CLINICAL REVIEW

Latest concepts on the association between nonsteroidalanti-inflammatory drug-induced small intestinal injuryand intestinal bacterial flora

Shunji Fujimori • Choitsu Sakamoto

Received: 19 August 2013 / Accepted: 23 August 2013 / Published online: 20 September 2013

� Springer Japan 2013

Abstract Luminal bacteria, one of the main aggressive

factors of nonsteroidal anti-inflammatory drugs (NSAIDs),

induce small intestinal mucosal injury. Because most

bacteria invading from the mouth are eliminated by the

highly acidic gastric environment, the upper small intestine

contains relatively low numbers of microorganisms. With

decreased peristalsis, decreased acidity, and lower oxida-

tion-reduction potential, the ileum maintains a more

diverse microflora and a higher bacterial population. As

NSAID-induced small intestinal ulcerations tend to local-

ize in the small intestinal distal part, as viewed by capsule

endoscopy, the ulcers are in contact with a large amount of

luminal bacteria. Recently, it was reported that proton-

pump inhibitors (PPIs) exacerbate NSAID-induced small

intestinal injury in rats. The study showed that PPIs impair

the ability to disinfect due to the PPI-induced low acidic

gastric environment, and this resulted in transubstantiation

of intestinal flora which exacerbated NSAID-induced small

intestinal injury. If it is true that PPIs exacerbate small

intestinal injury, the methods of preventing NSAID-

induced gastroduodenal injury to defend PPI-induced small

intestinal injury should be reconsidered. Following several

studies, there may be a possibility that probiotics and

prebiotics are useful treatments for the prevention of

NSAID-induced small intestinal injury. A method of

determining bacterial flora maintenance including alter-

ation of the environment and the administration of various

drugs is required.

Keywords Small intestine � NSAID � PPI �Flora � Bacteria

Introduction

There is a great variety of bacteria in the small intestine;

some live in peaceful coexistence with the host, while

others have harmful effects. Because most bacteria invad-

ing from the mouth are eliminated by the highly acidic

gastric environment, the upper two-thirds of the small

intestine contain relatively low numbers of microorgan-

isms, and mainly consist of acid-tolerant Lactobacilli and

Streptococci ranging in concentration from 103 to 104

bacteria/mL. In the distal small intestine, the microflora

begin to resemble those of the colon, with concentrations

of around 107–108 bacteria/mL of intestinal content. With

decreased peristalsis, decreased acidity, and lower oxida-

tion-reduction potential, the ileum maintains a more

diverse microflora and a higher bacterial population [1].

Superficial luminal mucosa of the small intestine create

a wide surface area with an extraordinarily large number of

villi and microvilli for nutrient absorption. Luminal con-

tents such as bacteria, bile acid, and drugs are able to affect

the luminal mucosa because the extensive epithelium clo-

ses against the luminal contents. The increasing luminal

bacterial load when passing from the proximal to the distal

small intestine may play a pathogenic role in NSAID-

induced damage.

In the stomach, the main aggressive factors of NSAIDs

are hydrochloric acid and pepsin which induce peptic

ulcerative lesions. However, in the small intestine, one of

the main aggressive factors of NSAIDs is luminal bacteria

which induce small intestinal mucosal injury. Here, our

aim is to understand the association between luminal

S. Fujimori (&) � C. Sakamoto

Department of Gastroenterology, Graduate School

of Medicine, Nippon Medical School, 1-1-5, Sendagi,

Bunkyo-ku, Tokyo 113-8603, Japan

e-mail: s-fujimori@nms.ac.jp

123

Clin J Gastroenterol (2013) 6:345–351

DOI 10.1007/s12328-013-0424-8

bacteria and NSAID-induced small intestinal injury using

recent reports.

Key process of NSAID-induced small intestinal injury

The first step leading to small intestinal mucosal injury is

considered to be the topical toxicity of NSAIDs, which

induces the uncoupling of mitochondrial oxidative phos-

phorylation in epithelial cells, and which impairs the

intercellular junction, especially the tight junction [2].

NSAIDs have been shown to undergo enterohepatic cir-

culation in rats, and this process has been implicated in

small intestinal injury caused by the topical toxicity of

these drugs [3]. The topical action is followed by increased

mucosal permeability [4]. Increasing small intestinal

mucosal permeability induces aggressive factors in the

luminal content to invade into intraepithelial mucosa and/

or sub-epithelial mucosa. The aggressive factors invade

into luminal mucosa to induce local inflammation [3].

The main aggressive factors in the small intestine are

digestive juice, especially bile acid, and luminal bacteria.

