Review article: uncomplicated diverticular disease of the colon

Review article: uncomplicated diverticular disease of the colonL . PETRUZZIELLO, F . IACOPINI , M. BULAJIC, S . SHAH & G. COSTAMAGNA

Digestive Endoscopy Unit, Department

of Surgery, Universita Cattolica ‘A.

Gemelli’, Rome, Italy

Correspondence to:

Dr L. Petruzziello, Universita Cattolica

del Sacro Cuore, Largo A. Gemelli 8,

00168 Rome, Italy.

E-mail:

[email protected]

Publication data

Submitted 21 November 2005

First decision 27 November 2005

Resubmitted 17 February 2006

Accepted 22 February 2006

SUMMARY

Diverticular disease of the colon is the fifth most important gastrointes-tinal disease in terms of direct and indirect healthcare costs in westerncountries. Uncomplicated diverticular disease is defined as the presenceof diverticula in the absence of complications such as perforation, fis-tula, obstruction and/or bleeding. The distribution of diverticula alongthe colon varies worldwide being almost always left-sided and directlyrelated to age in western countries and right-sided where diet is rich infibre.

The pathophysiology of diverticular disease is complex and relates toabnormal colonic motility, changes in the colonic wall, chronic mucosallow-grade inflammation, imbalance in colonic microflora and visceralhypersensitivity. Moreover, there can be genetic factors involved in thedevelopment of colonic diverticula. The use of non-absorbable antibi-otics is the mainstay of therapy in patients with mild to moderatesymptoms, and the effect of fibre-supplementation alone does notappear to be significantly different from placebo, although no definitedata are available.

More recently, alternative treatments have been reported. Mesalazineacts as a local mucosal immunomodulator and has been shown toimprove symptoms and prevent recurrence of diverticulitis. In addition,

probiotics have also been shown to be beneficial by re-establishing anormal gut microflora. In this study, the current literature on uncompli-cated diverticular disease of the colon is reviewed.

Aliment Pharmacol Ther 23, 1379–1391

Alimentary Pharmacology & Therapeutics

ª 2006 The Authors 1379

Journal compilation ª 2006 Blackwell Publishing Ltd

doi:10.1111/j.1365-2036.2006.02896.x

INTRODUCTION

Colonic diverticulosis is a common acquired condition

characterized by the presence of mucosal and sub-

mucosal outpouchings at points of weakness in the

muscularis propria where feeding blood vessels (vasa

recta) penetrate the muscle layer. These pseudodiver-

ticula frequently occur mostly in the sigmoid colon,

usually in parallel rows, vary in number and are gen-

erally 5–10 mm in diameter.1, 2 Recently, this condi-

tion has been defined in a consensus conference in

Rome3 according to the presence of symptoms: diverti-

culosis when asymptomatic and diverticular disease

(DD) when associated with symptoms. Diverticular dis-

ease is subdivided into uncomplicated or complicated

when perforation, fistula, obstruction and/or bleeding

are present.

Diverticular disease represents the fifth most

important gastrointestinal (GI) disease in western

countries in terms of direct and indirect healthcare

costs with an estimated mortality rate of 2.5 per

100 000 per year.4 Although present worldwide, DD

is highly prevalent in industrialized countries with

the highest rates reported in the United States, Eur-

ope and Australia.5–8 The prevalence rises with age

and diverticulosis in the UK affects approximately

5% of people in the fifth decade of life increasing

to almost 50% by the ninth decade9–11 with the

exception of vegetarians in whom the frequency of

DD is much lower.12 In contrast to the west, DD is

almost unknown in rural Africa and Asia where the

prevalence is <0.2%,9, 13 even if in urbanized areas

such as Singapore, Japan and Hong Kong, it occurs

in about 20% of people.14–17 The distribution of DD

also varies between western and eastern countries. In

western countries diverticulosis is mostly limited to

the left colon6, 18 whereas in Asia isolated right-

sided diverticulosis is common.14, 15 The process of

urbanization with the introduction of a western-style

diet lacking in fibre has been associated with a

gradual rise in the prevalence of diverticulosis in

developing countries, but the disease remains pre-

dominantly right-sided.16, 19–21

PATHOGENESIS

Diverticular disease of the colon is the result of com-

plex interactions between dietary fibre, colonic wall

structure and intestinal motility.

