fecal microbiota therapy and its potential in ...2016/03/03 · clostridium difficile can flourish...

Mil. Med. Sci. Lett. (Voj. Zdrav. Listy) 2016, vol. 85(3), p. 111-120ISSN 0372-7025

DOI: 10.31482/mmsl.2016.020

REVIEW ARTICLE

FECAL MICROBIOTA THERAPY AND ITS POTENTIALIN MEDICAL PRACTICE

Haskova Katerina 1,2, Dyrhonova Marketa 2, Bostikova Vanda2,3

1 Department of Infectious Diseases, Hospital Melnik, Melnik, Czech Republic2 Department of Epidemiology, Faculty of Military Health Sciences, University of Defence, Hradec Kralove,

Czech Republic3 Faculty of Informatics and Management, University of Hradec Kralove, Hradec Kralove, Czech Republic

Received 30th August 2016.Revised 16th September 2016.Published 27th September 2016.

SummaryFecal microbiota therapy is going through its renaissance period. Even in ancient China, stool and

its derivats were used for therapy of various diseases. Now thanks to new molecular methods a newknowledge about the intestinal microbiome and its interference with the human physiology, this methodcan be used for concrete therapy of disease.

Key words: fecal microbiota therapy; Clostridium difficile; infection; immunocompromised patients

INTRODUCTION

The human body is home to trillions of bacteria,which is 10 times more than the number of cellsin the body. Most of the bacteria of our body are lo-calized in the intestine. There are up to 36 thousandbacteria capable of inhibiting the gastrointestinaltract, most of which are yet to be differentiated. Eachperson has 500 to 1000 species of bacteria in theirgastrointestinal tract. The microbiota consisting of bac-teria, eukaryotes, viruses, and archaeon of the gut arein a close symbiosis with the human body and caninfluence the entire organism both directly and indi-rectly [1, 2, 3]. Most types of bacteria that colonizeour body cannot yet be cultivated by existing micro-

biological methods, but a gateway to decipheringthe human microbiome has opened with new molec-ular biological methods such as 16S RNA gene se-quencing [1, 2].

With the evolution of these new technologies,new projects are organized such as The Human Mi-crobiome Project, which is built by the National In-stitutes of Health to research the links betweenhuman microbiome and disease in humans [2, 4].

The main part of development of a human micro-biota happens in the first year of a person’s life.The bacteria produce a number of molecules thatclosely interact with the human intestine, immunesystem and other parts of the host organism.

Four main phyla dominate the populationin the human intestinal microbiome –Bacteroidetes,Firmicutes, Actinobacteria and Proteobacteria [2, 4].

The epithelial cells of the intestine are coveredby a layer of glycocalyx and mucous gel. Its main

University of Defence, Faculty of MilitaryHealth Sciences, Department of Epidemiol-ogy, Trebesska 1575, 500 01 Hradec Kralove,Czech [email protected](420) 973 253 205

function is to nourish bacteria which are commensalto the human intestine and serve as a barrier to thosethat are pathogenic, this has a clear effect on the com-position of the microbiota. The gel layer is activelyregulated and differs in thickness and compositionin different part of the intestine and is constantly re-newed [5, 6]. Due to the absence of effective and safetreatment for certain diseases, interest in microbiomebased therapies is at rise. Diseases that are derivedfrom disturbances of the homeostasis of the humanmicrobiome or dysbiosis such as Clostridium difficileinfection or idiopathic bowel disease can be poten-tially treated and even cured by fecal microbiotatherapy [7, 8].

Fecal microbiota therapy has many synonymssuch as human probiotic infusion, stool transplant,fecal transplant. This procedure has been a questionof great interest in the recent years mainly dueto the increased burden of Clostridium difficileinfection [9, 10].

Fecal microbiota therapy has been known tomodern medicine since 1958; even so, the precisemechanism of action of this procedure in restoringgut function is not yet fully understood. It isspeculated that the fecal microbiota transplantrestores the structure and composition of the coloniccommunity and therefore suppresses the growth atoxin formation of Clostridium difficile and possiblyother pathogenic bacteria [4, 11].