Bjarnason et al. reported that 800 mg/day of metronida-

zole, which is an antimicrobial agent, reduced intestinal

permeability, blood loss, and inflammation in 32 patients

receiving continuous traditional NSAID treatment. This

study proved that luminal bacteria are extremely important

in NSAID-induced small intestinal injury [5]. However, the

defense ability, including mucosal immunity on the small

intestine, is too strong to induce severe small intestinal

mucosal damage such as mucosal breaks by the topical

action of NSAIDs followed by bacterial invasion to intes-

tinal mucosa.

Cyclooxygenase-1 (COX-1) inhibition by NSAIDs plays

an important role in the occurrence of severe NSAID-

induced small intestinal mucosal damage. The magnitude

of the increasing intestinal permeability by the topical

action of NSAIDs directly correlates to the potency of their

ability to inhibit COX-1 [3, 6]. Inhibition of COX-1

reduces levels of protective mucosal prostaglandins in the

small intestine [7]. The precise mechanism by which the

inhibition of COX by NSAIDs translates into injury of the

small intestine is poorly understood. Nevertheless, this

appears to be a prerequisite for NSAID-induced small

intestinal injury and ulceration. However, it has been

clearly shown that COX-1 inhibition is also required to

convert topical toxicity into ulcerative damage.

Somasundaram et al. [4] have shown that co-adminis-

tration of acetylsalicylic acid [ASA] (a COX-1 inhibitor

that is mainly absorbed through the stomach and duode-

num) and dinitrophenol (which increases intestinal per-

meability through the disruption of mitochondrial activity)

induce intestinal ulceration similar to that induced by

indomethacin. Meanwhile, transgenic COX-1 knockout

mice have no apparent intestinal pathology and are less

sensitive to NSAID-induced ulceration [8]. Small intestinal

damage (NSAID enteropathy) is triggered by the syner-

gistic action of two or more of the biochemical actions

common to all NSAIDs (COX-1 ? COX-2 inhibition,

COX-1 inhibition ? ‘topical’ effect, etc.) [9]. Topical

effects include effects by luminal content such as luminal

bacteria, bile, food and enzymes, and changes in intestinal

motility, etc. [3, 9, 10]. Thus, small intestinal injury is not

only induced by COX-1 inhibition. However, previous data

suggest that the inhibition of COX-1 is likely to be a key

process in intestinal ulceration. Therefore, many factors are

involved in the occurrence of NSAID-induced small

intestinal injury.

Types and distribution of NSAID-induced small

intestinal injuries

Capsule endoscopy and balloon-assisted endoscopy [11,

12], advanced modalities that now allow full investigation

of the entire small intestine, have revealed that NSAIDs

can cause a variety of abnormalities in the small intestine,

i.e., denuded areas, erosions, ulcerations, perforation,

bleeding and diaphragm-like strictures [13–19]. Denuded

areas are reddish areas without villi (Fig. 1a, b). Erosions

are lesions with small slough (Fig. 2a, b), and ulcers are

lesions with large slough (Fig. 3a, b). A diaphragm-like

stricture, a specific lesion caused by NSAIDs, is a mem-

branate stricture with an annular ulcer (Fig. 4a, b).

The concentrations of NSAIDs, bile acids, and intestinal

flora tend to differ in the proximal and distal small intestine.

NSAIDs have been shown to undergo enterohepatic circu-

lation in rats and this process has been implicated in the

intestinal injury caused by these drugs [20, 21]. The per-

meability of the jejunum to bile acids is twice that of the

ileum [22], and the concentration of bile acids decreases

from the upper to the lower jejunum [23]. As mentioned

above, there is an increasing luminal bacterial load when

passing from the proximal to the distal small intestine which

may play a pathogenic role in NSAID-induced damage.

With decreased peristalsis, decreased acidity, and lower

oxidation-reduction potentials, the ileum maintains a more

diverse microflora and a higher bacterial population [1].

Thus, one may speculate that the effect of NSAIDs may also

differ in the proximal and distal small intestinal tract.

Therefore, we previously investigated the types and

distribution of small intestinal injuries induced by short-

term NSAID medication as evaluated by capsule endoscopy

[24]. The above study expands on the work of two of our

recent studies on the prevention of NSAID-induced small

intestinal injury by prostaglandins and rebamipide [25, 26].

346 Clin J Gastroenterol (2013) 6:345–351

123

Fifty-three control subjects from these two studies who

were receiving NSAID and proton-pump inhibitor (PPI)

medication, but not receiving prostaglandins or rebamipide

therapy, were further analyzed for extent and location of

small intestinal injury. The study showed that denuded

areas occurred mainly in the oral side of the jejunum,

whereas ulcerations developed exclusively in the anal side

of the ileum. The study defined ulcers as mucosal breaks

with a diameter[10 times that of the surrounding villi.