Fibre intake

The recommended dietary fibre intake for adults is

about 20–35 g/day, but the average intake in the west

is only 14–15 g/day.22 Painter and Burkitt7 were the

first to report on the importance of dietary fibre in the

pathogenesis of DD, coining the term ‘a deficiency dis-

ease’ in 1968. Cellulose (a fibre that is not hydrolysed

by human digestive enzymes23) has been shown to be

particularly protective leading to more bulky and

voluminous stools, resulting in a wider-bore colon and

thus preventing hypersegmentation and high intralu-

minal colonic pressures.24, 25 The amount of dietary

fibre intake is the principal factor that influences

bowel transit times and stool volume, both of which

are markedly reduced in the UK subjects compared

with Ugandans.26 However, a difference in dietary

composition does not entirely explain the pathogenesis

of DD as no differences have been demonstrated in

transit times and stool volume in patients with and

without DD.27

Changes in the colonic wall

A decrease in tensile strength of both the collagen and

muscle fibres of the colonic wall, which occur as a

result of ageing, may also be an important factor.28

The reason for this change seems to be related to an

increase in cross-linking of abnormal collagen

fibrils29–31 and to the continuous deposition of elastin

throughout life in all layers of the colonic wall.24 The

extracellular matrix (ECM) is important in maintaining

the strength and integrity of the colonic wall.32 It has

been postulated that both damage and breakdown of

mature collagen, and the synthesis of immature colla-

gen may lead to a weakened colonic wall23 and to

more distensible muscle fibres.33, 34 Colonic compli-

ance in the sigmoid and descending colon has also

been demonstrated to be lower than that in the trans-

verse and ascending colon, explaining at least in part

the left-sided predominance of diverticulosis in west-

ern countries.23 Thompson et al.30 reported that colla-

gen fibrils in the left colon were smaller and more

tightly packed than those in the right colon with

increasing age, and that this difference was accentu-

ated in DD. However, abnormalities of both the circu-

lar and longitudinal muscle layers (taeniae coli) of the

colon in DD exceed the effect ascribed to ageing

alone.35 Structural changes in the colonic wall may

1380 L . PETRUZZIELLO et al.

ª 2006 The Authors, Aliment Pharmacol Ther 23, 1379–1391


also be responsible for the appearance of diverticula at

an early age in connective tissue disorders such as

Marfan’s and Ehlers-Danlos syndrome and polycystic

kidney disease.36, 37

Matrix metalloproteinases (MMP) are a group of

zinc-dependent endopeptidases that are involved in

ECM degradation and remodelling.38, 39 They are

secreted as inactive precursors by a variety of cells

including mesenchymal cells, macrophages, mono-

cytes, T cells, neutrophils, myofibroblasts and tumour

cells.40 Conversion into the active enzyme usually

occurs in the pericellular or extracellular space. MMPs

are structurally related but can be divided into sub-

classes: collagenases (MMP-1, -8, 013 and 018), gela-

tinases (MMP-2 and -9), stromelysins (MMP-3, -7, -10

and -11), elastase (MMP-12), membrane types (MMP-

14, -15, -16, -17, -24 and -25) and others (MMP-19,

-20, -23, -26, -27 and -28).40 Activation of an MMP

usually results in an enzymatic cascade resulting in

degradation of all classes of ECM, including collagens,

non-collagenous glycoproteins and proteoglycans. Tis-

sue inhibitors of metalloproteinases (TIMPs) are also

present, which block the effects of endogenous MMP,

and are produced by the same cells that produce

MMPs. Under normal conditions, MMPs are present at

low levels, usually in the inactive form, and are

responsible for normal physiological tissue turnover.40

Tissue expression of MMP is regulated by several

mechanisms;41 TIMPs control the local activity of

MMPs in tissues. However, if the production of MMPs

exceeds that which can be regulated by TIMPs, break-

down of ECM occurs. MMPs have been shown to have

an important role in both tissue injury and healing in

the gut.40 Recent studies have shown an increase in

MMPs in the inflamed gut and in fistulae associated

with inflammatory bowel disease.42, 43 In stenotic

Crohn’s disease, isolated tissue myofibroblasts have

been shown to express high levels of TIMP-1, which

inhibits MMP-mediated ECM degradation.44 An

increase in collagen synthesis and TIMP-1 has also

been demonstrated in collagenous colitis45 and DD.38

Mimura et al. demonstrated an increase in collagen

deposition in the mucosa, submucosal layer and mus-

cularis propria together with increased expression of

TIMP-1 and TIMP-2 in both complicated and uncom-

plicated DD.38 Stumpf et al. also demonstrated changes

in tissue expression of MMPs in DD, reporting a

decrease in the expression of MMP-1 in association

with decreased levels of mature collagen type 1, in

patients with diverticulitis.46 These studies suggest that

changes in MMP and TIMP expression may contribute

to the structural changes in the colonic wall seen in

patients with DD.

