REVIEW

Influence of Microbiota on NSAID Enteropathy:A Systematic Review of Current Knowledgeand the Role of Probiotics

Martina Rekatsina . Antonella Paladini . Maria Grazia Cifone .

Francesca Lombardi . Joseph V. Pergolizzi . Giustino Varrassi

Received: March 11, 2020 / Published online: April 10, 2020� The Author(s) 2020

ABSTRACT

Microbiota are increasingly studied, providingmore precise information on their importantrole in physiologic processes. They also influ-ence some pathologic processes, such as NSAID-induced enteropathy. This side effect is muchmore diffuse than it has been described in thepast. It derives mainly from the local action ofthe medicines and is caused by the local bindingof gram-negative bacterial lipopolysaccharides

and infiltration of neutrophils into the intesti-nal mucosa. The initial interest in the interac-tion between these damages and microbiota isvery old, but new and interesting data areavailable. This review aims to focus on recentstudies on NSAID-induced enteropathy, anoften-underestimated medical condition, andon the influence of microbiota on this condi-tion. Apart from the broadly investigated use ofantibiotics and other mucosal protective solu-tions, this systematic review focuses mostly onthe use of probiotics, which directly influenceintestinal microflora. Other important factorsinfluencing NSAID-induced enteropathy, suchas sex, advanced age, infection and use of pro-ton pump inhibitors, are also discussed.

Keywords: Enteropathy; Gut microbiota;NSAIDs; Probiotics

Enhanced Digital Features To view enhanced digitalfeatures for this article go to https://doi.org/10.6084/m9.figshare.12063216.

M. RekatsinaAnaesthetic Department, Moorfields Eye Hospital,London, UK

A. Paladini � M. G. Cifone � F. LombardiDepartment of Life, Health and EnvironmentalSciences, University of L’Aquila, Building Delta 6,67100 L’Aquila, Italy

J. V. PergolizziNEMA Research Group, Inc, Naples, FL, USA

G. Varrassi (&)Paolo Procacci Foundation, Via Tacito 7, 00193Rome, Italye-mail: giuvarr@gmail.com

G. VarrassiWorld Institute of Pain, Winston Salem, NC, USA

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https://doi.org/10.1007/s12325-020-01338-6

Key Summary Points

NSAIDs may be responsible forgastroenteric side effects. Enteritis of thisorigin is frequently not diagnosed

Microbiota have a crucial role in thehomeostasis of the intestinal mucosa andits functionality

This systematic review analyzes what hasbeen studied on the interaction betweenthe microbiota and possible NSAID-induced enteritis

Many studies, both experimental and onhumans, have investigated the topic

Currently, it is clear that the use ofprobiotics may help in preserving thefunctionality of the enteral mucosa inpatients treated with NSAIDs

It would be interesting to have clearer dataon the the real relationship between thetwo. These should be based on clinicaltrials in humans aiming to clarify whichkinds of probiotics are most useful toprevent or treat enteritis due to use of anyNSAID, especially in patients using themchronically or in combination with low-dose aspirin for cardiovascular riskprevention

INTRODUCTION

Microbiota affect NSAID-induced enteropathyin several ways. They influence the cytotoxicityof bile, enterohepatic circulation of NSAIDs andphysiologic process of ulcer healing [1]. Theimportant role of microbiota in NSAID-inducedenteropathy was explored many years ago. Itwas noted that in 3 days oral indomethacinadministered to conventional rats produced asyndrome of often fatal of intestinal lesionscharacterized by multiple ulcers and peritonitis[2]. Germ-free rats were found to be resistant ordeveloped very mild lesions, but they were re-sensitized when exposed to Escherichia coli.

Due to the alarming clinical symptoms ofNSAID-induced enteropathy, which include thepresence of blood in the stool due to ulceration,anemia of unknown etiology or symptoms ofobstruction due to ‘diaphragm-like’ intestinalstrictures, many researchers have tried to identifythe underlying mechanisms [3]. The initial dam-age to themucosal barrier function is attributed toNSAID-induced prostaglandin deficiency andmitochondrial malfunction [3]. The binding ofgram-negative bacterial lipopolysaccharides (LPS)aswell as thehigh-mobility groupbox1 (HMGB1)from the injured epithelial cells to Toll-likereceptor 4 (TLR4) on macrophages leads to theactivation of many pathways that release proin-flammatory cytokines such as tumor necrosisfactor-a (TNF-a), interleukin-1b (IL-1b) and che-mokines. This inducesneutrophil infiltration intothemucosa and submucosa of the small intestine,causing damage [4] (Fig. 1).