The study showed that the distribution of denuded areas

and ulcerations in the small intestine clearly differs within

the two tertiles; the majority of denuded areas tended to

localize in the proximal part, whereas ulcerations were

segregated in the distal part. In contrast, unlike denuded

areas and ulcerations, we found erosions scattered

throughout the small intestine. The significant difference in

the distribution of NSAID-induced denuded areas and

ulcerations in the small intestine implies that there might

also be a difference in the pathogenesis involved in the

induction of these two lesions [24].

Most denuded areas were detected in the proximal small

intestine. Concentrations of ingested NSAIDs are higher in

the jejunum than in the ileum due to enterohepatic recy-

cling of NSAIDs. Such recirculation and excretion of

NSAIDs into the gut lumen via the bile might thus produce

more prolonged exposure of the jejunum mucosa to high

concentrations of these agents and their active metabolites

[3]. In experiments with rats, microvascular damage and

distortion followed by jejunum villus shortening have been

shown to be early morphological changes induced by

90 min exposure to indomethacin [27]. These studies

together with our results suggest that denuded areas may be

caused by a high concentration of NSAIDs.

On the other hand, NSAID-induced small bowel ulcer-

ations were caused following increased mucosal perme-

ability and inflammation [3, 28, 29]. NSAID-induced

progressive loss of structural integrity and the consequent

increases in intestinal permeability might expose the

underlying mucosal tissues to gut-luminal contents

including antigens and microorganisms [3]. Pretreatment

with ampicillin or metronidazole has been shown to

Fig. 1 a Capsule endoscopic image of the denuded area in the oral

side of the jejunum induced by diclofenac sodium. b Duodenoscopic

image of the denuded area in the second part of the duodenum

induced by loxoprofen

Fig. 2 a Double-balloon endoscopic image of erosion in the jejunum

induced by loxoprofen. b Colonoscopic image of erosion in the

terminal ileum induced by loxoprofen

Clin J Gastroenterol (2013) 6:345–351 347

123

prevent Gram-negative bacteria from adhering to, and

invading the small intestinal mucosa, thereby preventing

the development of intestinal mucosal injury [30]. Studies

in human volunteers have shown that metronidazole can

reduce NSAID-induced small intestinal injury, as deter-

mined by changes in the excretion of radio-tagged eryth-

rocytes and white cells, and by intestinal permeability

probes [5, 31]. Intestinal bacterial flora is likely poor in the

jejunum and would increase in the ileum. Together, these

previous observations and the present results raised the

interesting speculation that the pathogenesis involved in

the induction of denuded areas might differ from that in

ulcerations; denuded areas might be induced by the direct

action of NSAIDs, while ulcers could result from complex

mechanisms including luminal factors such as bacteria.

The influence of PPIs on the small intestine

Until recently, most studies of NSAID-associated injury

have focused on the upper gastrointestinal tract, since the

stomach and duodenum are sites generally associated with

major morbidity and mortality in the clinical setting.

Therefore, PPIs and prostaglandin analogs have become

the established treatment against NSAID-induced gastro-

duodenal injuries [32]. Many physicians consider the use of

traditional NSAIDs in combination with a PPI, a recom-

mendation found in major treatment guidelines for patients

with a history of gastrointestinal events or for those at a

high risk of developing complications [32]. A common

aspect of studies performed on healthy volunteers as pre-

viously mentioned is that PPIs are co-administered with

traditional NSAIDs to prevent NSAID-induced gastroduo-

denal injury. However, these studies have shown that the

preventive effect of PPIs does not extend to the small

intestine [33]. The studies suggest that treatment for

2 weeks with traditional NSAIDs with PPI medication

causes small intestinal injuries in [50 % of subjects.

Fig. 3 a Capsule endoscopic image of an ulcer in the mid-small

intestine induced by aspirin. b Colonoscopic image of an ulcer in the

terminal ileum induced by aspirin

Fig. 4 a Capsule endoscopic image of a diaphragm-like stricture in

the mid-small intestine induced by diclofenac sodium. b Double-

balloon endoscopic image of a diaphragm-like stricture in the mid-

small intestine induced by loxoprofen

348 Clin J Gastroenterol (2013) 6:345–351

123

Recently, Wallace et al. [34] reported that PPIs exac-

erbate NSAID-induced small intestinal injury in rats. The

study showed that omeprazole and lansoprazole impair the

ability to disinfect due to the PPI-induced low acidic gas-

tric environment, and resulted in transubstantiation of

intestinal flora which exacerbated NSAID-induced small

intestinal injury.

In our experience, a male patient found to have six small

intestinal mucosal breaks by capsule endoscopy, was

administered omeprazole 20 mg once daily immediately

after dinner for a period of 2 weeks. After treatment,

twelve small intestinal mucosal breaks were detected in the

subject. Figure 5a shows the pre-treatment capsule endo-

scopic image of the most severe small intestinal mucosal

breaks in the subject. Figure 5b shows the post-treatment

capsule endoscopic image of the most severe small intes-

tinal mucosal breaks in the subject. A follow-up capsule

endoscopy performed 3 weeks after withdrawal of ome-

prazole administration revealed seven small intestinal

mucosal breaks showing restitution of the small intestinal

mucosal injury [35].