Short history

The first mention of fecal microbiota therapydates back to the fourth century ancient Chinawhere Ge Hong treated different maladies with fecalmatter such as food poisoning and other gas-trointestinal disease, but also other symptoms, likefever. Later findings bring us back to China with LiShizhen who gave this therapeutic method a moresophisticated name of “yellow soup” which wasalso fecal matter dissolved in a liquid and used fortreating consti-pation, diarrhea and other diseasesof the gastrointestinal tract not only in humans, butalso in animals [12]. The next big name which hadan impact in fecal microbiota therapy was ChristianFranz Paullini, a German physician who workedin the seventeenth century. He also treated patientswith gastrointestinal disturbances, other bodily ma-terials such as urine was used in treatment of otherdiseases. He left traceable works on the mattersof his investigation, which have been preserveduntil this day.

The first modern day application of fecal matterwas in 1958 when Dr. Ben Eisman and his team whotreated patients with fulminant pseudomembranouscolitis with an enema of fecal matter with a positiveeffect and full recovery of the severely ill. It is spec-ulated that the pseudomembranous colitis may nothave been caused by Clostridium difficile [8].

Safety

There are yet to be case reports on adverse effectswhich can be traced back directly to fecal microbiotatherapy, there are no cases of acquired infections, evenwith immunocompromised patients, even thoughthe donor screening schemes differ from countryto country. The only potentially harm can be causedvia endoscopic methods with direct trauma fromthe endoscopic tools. There are a few speculatedcases of obesity which evolved after fecal microbiotatherapy, however a direct cause is still to be proven.

Ethical aspects

A few questionnaire based studies were con-ducted to find out the attitude of patients towardspotential fecal microbiota transplant. The patientsfor whom fecal microbiota transplant is a potentialtherapy are more reserved than the caregiversof patients for whom fecal microbiota transplantis considered. Test subjects consider fecal microbiotatransplant as the more “natural” treatment and,therefore, the safer option compared to standardmedications. Potential patients consider probioticsto have the same effect as fecal microbiota transplant.

The major ethical aspect is the method of ad-ministration of homogenized stool. Routes throughwhich this can be done are nasogastric tube,colonoscopy and enema. Nasogastric route of admin-istration was least appealing to patients. Potentialrecipients prefer their relatives to be donors.

Another aspect of concern is whether donors arethoroughly screened for potential transmittabledisease and the risk of gaining diseases that are notroutinely screened for or diseases that are not infec-tious in origin. The initial disgust does not alterpatient’s interest in fecal microbiota therapy andwould not play and important role if this therapy wasconsidered helpful [13]. Neither religious, nor cul-tural aspects play a role in making a decision [15, 16].A colorless, odorless pill would be the preferredmethod of application if possible. The amount of peo-ple interested in fecal microbiota therapy is the same

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percentage in both sexes. However the reasons whypeople would not consider fecal microbiota therapydo differ, men are more concerned by the safetyaspect of the procedure, whereas women are morediscouraged by the possible disgust by the procedure.Neither age, nor level of education had any impacton the potential decision. People considered the as-pect of discussing the procedure with the potentialdonor as the most unappealing of all the factors.

Procedure of transplantation

Fecal mirobiota therapy involves collecting stoolfrom a healthy donor who has been screened fortransmittable diseases such as HIV, hepatitis A, B andC, syphilis, intestinal infections and other disease.The potential donor should be of general good healthwith no known chronic diseases including, for exam-ple, atopic disease, obesity, hypertension, and so on.The stool is then prepared and administeredto the patient [12, 14, 15].

Routes of administration

There are three main routes of admission of fecalmicrobiota therapy - naso-duodenal, transcolono-scopic or enema based.

The naso-duodenal route may be complicatedby vomiting and aspiration, colonoscopic routerisks damage of the colonic mucosa, but the mi-crobiota is delivered directly to the predicted placeof action. Enema administration is the safest andcheapest method of administration and can also beadministered without the assistance of a doctor orany other healthcare professional for that matterby the patient himself outside a healthcare facility.So far, it seems that the methods of administrationthrough the lower parts of the gastrointestinaltrack have a higher cure rate for infection withClostridium difficile compared to the naso-gastricroute, although in different studies comparingthe routes of administration differed in the amountof homogenized stool used for either route.The route of administration depends on the typeof patient. In more severe forms of colitis, a gentleenema can be the best choice, but it does not offera view of the colonic epithelium like colonoscopyin patients with underlying gastrointestinal disease,for example, and stool can be delivered via eyecontrol in places that can be hard to access such asdiverticules, in severe forms of colitis there is a riskof perforation and an experienced endoscopistis crucial. Fecal microbiota therapy does not seem

to work in patients with Clostridium difficileinfection post colectomy [10, 17–19].

