153. A similarly designed study in 2 x 30 patients

found most modest influence of L299V-treatment;reduction in flatulence but no influence on bloating76. Thethird study reported no effect at all of L299V-treatment77.Total microbiota replacement has also been tried in a fewpatients, but this far the experience is at the best anecdo-tal.

Helicobacter pylori infections (HP)

A few lactobacillus strains have, in sharp contrast toother microbes, the ability to tolerate low pH and survi-ve and grow in the otherwise to microbes hostile envi-

ronment of the stomach78. This could offer uniqueopportunities to prevent overgrowth ofHelicobacterpylori, the main cause of chronic gastritis, peptic ulcersand an important risk factor for gastric malignancies.An interesting study compared seventeen differentLAB and their ability to inhibit growth of ten different

H pylori strains79. All strains inhibited the growth atlow pH but pH was elevated to 6.0 did all exceptL aci-dophilus CRL639 loose that ability. This observationspeaks against simultaneous use of H2-blockingagents. 120 patients were randomized to either receive

L acidophilus or placebo as supplement to 7-day courseof triple therapy (rabeprozole, chlarithromycin, amoxi-

cillin)80

. The eradication rates were 52/59 (88%) and42/58 (72%) resp. (p = 0.03). However, when repeatedwith Lactobacillus GG, no such triple-therapy-poten-tiating effect could be observed81,82. Daily consumptionof 4 x 50 ml of supernatant from a whey based culturewith L acidophilus (La1) is reported to significantlyreduce breath test83 and to decrease density ofH pyloriin the stomach84. Subsequent studies with La170 anda variety of otherLactobacillus andBifidobacteriumspecies85,86 seem, however, to a rather demonstrate uni-versal suppression ofH pylori by various LAB, whichseemingly is much independent of strains used87.

Chronic liver disease (CLD)

Endotoxin-induced activation of macrophages isassumed responsible for increased levels of circulatingTNF- and soluble TNF receptor (sTNFR) observed incirrhotics and the expression of Toll-like receptorsTLR2 and TLR4 is critically involved. Circulatingendotoxin, TNF-, and sTNFR levels, peripheralblood mononuclear cell (PBMC) expression of TLR2and TLR4, and in vitro TNF- production by PBMCswhen stimulated with endotoxin or Staphylococcus



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aureus enterotoxin B (SEB) were measured in 36 cirr-hotic patients supplemented Synbiotic 2000 and 32controls87. Supplementation of synbiotics resulted insignificant up-regulation of PBMC expression ofTLR2.

In a subsequent study 55 patients with minimalhepatic encephalopathy (MHE) were randomized toreceive Synbiotic 2000 (n = 20), only the fiber in

Synbiotic 2000 (n = 20), or placebo (n = 15) for 30days88. The patients with cirrhosis and MHE werefound to have substantial derangements in the gutmicro-ecology, with significant fecal overgrowth ofpotentially pathogenicEscherichia coli and Staphylo-coccal Staphylococcus. Synbiotic treatment signifi-cantly increased the fecal content of non-urease-pro-ducingLactobacillus species and significantly reducedthe endotoxemia and the potentially pathogenic micro-biota. The observed alterations in gut microbiota wereaccompanied by a significant reduction in bloodammonia levels and reversal of MHE in half of thepatients; the Child-Turcotte-Pugh functional class

improved in nearly 50% of cases. Treatment with onlyfermentable fiber was beneficial in a substantial pro-portion of patients. Interventions aimed at reducingintestinal levels of endotoxin-containing Gram-negati-ve bacteria have been suggested to also improve syste-mic hemo-dynamic disturbance in cirrhosis, but effectson hepatic blood flow was never reported. A study bythe same group performed in 15 cirrhotic patientsdemonstrated a significant reduction (median 17.5%,range 1.4-65%) in indocyanine green retention at 15minutes (ICG

R15) in the cirrhotic patients following

seven days of supplementation with Synbiotic 2000(P = 0.003)89.

Orthotopic liver transplantation (OLT)

Two prospective randomized trials with supply ofsynbiotics have also been performed. In the first studythe single-strain/single-fiber synbiotic preparationbased on 1 x 109L plantarum 299 and 10 g oat fiber(L299) was compared to 1 x 109 heat-killed L299 and10 oat fiber (H299) and to selective digestive tractdecontamination (SDD)90. A total of 95 patients divi-ded into three groups entered the study: 1. (SDD) fourtimes daily for six weeks (n = 32), 2. L299 (n = 31)during 12 postoperative days 3. H299 (n = 32) during12 postoperative days. The same enteral nutrition wassupplied to all patients. There were no deaths. Signs ofinfections occurred in SDD 48% (15/32), in H299 34%(11/32) and in L299 13% (4/31), p = 0.017 respecti-vely. The numbers of postoperative infections wereSDD 23, H299 17 and L299 4. The numbers of patientsrequiring hemo-dialysis were SDD 8, H299 4 and L2992. In a subsequent double-blind randomized study 33patients were supplemented the multi-strain/multi-fiber Synbiotic 2000 and another 33 patients recei-ved only the four fibres in the synbiotic composition91.