In general, an increase in the number of gram-negative bacteria and their LPS in the mucosainduces activation of neutrophils along with theNSAID action and causes ulcer formation [5]. Arecent paper has suggested that the correction ofthe dysbiosis could be an important target totreat intestinal damage after NSAID use andrestore normal functionality [6]. It was statedthat although it is not always feasible to avoid aninduction of dysbiosis, probiotics can be used tocorrect it. All thementioned studies attractedourinterest and ledus to carry out an investigationofwhat has happened in the last few years in theresearch on the role of microbiota related to theuse of NSAIDs. This systematic review focuses onsome aspects of NSAID-induced enteropathy,especially on the use of probiotics to prevententeric mucosal damage induced by NSAIDs.This article is based on previously conductedstudies and does not contain any studies withhumanparticipants or animals performedby anyof the authors.

METHODS

Search

The search was made of electronic databases inDecember 2019, including PUBMED, Scopus

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and Cochrane Database of Systematic Reviews.We used a series of logic combinations andresearch terms related to the topic (‘‘micro-biota,’’ ‘‘NSAIDs,’’ ‘‘small intestine,’’ ‘‘gut,’’ ‘‘gas-trointestinal tract’’) to perform searches in eachdatabase. Published systematic reviews on thesame topic were reviewed to identify the addi-tional randomized controlled trials. An exampleof the searching strategy for PUBMED is: (‘‘mi-crobiota’’ [All Fields]) AND (‘‘Non-SteroidalAnti-Inflammatory Drugs’’ [All Fields]) AND(‘‘small intestine’’ [All Fields] OR ‘‘gut’’ OR‘‘gastrointestinal tract’’ [All Fields]). An addi-tional search was conducted in January 2020 toidentify possible studied probiotic supplementsagainst the microbiota dysbiosis. The searchwords were: (‘‘probiotics’’ [All Fields] or ‘‘probi-otic strains’’ [All Fields] AND ‘‘NSAIDS’’ [AllFields]) AND (‘‘small intestine’’ [All Fields] or‘‘small bowel’’ [All Fields] or ‘‘large intestine’’

[All Fields] or ‘‘large bowel’’ [All Fields] or ‘‘gas-trointestinal tract’’ [All Fields]). Only paperspublished in English and whose full text wasavailable were included in this study.

Selection Process

The initial screening of the literature was madeexamining titles and abstracts and removingduplicates. The eligibility of the studies wasdouble-checked by two independent authorsreviewing the full text. Other authors wereconsulted when uncertainty appeared, such aswhether different publications were from thesame trial. Disagreements were resolved by dis-cussion between the authors, followed by con-sulting an external reviewer.

Fig. 1 Mechanism underlying the pathophysiology ofNSAID-induced intestinal damage. PG prostaglandins,HO-1 heme oxygenase-1, ONOO- peroxynitrite, NO nitricoxide, iNOS inducible nitric oxide synthase, NF-jB

nuclear factor-jB, NLRP3 pyrin domain-containing 3,TLR4 Toll-like receptor 4, LPS lipopolysaccharide, TNFatumor necrosis factor a, IL-1b interleukin-1b

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Inclusion and Exclusion Criteria

For the first search, the inclusion criteria were:(1) studies focusing on microbiota changes inthe small intestine; (2) the study subjects hadreceived NSAIDs during the study; (3) thestudies suggested a mechanism of NSAID actionon the small intestine or suggested a treatment/therapeutic approach to lesions in the smallintestine. The exclusion criteria were: (1) studieswithout sufficient data for microbiota; (2) studysubjects had received medication other thanNSAIDs. The second search was conducted toidentify possible therapeutic approaches tar-geting microbiota alterations in subjects whosuffered from NSAIDs enteropathy using thesame inclusion and exclusion criteria.

This review also examined the bibliographiesfrom the most recent reviews and additionalprimary literature sources as well as referencescited by relevant articles. All the articles iden-tified were imported to Rayyan. Finally, allincluded articles were imported to Mendeley asa citation tool.