If it is true that PPIs exacerbate small intestinal injury,

most capsule endoscopy studies as previously mentioned,

which evaluated NSAID-induced small intestinal injury

with concomitant administration of PPIs, might have over-

evaluated the frequency of NSAID-induced small intestinal

injury. Accordingly, the methods of preventing NSAID-

induced gastroduodenal injury to defend PPI-induced small

intestinal injury should be reconsidered.

Approach of probiotics for NSAID-induced small

intestinal injury

Probiotics are viable micro-organisms with beneficial

physiologic or therapeutic properties. Biotic therapies have

been put to practical use for inflammatory bowel diseases

including ulcerative colitis and Crohn’s disease [36–41].

Many studies suggest that probiotics might be useful for

the maintenance of remission or prevention of recurrence

in patients with ulcerative colitis. Multiple mechanisms of

action have been suggested to explain how probiotics exert

their effect on intestinal inflammation. These mechanisms

can be classified broadly as the suppression of pathogenic

bacterial growth, prevention or inhibition of bacterial

binding and invasion of the epithelium, and improved

epithelial barrier function and immunoregulatory activities

[42, 43].

Recently, Endo et al. used Lactobacillus casei to prevent

aspirin-induced small intestinal injury in 13 patients. They

found small intestinal injury significantly decreased in a

probiotic-treated group compared with 12 patients in a

control group and concluded that probiotic administration

may prevent NSAID-induced intestinal injury [44]. How-

ever, the study was a small-scale pilot study using one

bacterial strain, and more extensive studies with many

subjects and comparing many bacterial strains are clearly

necessary to determine whether probiotic administration

prevents NSAID-induced small intestinal injury.

Prebiotics are dietary components that foster the growth

of beneficial bacteria. Recently, oligosaccharide and psy-

lium, which have a prebiotic effect on intestinal bacterial

flora, have been added to health food throughout the world.

Prebiotics may also have a preventive effect on NSAID-

induced small intestinal injury by improved intestinal

bacterial flora. The combined use of probiotics and prebi-

otics is known as a synbiotics. Probiotic therapy can

potentially be improved through combination with a pre-

biotic that promotes growth of the probiotic population in

the large intestine [45, 46]. We reported that patients with

ulcerative colitis treated with synbiotic therapy using

psyllium as a prebiotic and a strain of Bifidobacterium

longum as a probiotic experienced higher quality of life

than patients with ulcerative colitis treated with only

Fig. 5 a Capsule endoscopic image of the most severe small

intestinal mucosal breaks in a subject with enteropathy before PPI

treatment. b Capsule endoscopic image of the most severe small

intestinal mucosal breaks in the subject after PPI treatment

Clin J Gastroenterol (2013) 6:345–351 349

123

probiotics or prebiotics [47]. The study suggested that

synbiotic therapy may have a synergistic effect of probio-

tics and prebiotics in the treatment of patients with ulcer-

ative colitis.

Further studies evaluating the influence of luminal

bacteria using various strains of both probiotics and pre-

biotics for intestinal diseases are required. Following fur-

ther studies, there may be a good possibility that

established probiotics and prebiotics are useful treatments

for the prevention of NSAID-induced small intestinal

injury.

Conclusions

Luminal bacteria have a significant relationship with

NSAID-induced small intestinal injury. It is an important

fact that PPIs exacerbate NSAID-induced small intestinal

injury by transubstantiation of intestinal bacterial flora. It is

necessary to determine a method of bacterial flora main-

tenance that includes alteration of the environment and the

administration of various drugs.

Disclosures

Conflict of Interest: Authors disclose the following: Dr Fujimori

serves as interpretation service of capsule endoscopy and lecture to

Given Imaging Ltd. Dr Sakamoto has served as a consultant and

speaker for Astellas Pharma Inc., AstraZeneca, Eisai Co., Ltd.,

Otsuka Pharmaceuticals Co., Ltd., Pfizer Japan Inc., and Takeda

Pharmaceuticals Co., Ltd. Dr Sakamoto has also received grant/

research support from Astellas Pharma Inc., AstraZeneca, Eisai Co.,

Ltd., Otsuka Pharmaceutical Co., Ltd., Pfizer Japan Inc., and Takeda

Pharmaceutical Co., Ltd.

Human/Animal Rights: All procedures followed were in accordance

with the ethical standards of the responsible committee on human

experimentation (institutional and national) and with the Helsinki

Declaration of 1975, as revised in 2008(5).

Informed Consent: Informed consent was obtained from all patients

for being included in the study.

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