Another more modern and esthetic form of fecalmicrobiota therapy is capsules filled with homoge-nized fecal bacterial matter, another potential methodof administration. Stool not more than 6 hours afterdefecation is applied into sterile vessels sealedby plastic, after that the top coat is disinfected again.These formed capsules are frozen at -80 °C and keptat -20 °C. Prior to use these capsules are thawed.In some studies centrifuged supernatant of fecal mat-ter is used, which allows a smaller amount of stoolending up to 8-12 capsules. The cumulative cure rateof these patients is comparable with other routesof administration [20, 21]. Certain companies,mainly in the USA, offer stool from prescreeneddonors. This stool can be ordered directly and deliv-ered to a patient’s home to be administered via enema.The screening of one donor with his fecal matterbeing transplanted to a larger number of patientssignificantly reduces the cost of therapy when a donordoesn’t have to be screened per patient. These donorsare paid for their fecal matter [22].

Clostridium difficile infection

Clostridium difficile is a gram-positive, rod-shaped, spore-forming bacterium which spreads fromone person to another through fecal-oral route.Spores can survive the stomach acidity and can ger-minate in the gut. This organism can outgrowthe normal flora leading to the disease. Clostridiumdifficile can flourish in an anaerobic environment, butcan survive on different surfaces for long periodsof time. The eradication of these spores isn’t easy andcannot be done by regularly used disinfectants.

Clostridium difficile produces toxins which cancause inflammation and disrupt the mucosa causingdiarrhea. When toxins get into the intestinal cell, theyinterfere with cell function causing cell death.

Toxin A is an enterotoxin which causes increasedintestinal permeability and the secretion of fluids,Toxin B is a cytotoxin which leads to colonic inflam-mation. All of these toxins cause the loss of barrierfunction of the intestine making granulocytesinfiltrate the intestine and support diarrhea.

Clostridium difficile infection is the mostcommon health care-associated infection of the lastdecade, it is a public health matter of first priorityand also an enormous economic burden, a disease

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with a high morbidity and mortality rate, whichgreatly alters the quality of life of diseased patients.The complications are severe and life threatening.The incidence of severe and recurrent Clostridiumdifficile infections is on the rise.

Clostridium difficile infection is the perfect condi-tion for fecal microbiota therapy. The primary causeof the disease is intestinal microbiotic dysbiosis, andClostridium difficile overgrowth. When treatedwith antibiotics, Clostridium difficile is killed, butthe intestinal microbiota is damaged even more,leading to relapse rates of 20% where this numberrises with every subsequent Clostridium difficileinfection episode and every following antibiotic treat-ment. Altogether antibiotics in mono and combinedtherapies fail to eradicate this disease, because theydo not restore the correct flora, Vancomycin andMetronidazole alters microbiota diversity further,Vankomycine targers grampositive aerobic and anaer-obic bacteria, whereas Metronidazole targets mainlyanaerobes. Fidaxomicin is another drug of choice,this drug doesn’t alter the microbiota as much as otherantibiotics, has a higher cure rate and a lower relapserate compared to other antibiotics used for treatmentof Clostridium difficile infection, however, so fara very important aspect against therapy withFidaxomicin is it’s very high cost. All of this leadsto a need of a creative approach in new treatmentmethods. Fecal microbiota therapy amongst otherpositive aspects is relatively inexpensive and not onlydoes it eradicate Clostridium difficile, it also restoresdeficient intestinal bacteria. This makes fecal micro-biota transplant the most effective therapy for relapsingClostridium difficile infection. The cure rate isaround 90%. In the last few years, fecal microbiotatherapy for treatment of Clostridium difficile infectionhas transferred from being the” last resort” treatmentto a mainstream therapy method and is a known partof most Clostridium difficile infection guidelines,including the ones for Europe including the CzechRepublic in particular [23].

The microbiota of patients susceptibleto Clostridium difficile infection is altered, there isa reduced amount of Bacteroidetes and Fermicutesmost probably caused by previous antibiotictreatment, this deficiency most likely facilitatesthe growth of Clostridium difficile; however,the precise mechanism of action of fecal microbiotatherapy remains unknown.

New hypervirulent ribotypes 027 and 176 areon the rise. Infections with these ribotypes are in gen-

eral more vicious and severe and are followedby a higher colectomy rates and higher mortalityin comparison with previous decades. The strainsare unique in a higher toxin-producing potential,they also express binary toxin, and this leads to poorertreatment outcomes.