Objective

Chronic NSAID users are affected to variousextents by small intestine injury at a rate of50–70% [7]. Until recently, no specific therapyhad been identified against NSAID-inducedenteropathy. Therefore, we conducted thisreview, integrating a systematic approach todetermine any developments regarding thecurrent knowledge. We aim to shed light onpossibilities to prevent/cure these lesions usingprobiotic supplements or enhancing the naturaleffects of microbiota. This review includes con-trolled trials in both animals and humans.

RESULTS

The initial search identified 86 publications,while the second identified 53. After duplicateshad been removed, we screened 135 articles,excluding 67 of them. Sixty-eight articles wereassessed for eligibility to be included in ourmanuscript; 23 did not meet the inclusions

criteria and therefore were excluded. Finally,45 articles/book chapters were included in thequalitative synthesis (Fig. 2).

Antibiotics and Changes in Microbiota

The changes in gut microbiota after NSAID usewere the focus of Teran-Ventura et al. [8] intheir controlled trial, where they induced acuteindomethacin enteropathy in rats (injectingtwo doses of the medicine in 48 h) and observedthe animals for 4 days. After this period, whilethe controls showed no histologic changesconsistent with the presence of intestinalinflammation, the indomethacin-treated ani-mals showed microscopic signs of inflamma-tion, with significantly worse histopathologicscores. Moreover, although the luminal ilealmicrobiota of the controls was dominated byLactobacillus/Enterococcus spp., in the treatedgroup the dominant bacterial groups were Bac-teroides spp., Enterobacteriaceae and Clostridiumcoccoides/Eubacterium rectale, indicative of a stateof dysbiosis. The authors concluded that there isa potential role for gut microbiota in thepathophysiology of intestinal inflammation.

Recently, the effect of rifaximin on diclofe-nac small bowel enteropathy was studied on arat model [9]. The animals had receiveddiclofenac 4 mg/kg for 2 weeks. A delayed-re-lease formulation of the antibiotic was admin-istered 1 h before the NSAID. Diclofenacinduced ileal mucosal lesions through inflam-matory pathways and microbiota changes.Rifaximin seemed to prevent diclofenac-in-duced enteropathy through both antibacterialand antiinflammatory activities. After NSAIDadministration, TNF, IL-1b, TLR-2, TLR-4,MyD88 and NF-jB levels were increased, whilecaspase-1 was also activated. Ileal occludinexpression (an intestinal epithelial tight junc-tion protein) was decreased, and the balance ofbacteria turned with an increase in Proteobac-teria and Bacteroidetes. However, rifaximincompensated for all these changes by increasingthe proportion of Lactobacilli and also reducingIL-1b production and inhibiting the upstreamcaspase-1 activation.

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Regarding the mechanisms underlying theeffects of probiotics on the intestinal mucosa,some recent in vitro studies have shown evi-dence of the ability of a multistrain probiotic toprevent molecular and cellular damage causedby oxidative and heat-induced stress [10, 11].Another placebo-controlled study also attrib-uted ‘‘eubiotic’’ properties and antimicrobialactivities to rifaximin [12]. Healthy volunteersreceived diclofenac (75 mg twice daily) plusomeprazole (20 mg once daily) and eitherrifaximin (400 mg) or placebo twice daily for14 days. Subjects were assessed by videocapsuleendoscopy at baseline and after 2 weeks oftreatment. Mucosal breaks were detected in 20%of subjects given rifaximin and in 43% of sub-jects given placebo, leading the researchers tothe above conclusion.

Dealing with the intestinal flora itself, aresearch group evaluated the changes in mousegut microbiota following indomethacin

administration and observed a significantincrease of Firmicutes and decreased quantity ofBacteroidetes [13]. In their trial, the use ofantibiotics to reduce gut microbiota led to ahigher mortality rate in mice than controls,indicating the crucial role of microbiota. How-ever, mice pre-transplanted with adaptivelychanged microbiota had less small bowel injuryand lower levels of proinflammatory cytokineswhen exposed to the NSAIDs, showing theimportance of bacteria [13]. Moreover, it issuggested that antibiotics targeting gram-nega-tive bacteria are usually effective in reducing theextent of NSAID-induced intestinal ulceration.In contrast, antibiotics against gram-positivebacteria do not appear to play a significant role[14]. Other important information regardingantibiotics and NSAIDs is the dynamic interplaybetween the two medication groups. One studyshowed that a single oral dose of indomethacinelicited changes in the composition and

Fig. 2 PRISMA flow diagram

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diversity of the microbiota. Moreover, themicrobiota changed indomethacin’s pharma-cokinetics and pharmacodynamics as well as itseffectiveness [15].