Colonic motility

Abnormal colonic motility is thought to be an import-

ant factor in the pathogenesis of DD.1, 34, 37 Patients

with diverticulosis demonstrate abnormal motility and

excessive colonic contractility, particularly in seg-

ments bearing diverticula.47–50 Studies in patients with

DD have shown either a normal51 or increased resting

intracolonic pressure52, 53 with a significant increase

in intraluminal pressure, or colonic activity, after a

meal or prostigmine provocation.51–53 Myoelectrical

recordings from implanted catheters in patients with

DD demonstrate an alteration in ‘slow waves’,54 cor-

responding to colonic pacemaker activity, and exces-

sive segmental activity55 or ‘spikes’, reflecting muscle

contractions.56 The term ‘slow waves’ is used to des-

cribe the spontaneous rhythmic electrical activity that

is present within the circular and longitudinal smooth

muscle layer of the gut wall.57 Slow waves are gener-

ated by a specialized network of cells of mesenchymal

origin, the so-called interstitial cells of Cajal (ICC).58

When excited sufficiently, a slow wave is associated

with circular muscle contraction; slow waves deter-

mine the frequency and propagation of smooth muscle

contractile activity.59 The ICC are crucial to the

generation and propagation of pacemaker activity and

together with the enteric nervous system57 is respon-

sible for the control of GI motility. ICC are necessary

for normal intestinal motility,60 and also mediate neu-

rotransmission from enteric motor neurones61, 62 to

the muscle in the gut wall.57, 63 The role of ICC as

intestinal pacemakers has been demonstrated in

experimental animal models, which have shown that a

lack of ICC networks leads to the absence of slow

waves, and delayed or absent intestinal motility.64, 65

Furthermore, ICC have also been shown to be reduced

or absent in diseases associated with alterations in GI

motility, such as hypertrophic pyloric stenosis,66 dia-

betic gastroparesis,67 intestinal pseudo-obstruction,68

slow-transit constipation60, 69, 70 and congenital

absence of the enteric nervous system, or Hirsch-

sprung’s disease.66 Morphological abnormalities of ICC

have also been demonstrated in patients with ulcera-

tive colitis71 and in animal models of colonic inflam-

mation, and this may explain the colonic dysmotility,

which is described in colitics.72

REVIEW: UNCOMPLICATED DIVERT ICULAR DISEASE 1381



In the human colon, three populations of ICC have

been identified:73, 74 ICC-SM (submuscular plexus),

along the submucosal surface of the circular muscle

layer;57 ICC-MY (myenteric plexus), within the inter-

muscular space between circular and longitudinal

muscle layers and ICC-M (intramuscular), within the

muscle fibres of the circular and longitudinal muscle

layers. In normal healthy tissue, the majority of ICC

are found in the myenteric plexus and are equally dis-

tributed throughout the entire colon.60 Slow wave

activity is generated by the ICC-SM and ICC-MY75

whereas ICC-IM is involved in neurotransmission from

the enteric nervous system to muscle cells.76 A recent

study by Bassotti et al.77 demonstrated that patients

with diverticulosis have significantly reduced numbers

of all subpopulations of colonic ICC and enteric glial

cells, but normal numbers of enteric neurones com-

pared with healthy controls. A reduction or loss of ICC

function may decrease or eliminate colonic electrical

slow wave activity, thereby resulting in delayed tran-

sit.77 Although the ICC is essential for normal motility

in the gut, the enteric nervous system may also play a

role. In diverticulosis, loss of smooth muscle choline

acetyltransferase activity, upregulation of M3 recep-

tors, and increased in vitro sensitivity of the smooth

muscle to exogenous acetycholine have been docu-

mented, suggesting that cholinergic denervation

hypersensitivity may occur in this condition.55, 78 This

together with a decrease in ICC may explain the motor

abnormalities described in DD. However, what is

unclear is whether the abnormal motility precedes29 or

follows the development of diverticula.49

Visceral sensation

Symptoms in symptomatic uncomplicated DD may be

indistinguishable from those of the irritable bowel

syndrome (IBS). Visceral hypersensitivity is the term

used to describe an excessive perception or an exces-

sive neural afferent response to physiological stimuli.79

Patients with IBS demonstrate an increased visceral

perception in response to rectosigmoid distension.80–83

Recent study has also suggested that visceral sensation

is altered in patients with DD. Clemens et al. compared

visceral perception of pain in response to rectal and

sigmoid colon distension in patients with symptomatic

uncomplicated DD, asymptomatic DD and healthy con-

trols.84 Patients with symptomatic uncomplicated DD

showed an increase in pain perception in the sigmoid

colon compared with healthy controls, and also

increased pain perception in the rectum compared with

asymptomatic diverticular patients and healthy con-

trols. Hence, patients with symptomatic uncomplicated

DD show a heightened visceral perception to rectosig-

moid distension, which is not found in asymptomatic

diverticular patients. This visceral hypersensitivity is

not limited to the diverticula-bearing sigmoid colon

and is not due to altered compliance of the gut wall.