Different centers that offer fecal microbiotatherapy have different protocols of quantity, methodof infusion, methods of preparation of recipients anddonor differ, there is no standard protocol in ourcountry either [7, 9, 23–25].

Adverse effects

No significant adverse effects have yet beendescribed, discomfort such as mild diarrhea anddyspepsia may occur which is usually resolvedspontaneously shortly after treatment [10, 26, 27]

The immunocompromised recipients

There are limited studies of immunocom-promised patients receiving fecal microbiota therapy;there are no described cases of infection resultingfrom this procedure.

Clostridium difficile infection is the most com-mon intestinal infection in the adult immunocom-promised hosts such as patients with AIDS andsolidorgan transplant recipients whereas not all of thesepatients have known prior antibiotic exposure,therefore immunocompromision is an independentrisk factor for infection with Clostridium difficile,and both innate and adaptive immune mechanismsplay a role in protection against Clostriudm difficile.Signaling includes recruitment of neutrophilsin the location of inflammation. Immunocompro-mised patients have multiple out-patient visits andextended periods of hospitalization and are oftentreated by broad-spectrum antibiotics. All of thisplays a major impact in Clostridium difficileinfection. Clostridium difficile infection together withidiopathic bowel disease is also a major problem.The mucosal barrier of the intestine in the patient withidiopathic bowel disease is disrupted, immunocom-promising therapy is also a risk factor and all of thisincreases the risk of Clostridium difficile infectionsin these patients three fold compared to healthypopulation. Most patients treated for Clostridiumdifficile infection with fecal microbiota therapy hada positive effect after the first dose of therapy, the ef-fect is similar to that of patients with Clostridiumdifficile infection without immunocompromision.

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There are no deaths related to infection in this groupof patients. However, deaths related to the procedureof application of fecal material were described in lit-erature. Some people with severe immunocompromisewith idiopatic bowel disease did need colectomyfollowed by fecal microbiota therapy due to diseaseflare. These studies are based of retrospective studiesand more information is needed [9, 23, 28–30].

The role of microbiota in altering the brain

200 to 600 million neurons connect the humangut and brain, the bidirectional gut-brain axis is a pointof investigation in many studies. Changes in the gutmicrobiota of rodents occur after they are exposedto stress and begin showing signs of anxiety-likebehavior and depression, also maternal separationof rat pups leads to increased intestinal permeabilityand altered microbiota, these changes remain untilthe rodent’s adulthood. In rhesus monkeys this sepa-ration leads to decrease in lactobacilli in feces andincreased susceptibility to infection.

Campylobacter jejuni infection is correlated with in-creased anxiety. Interventions with Bifidobacteriastrains decrease depressive and anxiety behavior.

This effect of probiotic strains seems to be medi-ated by the Vagus nerve, the metabolites of microbialcolonization initiate signaling mecha-nism of neu-ronal circuit which lead to behavior such as anxietyand decreased motor control. Also neurodevelop-mental disorders such as autism spectrum disordersare linked not only to environmental factors such asexposure to pollution, chemicals, drugs, maternalstress, maternal infection, but also to microbiotacomposition, with the alteration of which the coursedof disease can also be slightly altered [31-33].

Autism spectrum disorders

Autism spectrum disorders are neurodevelop-mental dysfunctions characterized by impairmentof capability of communication and social interac-tions. Among other symptoms, patients with autismspectrum disorder are prone to have gastrointestinalproblems such as diarrhea, bloating and otherdyspeptic problems. The intestinal permeabilityof these patients is increased. This seems to be causedby altered composition and metabolic activitiesof intestinal flora. Environmental and genetic factorsseem to play an important role in the developmentof those symptoms. A few studies have observedan effect of Vancomycin treatment and certain diet

changes, which alters not only the microbiota of pa-tients, but also social functions of patients with autismspectrum disorders. In comparison with healthycontrol groups, the microbiota of patients with autismspectrum disorders have more Clostridia,Bacteroidetes, Desulfovibrio and Sutterella spp andlower levels of Firmicutes and Verrucomicrobia, alsothe composition of Lactobacillus a Bifidobacteriumspecies differ in patients with autism spectrumdisorders compared to healthy control groups, includ-ing healthy siblings and family members who sharehousehold. However, these observations are not con-sistent. Some studies do not observe any significantchanges in the microbiota in patients with autismspectrum disorders compared to healthy individuals.There are certain limitations to a high-qualitymicrobiota observation in these patients, becausecontrol groups and patients differ in age, presenceof concomitants and gastrointestinal diseases, the con-trol groups are usually members of a commonhousehold. There is hope that a more thoroughobservation will be conducted with the use of newbacteria detection methods. Another aspect whichhelps the theory that microbiota is altered in patientswith autism spectrum disorders is the fact that patienttreated with Vancomycin improve both in gastroin-testinal and cognitive symptomology. However,antibiotic use does not have a long term effect.