Type of NSAID and MicrobiotaComposition Difference

Although many studies consider NSAIDs as asingle category of medication, when it comesto microbiota changes, significant differencesseem to take place. In aspirin-treated patients,Prevotella spp., Bacteroides spp., family Ru-minococaceae and Barnesiella spp. were identi-fied. In contrast, in the celecoxib/ibuprofenusers there was an abundance of Aci-daminococcaceae and Enterobacteriaceae. More-over, bacteria from the familiesPropionibacteriaceae, Pseudomonadaceae, Punice-icoccaceae and Rikenellaceae were most commonin people on ibuprofen rather than naproxen[16]. Finally, in the same study, Bacteroides spp.and Erysipelotrichaceae spp. discriminatedbetween subjects using NSAIDs with protonpump inhibitors (PPIs) and those using NSAIDsalone. The role of PPIs will be more extensivelydiscussed in this article.

A very important pilot study showed ame-lioration of small bowel injury by switchingfrom non-selective NSAIDs to celecoxib inpatients with rheumatoid arthritis [17]. Con-version to COX-2 selective NSAIDs for 12weeks significantly reduced the number ofpetechiae and red spots in the gut, the numberof mucosal breaks and Lewis scores in endo-scopic images.

A former study investigated two COX-2selective NSAIDs, celecoxib and etoricoxib,along with two nonselective NSAIDs, indo-methacin and diclofenac. The latter reducedhemoglobin levels, whereas etoricoxib andcelecoxib did not have any effects. Moreover,celecoxib caused less damage compared withthe other NSAIDs. Their findings suggest thatnonselective NSAIDs and etoricoxib can induceenteropathy through a topical action, whereascelecoxib lacks relevant detrimental actions[18].

High Fat Diet and Dysbiosis

As lower intestinal damage comprises animminent danger, many scientists have tried tocome up with protective solutions againstinflammation and dysbiosis. Sugimura et al.[19] showed that a high fat diet could inducesmall intestinal damage through gut dysbiosisin NSAID-treated animals. The mice fed thistype of diet for 2 months ended up with sig-nificantly decreased Bifidobacterium spp. popu-lations. Moreover, the intestinal permeabilitywas increased, while there was a ptosis in pro-tein expressions of zonula occludens-1 (ZO-1)and occludin, which are both tight junctionproteins. Interleukin (IL)-17A levels in the smallintestine were also higher than expected. In thisstudy, normal diet-fed mice received smallintestinal microbiota from high-fat diet-fedmice and had the same symptoms and findings.Neutralizing antibodies against IL-17A weregiven to the transplanted mice, and the symp-toms were significantly reduced as a conse-quence. The researchers concluded that HFD-induced alterations of small intestinal micro-biota cause microinflammation through theinduction of IL-17A, suggesting a therapeuticstrategy against this factor. Moreover, anincrease in intestinal permeability was noted,which aggravated NSAID-induced small intesti-nal damage. Their suggestions were that low-fatdietary therapy and strategies to enhance indi-vidual-specific innate functions of Bifidobac-terium may be useful for the prevention andmitigation of NSAID-induced small intestinaldamage.

Influence of probiotics on NSAID-inducedenteropathy

Bifidobacterium breve

Recently, a randomized, double-blind trial ofhealthy volunteers who received 300 mgacetylsalicylic acid (ASA) daily for 6 weeksfound that the concomitant use of Bifidobac-terium breve (Bif195, 5 9 1010 colony-formingunits) safely reduced the risk of small-intestinalenteropathy caused by ASA [20].

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Lactobacillus gasseri (LG) OLL2716

Another group has identified Lactobacillus gas-seri (LG) OLL2716 as possibly useful in reducingaspirin-induced small bowel injuries and inmitigating gastrointestinal symptoms [21]. Inthis double-blind study, patients receivedaspirin for[ 1 month and 112 ml yogurt con-taining LG or placebo twice daily for 6 weeks.Before and after treatment, small bowel injurieswere evaluated by capsule endoscopy, andsymptoms were assessed using the FrequencyScale for the Symptoms of GastroesophagealReflux Disease (FSSG) and the GastrointestinalSymptom Rating Scale (GSRS) questionnaires.According to the findings, the LG group hadsignificantly fewer small bowel mucosal breaksand reddened lesions, while the FSSG and GSRSscores were also significantly improved.