The treatment started on the day before surgery andcontinued until the 14th day after surgery. Only onepatient in the Synbiotic 2000-treated group (3%)showed signs of infection (urinary infection) during thefirst month compared to 17/33 (51%) in the patientssupplied only the four fibres only. The infecting bacte-ria was with Synbiotic 2000Enterococcus faecalis in 1patient compared to 11 in the only fiber group. The

group supplied only fiber suffered in additionEscheri-chia coli in 3 patients, Enterobacter cloacae in 2patients, Pseudomonas aeruginosa in 2 patients andStaphylococcus aureus 1 patient. The use of antibioticswas also significantly shorter in the Synbiotic 2000-treated group.

Perioperative care and multiple trauma

In a prospective randomized study the effect of thesingle-strain/single-fiber synbiotic based onL planta-rum 299 in a dosis of 109 LAB per day 10 g of oat fiber

(L299) was compared with similar amount of heat-killedLactobacillus plantarum 299 and oat fiber (H299) andparenteral nutrition (PN) in 3 x 30 patients undergoingabdominal operations; liver resection, pancreas resec-tion, gastric resection, colon resection and intestinal by-pass92. Both the L299 and H299 groups suffered signifi-cantly less infections (3/30 patients in each group, 10%)compared to PN (9/30 patients, 30%) (p > 0.001). Aneven larger difference was observed when the subgroupof gastric and pancreatic surgery patients was separatelyanalyzed: None in the L299 group, 1/8 H299 patients(12%) and 3/6 (50%) PN suffered infections. A similarstudy was undertaken in patients undergoing abdominal

cancer operations. Forty-five patients undergoing majorsurgery for abdominal cancer were in a randomized con-trolled study divided into three treatment groups: 1. ente-ral nutrition (EN) supplemented with Synbiotic 2000(LEN), 2. EN supplemented with only the fibers in thesame amounts (20 g) (20 g) as in Synbiotic 2000(FEN) and 3. standard parenteral nutrition (PN). All tre-atments lasted for 2 preoperative and 7 days postoperati-ve days. The incidence of postoperative bacterial infec-tions was 47% with PN, 20% with FEN and 6.7% withLEN (p < 0.05). Significant improvements were alsoobserved in prealbumin (LEN, FEN), C-reactive protein(LEN, FEN), serum cholesterol (LEN, FEN), white cellblood count (LEN) , serum endotoxin (LEN, FEN) andIgA (LEN) (Han Chunmao et al., personal information).However other studies have not been able to documentsimilarly positive results. A standard commercial pro-duct (TREVIS, Ch Hansen, Denmark) containingLac-tobacillus acidophilus LA5, Bifidobacterium lactis

BP12, Streptococcus thermophilus, Lactobacillus bul-

garicus, mixed with 7.5 g oligofructose was supplied to72 elective abdominal surgery patients and 65 controls,respectively93 reported no differences in bacterial trans-location, gastric colonization, or systemic inflammation,or septic complications.


79Nutr. Hosp. (2006) 21 (Supl. 2) 72-84


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Acute pancreatitis

Patients with severe acute pancreatitis were randomi-zed to receive daily during the first 7 days through anasojejunal tube either a freeze-dried preparation contai-ning liveLb plantarum 299 in a dose of 109 together witha substrate of 10 g of oat fibre or the same preparation,after heat-inactivation94.The study designed to be inte-

rrupted when on repeat statistical analysis statisticallysignificant differences in favour of one of two groupwere obtained, which occurred when a total of 45patients had entered the study. At that time 22 patientshad received treatment with live and 23 with the heat-killedLb plantarum 299. Infected pancreatic necrosisand abscesses were seen in 1/22 (4.5%) in the live LABgroup vs 7/23 (30%) in the heat-inactivated group (p =0.023). The only patient in the live LAB group, whodeveloped infection, had signs of urinary infection onthe 15th day e.g. at a time when he had not received treat-ment during the last eight days. The length of stay wasconsiderably shorter in the live LAB group (13.7 days vs

21.4 days), but the limited size of the material did notallow statistical significance to be reached. Sixty-twopatients with severe acute pancreatitis (SAP) (Apache IIscores: synbiotic treated 11.7 1.9, controls 10.4 1.5)were in a second study by the same group supplementedfor 14 days with either two sachets/day of Synbiotic2000 (2 x 40 x 109LAB/day and totally 20 g fibers) oronly the same amounts of fibers in (20 g) as in Synbiotic2000. 9/33 patients (27%) in the Synbiotic 2000-trea-ted group and 15/29 patients (52%) in the only fiber-tre-ated group developed subsequent infections. 8/33 (24%)Synbiotic 2000-treated and 14/29 (48%) of the onlyfiber-treated patients developed SIRS, MOF or both (p

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Bioecological and Nutritional Control of Disease - Prebiotics, Probiotics

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