It seems that bacterial toxin over-abundancemight be involved in pathogenesis of autism spec-trum disorders, for example some Clostridiaceaesynthesize metabolites like phenols and indolederivates which are toxic for humans. The potentialof spore-forming is a concern of relapsing autismsymptoms after Vancomycin treatment. 31. Metabolitesproduced from the fermentation of undigested fooddiffer depending on the composition of the microbialflora, more specifically the levels of butyric, valeric,propionic and acetic acids, amino acids and freeamonia. All of these metabolites are increasedin children with autism spectrum disorders.

Few studies of administering fecal microbiotather-apy have shown to have positive, although notlasting, outcomes [31–34].

Inflammatory bowel disease and microbiota

Inflammatory bowel disease is a term for a groupof idiopathic, chronic, and relapsing inflammatorydisorders of the gastrointestinal tract. Specific changesin microbiota were described: Bifidobacteriam,Lactobacillus and Faecalibacterium prausnityii seem

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to be decreased, and mucosal-adherent bacteria areincreased. The metabolites of Firmicutes are mostlyshort-chain fatty acids such as butyric acid, which isa substrate with strong immunoregulatory properties.This is shown by a described positive effect in pa-tients with ulcerative colitis who were treated by ene-mas with butyrate. Main treatment for ulcera-tivecolitis includes steroids, aminosalycilates, immunosu-pressants including corticosteroids and biologic ther-apy. Not only are all these standard therapy regimensusually complicated by adverse effects, but there arestill a number of patients who remain refractory tothese therapies and require surgery. Those patientswho do have an effect on therapy usually have to copewith mild lasting symptoms and a lower life quality.

Intestinal microbiota has been suspectedas an ethiopathologic aspect of idiopathic boweldisease and different treatment regimens with pro-biotics a prebiotics where tested with variableevidence of efficacy. An alternative managementin altering the gut microbiota is management withfecal microbiota therapy where Clostridium difficileinfection is more common in patients with idiopathicbowel disease [25, 35–37].

Ulcerative colitis

Ulcerative colitis is an idiopathic inflammatorybowel disease confined most commonly to the rec-tum and colon from the gastrointestinal tract. It issuspected that the immune response to fecal flora isinappropriate, thus causing an inflammatory responseas part of the ethiopathogenesis, however no specificorganism has yet been identified as the culprit. Thereare documented cases of long term remission withoutthe need of immunosuppressive therapy after fecalmicrobiota therapy, this greatly increases the qualityof life in these chronically ill patients [16]. The pa-tients with ulcerative colitis are willing and motivatedto try out novice methods of therapy with a high remis-sion potential and which are relatively safe even whentheir current therapy regime is satisfactory [14, 15].

The spectrum of bacteria is altered in patientswith ulcerative colitis compared to healthy individ-uals. Patients with ulcerative colitis seem to havea lower count of Bacteroidetes a Fermicutes. Judgingmy mucosal models these bacteria play an importantrole in T-cell activation routes.

The first patient was treated by fecal microbiotatherapy for ulcerative colitis in 1988, followedby other 55 with different gastrointestinal diseases.

Six of those patients followed up with ulcerativecolitis remain asymptomatic until this day.

The first study published on non- Clostridiumdifficile infection patients with ulcerative colitis wasin 1989 by Bennet and Brinkman, the first patient wasBennet himself who suffered from active colitis fora 7 year period prior to the self-administration of fecalmicrobiota from a healthy donor, this was followedby a 3 month remission period without the need of anyother medication for the first time in all the yearsof his disease. However evidence of fecal microbiotatherapy curing patients with ulcerative colitis islimited to a small group of patients. Why treatmentworks on some patients and doesn’t work on othersis yet to be found out. The curing effect of fecalmicrobiota therapy for ul-cerative colitis is not asimmediate as that for Clostridium difficile infection,but there are lasting changes in the inflamed mucosaof the gut for better, which in years can causeuninflamed mu-cosa. There are trials currentlyconducted for the use of fecal microbiota therapyfor ulcerative colitis[14, 17, 38–41].