Lactobacillus plantarum TIFN101and WCFS1

Three Lactobacillus plantarum strains (L. plan-tarum WCFS1, CIP104448, TIFN101) wereinvestigated for their effects on in-vivo smallintestinal barrier function and gut mucosalgene transcription [22]. The selection of thesespecific strains was made through their differ-ential effects on Toll-like receptor signaling andtight junction protein rearrangement. In thisrandomized, double-blind placebo-controlledcross-over trial, the patients received indo-methacin and then sequentially the differentstrains with a washout period. None of thestrains had an effect on the lactulose-rhamnoseratio (an indicator of small intestinal perme-ability), which increased after administration ofindomethacin. However, L. plantarum TIFN101proved to have more repairing properties. L.plantarum TIFN101 was also found to preventthe serum reduction of CD4?/Foxp3 regulatorycells, caused by NSAIDs, by enhancing theresponses against tetanus toxoid (TT) antigen. Itwas also found to upregulate genes associatedwith the maintenance of T- and B-cell functionand antigen presentation. Finally, L. plantarumTIFN101 and WCFS1 were both able to down-regulate immunologic pathways involved in

antigen presentation, showing indications oftissue repair [23].

High-concentration multi-strain probioticmixture

The probiotic mixture VSL#3 has been exten-sively investigated and is currently recom-mended for the prevention and treatment ofchronic pouchitis and ulcerative colitis [24–26].A study describes the effects of VSL#3, con-taining 450 billion freeze-dried bacteria (Strep-tococcus thermophilus, Bifidobacterium longum, B.breve, B. infantis, Lactobacillus acidophilus, L.plantarum, L. casei, L. Bulgaricus), administeredfor 3 weeks, on the survival rates and smallintestinal injuries in indomethacin-treatedsubjects [27]. The improvements appeared to beclosely associated with a decrease in proin-flammatory cytokines such as IL-1b, IL-6 andTNF-a as well as an increase in the antiinflam-matory cytokine IL-10 [27, 28].

Bifidobacterium adolescentis

This was found to significantly reducenaproxen-induced small intestinal enteropathyin rats, which was attributed to its ability toproduce high levels of lactic acid [29]. Rats wereallocated to three different groups, where for5 days they were administered a prebiotic inu-lin, or a vehicle, or a high lactate-producingBifidobacterium adolescentis (109 CFU) or a lowlactate-producing Bifidobacterium longum strain(109 CFU). After that, naproxen small intestinalenteropathy was induced, and the damage wasblindly scored at the end of the treatment per-iod. Their results showed that intestinal damagewas similar in rats treated with inulin or vehicle,while treatment with B. adolescentis resulted inan 82% reduction in the extent of intestinaldamage. Additionally, B. longum did not showany beneficial effect. Therefore, it was suggestedthat the high lactate-producing Bifidobacterium-based probiotics might represent a viableapproach to NSAID-induced enteropathy.

A recent publication examined the protec-tive effects of a combination of the probioticBifidobacterium longum BB536 (2.5 9 106 CFU/

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rat twice daily) with the prebiotic lactoferrin(100 mg/kg twice daily) in a rat model ofdiclofenac-induced enteropathy [30].

Lactobacillus casei ShirotaLactobacillus casei Shirota exhibits a prophylacticeffect on indomethacin-induced enteropathy inrats by suppressing the lipoproteins/Toll-likereceptor 4 (LPS/TLR4) signaling pathway [31].This effect may be mediated by L-lactic acid.

Other Treatments Affecting Microbiota

Rebapamide

Rebapamide, a mucosal protective drug, apartfrom its inflammation-suppressing ability, wasfound to inhibit indomethacin-induced smallintestinal mucosal damage by modulating themicrobiota [32]. The number of Enterococcaceaeand Enterobacteriaceae in the jejunal mucosawere restored to normal levels, and the seg-mented filamentous bacteria were increased.

Diallyl disulfide (DADS)

The ability of a hydrogen sulfide donor, diallyldisulfide, an important mediator of gastroin-testinal mucosal defense, to protect againstNSAID-induced enteropathy has been investi-gated [1]. When rats were treated with a pro-tective dose of DADS (30 mmol/kg), multipleClostridiales families were significantlydecreased, such as Ruminococcaceae and Eubac-teriaceae; Enterococcaceae were decreased, andthe Mucispirillum family was increased. Thus,the above changes in the microbiota induced byadministration of diallyl disulfide may havecontributed significantly to the severity ofnaproxen-induced intestinal damage.

Other Information Regarding NSAIDEnteropathy (Stress, Age, CDI, PPIS)

Stress conditions

Stressful situations in mice were shown toexacerbate NSAID-induced small bowel injury

by inducing changes in intestinal microbiota[33]. Also, it was found to increase both thetotal number of bacteria and the proportion ofgram-negative bacteria as well as the perme-ability of enteral mucosa via glucocorticoidreceptor signaling.

Sex differences

As sex is a variable for multiple health condi-tions, a clinical study investigated the differ-ences in microbiota and NSAID enteropathy inhealthy men and women studying biopsy sam-ples [34]. An important finding was that thecomposition of intestinal flora did not differbetween sexes. However, one further observa-tion was that after indomethacin administra-tion, women had lower intestinal permeabilityand higher microbial diversity than men. Thesechanges were normalized after discontinuationof the medication. Moreover, only womendemonstrated decreased fecal microbial diver-sity after indomethacin, including an increasein Prevotella abundance.

Age

A very interesting study reported the impact ofage on microbial communities in people usingNSAIDs [35]. The total number of microbes inelderly NSAID users was higher than in theelderly without NSAIDs as shifts in all majormicrobial phyla, such as lower numbers of Fir-micutes and an increase in numbers of Bac-teroidetes, were observed. Moreover, in theelderly taking NSAIDs, there were reductions inthe proportion of butyrate producers belongingto Clostridium cluster XIVa, such as Roseburiaand Ruminococcus. Additionally, regarding theActinobacteria group, lower numbers of Col-linsella spp. were identified in contrast to youngadults or elderly not using NSAIDs. The aboveserved as an indication that NSAID usage alongwith advanced age could influence the compo-sition of intestinal microbiota. Finally, rela-tively high numbers of Lactobacillus appearedonly in the NSAID-free elderly patients.

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Clostridium difficile infection

Important information regarding NSAID useand the disturbance of microbiota was obtainedduring Clostridium difficile infection (CDI) [36].The use of NSAIDs has been associated withenhanced susceptibility and severity of CDI. Inmice, the experimental use of indomethacinbefore infection dramatically increased mortal-ity and intestinal pathology. Alterations inmicrobiota seem to play an important role inthe underlying mechanisms.

Proton Pump Inhibitors

Wallace et al. [37] investigated the effect of thesimultaneous consumption of NSAIDs andproton pump inhibitors (PPIs) on the gutmicrobiota. After administering antisecretorydoses of omeprazole or lansoprazole for 9 daysand antiinflammatory doses of naproxen orcelecoxib for 4 days to rats, they evaluatedenteropathy and measured possible microhem-orrhages. They concluded that both PPIs sig-nificantly worsen selective and non-selectiveNSAID enteropathy. A very important observa-tion was that omeprazole treatment signifi-cantly reduced jejunal Actinobacteria andBifidobacteria spp. (around 80%). In contrast,supplementation of selected commensal bacte-ria (Bifidobacteria enriched) during treatmentwith omeprazole and naproxen preventedintestinal ulceration and bleeding. Moreover,the severity of enteropathy increased whenimplanting germ-free mice with jejunal bacteriafrom PPI-treated rats. Physicians should care-fully consider the crucial importance of possibleintestinal damage and bleeding in their high-risk patients before prescribing PPIs and NSAIDsas well as low-dose aspirin concomitantly. It isessential to be aware of the new knowledgeregarding this coadministration. Although PPIsand NSAIDs have been investigated in manystudies in the past, the exact mechanisms oftheir interaction have not been clearly identi-fied. Recently, a group of researchers comparedPPIs with vonoprazan fumarate, a gastric acidsecretion inhibitor with a different mechanismof action, to identify whether the PPI drug class

induces dysbiosis or this depends on the inhi-bition of gastric acid itself [38]. They concludedthat the cause of deterioration of NSAID-in-duced enteropathy is the decreased populationof L. johnsonii in the small intestine, as theadministration of these bacteria amelioratedNSAID-induced small intestinal injury atdoses C 106. In contrast, a dose of 105 did notalter the injury. Moreover, they found that L.murinus but not L. intestinalis amelioratedindomethacin-induced minor intestinal injury.This group rejected Wallace’s proposal to treatNSAID-induced minor intestinal injury associ-ated with PPI treatment by administering Acti-nobacteria. They also found a reduction in thepopulation of Actinobacteria in the small intes-tine after rabeprazole and vonoprazan, but theystated that this reduction is negligible com-pared with the decrease in L. johnsonii.