Crohn’s disease

Crohn’s disease is another common idiopathicbowel disease. The first attempts to treat Crohn’s dis-ease with fecal microbiota therapy date back to 1988,however the results are poorly sustained. There arerecent studies conducted on this matter with no per-suasive histological or clinical effect in the diseaseprogression even with a qualitative change in the mi-crobiota. However anecdotal cases of self-adminsteredfecal matter with a positive affect are described [1,42, 43].

Irritable bowel syndrome

Irritable bowel syndrome is another diseasepotentially treatable by fecal microbiota transplant.One study was conducted with about 300 patientswith an effect in patients with more severe formsof diarrhea and abdominal pain. However, results arenowhere near as dramatic as those with Clostridiumdifficile infection. There are anecdotal reportsof others forms of irritable bowel syndrome such asconstipation, however further studies are neededto see a more clear picture [44, 45].

Metabolic syndrome, obesity and energy harvest

In animals and humans microbiota seems to havea direct role in the capability of energy harvest from

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food. Germ-free mice are altogether protected fromobesity and metabolic syndrome even when a Westerndiet is rich in fats. However these mice, whencolonized with microbiota of normal mice, gain upto 60% body weight in 2 weeks. This is followedby an increase in insulin resistance even after foodintake is reduced. Food which originally could not bedigested can be fermented and absorbed after inocu-lation of microbiota. Presence of bacteria in the gutincrease hepatic lipogensis via the suppressionof certain lipoprotein lipase inhibitors therefore withthese observations, the influence on energy homeo-stasis is suspected.

Some of the fermented metabolites serve as pre-biotics for beneficial intestinal bacteria. The reduc-tion of prebiotics and therefore bacteria can causeinflammatory states in the intestine.

Diets rich in fats seem to increase lipopoly-sacharide containing intestinal microbiota and alsodownregulate the amount of Bifidobacteria.This state is also called metabolic endotoxemia,which is accompanied by a pro-inflammatory stateweight gain and insulin resistance. Bifidobacteria arecapable of lowering levels of lipopolysacharied andnormalizing the levels of plasmatic endotoxins,it diminishes metabolic endotoxemia and glucosetolerance can improve, weight loss and increasedsatiety occurs in human subjects [15, 46].

Short-chain fatty acids such as acetate, butyrateand propionate can be fermented by microbes fromundigestable carbohydrates in the human gut. The mainshort-chain fatty acid in the human gut is acetate,some short-chain fatty acids such as propionate canbe used for de novo glucose synthesis and can serveas an energy source for the host. Germ-free mice aredeficient in short-free fatty acids. After a diet changethe composition of the gut microbiota is altered,therefore the availability of certain short-chain fattyacids is also altered. This directly modulates energyabsorption, possibly by stimulating peptide YY whichis the obesity hormone. The short chain fatty acidwith most potential as a stimulating molecule is bu-tyrate, however the precise role of mechanism isunclear. Experiments with mice who were fed witha high-fat western diet supplemented with butyratedid not seem to develop insulin resistance even withobesity[2, 15].

After gastric bypass surgery patients begin losingweight, suggesting that this surgery has a direct effectalso followed by an antidiabetic effect which is

prior to weight loss itself. Some bacteria likeFaecalibacterium prausnitzii are less present in obesepatients, but seems to increase after this surgery, alsothe amount of this bacteria negatively correlateswith the amount of inflammatory markers where allof this seems to indicate that there is a direct im-munomodulating effect of bacteria. Germ-free micecannot develop diet induced obesity and insulinresistance, this is also shown by the effect of antibi-otics on mice with normal microbiota, which havea reduction of adiposity after therapy and an im-provement in glucose metabolism [5, 33, 47].

Carbohydrates are the main source of energy forboth bacteria and human cells. The human body isnot capable of degrading complex plant poly-saccharides such as starch, inulin and xylans.The microbiota ferments these into end productslike short-chain fatty acids such as acetate,propionate a butyrate. Short chain fatty acids arealso an important substrate for inflammation, gutmotility, vasodilatation. Also short chain fatty acidsare important for nutrition of the colonic epitheliumand peripheral tissue. The patterns of fermentationdepend on consumed carbohydrates and the mi-crobiota composition.

The only direct proof of energy harvest comesfrom germfree rats. These rats have reduced amountsof short chain fatty acids in the intestine and twice asmuch excretion of urinary and fecal calories in com-parison with rats on a same diet with the presenceof gut microbiota. Germ-free mice must compensatewith the increased intake of food. Germ-free micegain weight within 14 days after being colonized withnormal flora. The obesity phenotype is transmissiblevia microbiota. Rodents colonized with microbiotaof obese mice tend to gain twice as much as thosecolonized by microbiota of lean mice. There areindirect studies which suggest a comparable effectin humans. These is a higher level of ethanol in breathof obese people in comparison to lean people, thissuggests, that there is more fermentation to shortchain fatty acids and energy harvest processes aremore capable in the gut of the obese [48, 49].

Diet directly influenced the composition of the in-testinal microbiota, changes in microbiota are notice-able three to four days after a major diet change, butcan be readily reversed with the reverse of diet.

It seems that the two main bacteria that are diet-dependent in animal models are Bacteroidetes andFermicutes.

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In rodent models a high-fat Western diet seemsto increase the abundance of Firmicutes and decreasethe abundance of Bacteroidetes. However, there arenow no studies that fully prove this in humans.

The microbiota composition depends on the foodwe consume, people with a higher amount of poly-saccharides in their diet, have a higher amountof Bacteroidetes in the gut, like the people of ruralAfrica with mainly Prevotella and Xylanibacter,on the other hand the people who have a western diethave a higher level of Enterobacteriaceae, for ex-ample Shigella and Escherichea.

Prevotella and Xylanibacter in the guts of peoplemainly on a polysaccharide diet, like the childrenof rural Africa are capable of degrading cellulosea xylans into fecal short chain fatty acids, thereforea maximal amount of energy can be harvested froma fibre rich diet. There are 3 main enterotypes.

The human microbiota can be divided into threemain types of enterotype, the division is not 3 discreteentities but more a fluent gradient. Three main bac-teria dominate these enterotypes being Bacteroides,Prevotella and Ruminococcus. These three enterotypesare not affected by age, gender or nationality. Howeverall of these are influenced by certain diets. Enterotypesdominated by Bacteroidets are associated with con-sumption of a diet dominant in animal proteins andfat, whereas the enterotype dominated by Prevotellais associated with a polysaccharide based diet.

The Ruminococcus enterotype is least separatedand more often merges with the Bacteroidesenterotype.

However, a 10-day diet change is not enoughto change the enterotype of one individual, a longterm change is necessary to make a main shiftin the microbiota composition to happen.

Specific changes in colonies of bacteria canhappen after daily consumption of polysaccharideseven after short periods of time. For example, usageof prebiotics such as inulin can induce growthof Bifidobacterium species. In obese mice, prebioticscause a reduction of adiposity and levels of inflam-matory molecules derived by bacteria such as somelipopolysacharides in comparison with obese micewho were not fed with prebiotics.

Dietary fat affects microbiota consumption in micewith a reduction of Bacteroides and the increase

in the number of Firmicutes and Proteobacteria.The transplantation of microbiota of a high fat dietfed mouse to a germ free recipient increasesthe adiposity of the recipient mouse significantly.The alteration of microbiota seems to contributeto dietary induced obesity. The precise mechanismis not known [4, 5, 18, 50].

Anecdotal cases of fecal microbiotia therapybeing applied to patients with multiple sclerosis,Parkinson’s disease, chronic fatigue syndrome,idiopathic thrombocytopenic purpura, rheumatoidarthritis sacroileitis, kalitosis, acne, insomnia,depression have been described in literature.A positive effect was observed in all cases.

The intestine with its immune system and mi-crobial ecosystem plays a crucial role in the humanbody. Different insults can alter this subtle balanceleading to a disease which can be life threatening. It iscertain that fecal microbiota therapy is an importantand rising method of therapy in the last few years, andwill be even more so in the years to come. More stud-ies on the precise mechanisms of action of this therapyand the composition of micobiota must be completedso that the therapy can be under-stood and preferablyone day personalized for the exact need of every pa-tient. Also a more standardized guideline for the com-position of the fecal matter and the route of adminis-tration and the preparation of the host and donoris needed worldwide to make this promising andinspiring method of treatment more standardized.

ACKNOWLEDGEMENT

The work was supported by FVZ SV2015.

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