CONCLUSIONS

This review has highlighted the latest informa-tion from the literature regarding the oftenunderestimated NSAID enteropathy. Specifi-cally, it has analyzed the most recent researchregarding the possible administration of probi-otics to restore the intestinal microbiota andreduce NSAID-induced enteric damages. Untilnow, the administration of selected probioticstrains seems very promising. However, it iscrucial that investigation continues, and thenext steps with larger human randomized clin-ical trials are made. This would definitely pro-vide more important scientific material todiscuss. It is important to highlight that trialsincluding human patients with chronic NSAIDuse have been conducted rather than clinicaltrials with a short-term high dosage of NSAIDs.The latter might reveal many differences in themicrobiota of chronic NSAID users. In additionto the patient’s sex and age, consistent with thegrowing need to provide tailored therapies,clinicians should also take into account thebroad diversity of the gut microbiota and theindividual susceptibility to NSAIDs, especiallyin the presence of intestinal infections such asC. difficile, and the contextual intake of otherdrugs such as PPIs.

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Finally, as strongly suggested by an increas-ing number of studies [39–45], a careful selec-tion of the probiotic agent, standardization ofthe dose and detailed characterization of thebeneficial effects are essential when consideringuse of a probiotic for the management ofNSAID-induced enteropathy. Indeed, thebioavailability of nutrients, drugs, probiotics orother substances administered orally dependson intestinal barrier integrity, which can becompromised in various inflammatory gut dis-eases, including NSAID-induced enteropathy.

ACKNOWLEDGEMENTS

The authors thank Mariella Fusco for herreviewer support in the selection of papers.They are also grateful to Luca Di Giacomo forthe assistance with the graphic design.

Funding. This research has been made pos-sible thanks to an unconditional grant providedby the ‘‘Paolo Procacci Foundation-ONLUS,’’ ViaTacito 7, 00193 Rome, Italy. It was also partiallyfunded by a grant received from ‘‘FondazioneInternazionale Salvatore Maugeri,’’ researchproject ‘‘Modello di Unita di Terapia del Doloree di Cure Palliative, integrate con Associazionidi Volontariato.’’ No Rapid Service Fee wasreceived by the journal for the publication ofthis article.

Authorship. All named authors meet theInternational Committee of Medical JournalEditors (ICMJE) criteria for authorship for thisarticle, take responsibility for the integrity ofthe work as a whole, and have given theirapproval for this version to be published.

Author Contributions. M. Rekatsina carriedout most of the research and drafted the initialmanuscript. All the authors have contributed toreviewing and ameliorating the quality of thepaper and have reviewed and approved the finaldraft of the manuscript.

Disclosures. Martina Rekatsina, Maria Gra-zia Cifone and Francesca Lombardi have

nothing to disclose. Antonella Paladini, JosephV. Pergolizzi and Giustino Varrassi are membersof the journal’s Editorial Board.

Compliance with Ethics Guidelines. Thisarticle is based on previously conducted studiesand does not contain any studies with humanparticipants or animals performed by theauthors without a previous Ethics Committeeapproval.

Data Availability. Data sharing is notapplicable to this article as no datasets weregenerated or analyzed during the current study.

Open Access. This article is licensed under aCreative Commons Attribution-NonCommer-cial 4.0 International License, which permitsany non-commercial use, sharing, adaptation,distribution and reproduction in any mediumor format, as long as you give appropriate creditto the original author(s) and the source, providea link to the Creative Commons licence, andindicate if changes were made. The images orother third party material in this article areincluded in the article’s Creative Commonslicence, unless indicated otherwise in a creditline to the material. If material is not includedin the article’s Creative Commons licence andyour intended use is not permitted by statutoryregulation or exceeds the permitted use, youwill need to obtain permission directly from thecopyright holder. To view a copy of this licence,visit http://creativecommons.org/licenses/by-nc/4.0/.

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