These findings indicate a generalized hyperperception

of intestinal stimuli in symptomatic diverticulosis

which resembles IBS.80, 82

The cause of the visceral hypersensitivity is not

entirely clear but there is increasing evidence of an

interaction between the enteric nervous and immune

systems.85, 86 In experimental models of colitis, local

tissue injury results in the release of proinflammatory

mediators that can sensitize enteric afferent nerve ter-

minals resulting in a heightened response to noxious

stimuli.79, 87 These changes may affect the muscle

layers as well as the mucosa88 and may also occur at

non-inflamed sites.89, 90 Furthermore, experimental

models of colitis also demonstrate that intestinal mus-

cle dysfunction and increased activity of primary

afferent enteric neurones may persist after resolution

of the acute mucosal inflammation.86, 91, 92 Low-grade

inflammation has also been demonstrated in the intes-

tinal mucosa of patients with postinfectious IBS, and

this may explain in part the heightened visceral sensa-

tion in these patients.93 Other inflammatory conditions

such as inflammatory bowel disease and coeliac dis-

ease are also associated with disturbed intestinal motor

function and increased sensory perception. Although

there is limited data on visceral hypersensitivity in

DD, persisting GI symptoms can occur after an episode

of diverticulitis, and low-grade inflammation has been

reported in patients with symptomatic DD.94 In keep-

ing with animal models of intestinal inflammation,95

neuronal changes have also been demonstrated in

patients with acute diverticulitis with neuronal prolif-

eration evidenced by increased nerve staining within

the muscularis propria.96

Genetic factors

The association of diverticula with Marfan’s and Ehler’s

Danlos syndromes indicates involvement of connective

tissue97, 98 and a possible genetic predisposition to the

development of diverticulosis. Case studies in siblings

have been reported99 but there have been no definitive

studies assessing familial risk in DD. Cross-linking of




collagen is a normal phenomenon which is essential for

maintaining the structure of collagen. However, exces-

sive cross-linking is thought to lead to rigidity and loss

of tensile strength.23 Wess et al.100 demonstrated an

increase in collagen-linking and the development of

diverticulosis in rats fed a fibre-deficient diet for

18 months. The concentration of short chain fatty acids

(SCFAs) particularly butyrate, was also lower in the

bowel of fibre-deficient rats. SCFAs are the principal

end products of microbial carbohydrate fermentation

(dietary fibre), and an important source of energy-yield-

ing substrates to the colonic mucosa101 In addition,

parental fibre intake may also influence the develop-

ment of diverticulosis in the offspring,102 suggesting an

interaction between possible genetic predisposition and

environmental factors. Thus, lower fibre diet may cause

higher collagen cross-linking possibly through a lower

production of SFCAs. Specific alterations in collagen

have also been demonstrated in patients with DD.

Stumpf et al.46 and Bode et al.103 demonstrated an

increased synthesis of type III collagen, but not type I

(mature) collagen, in colonic diverticulosis.

CLINICAL ASPECTS

An estimated 20% of patients with diverticulosis will

develop symptoms throughout their lifespan, 50–70%

of patients treated for the first episode of diverticulitis

will recover and have no further clinical problems and

only 20% of these patients will develop recurrent

symptoms. Furthermore, 25% of patients with recur-

rent uncomplicated DD will develop complications,

and about 1–2% will require hospitalization and 0.5%

surgery.104 In addition, 25% of patients with DD may

present with diverticular colitis105–107 characterized by

oedematous, hyperaemic, granular and occasionally

ulcerated mucosal folds with sparing of the diverticu-

lar orifices. The pathogenesis of the colitis and its

association with the presence of diverticula remains

unclear. Histologically, diverticular colitis may be

indistinguishable from that of Crohn’s colitis.106, 108

The mechanisms by which symptoms develop are

still unclear56, 109 and probably relate to the interac-

tion between colonic dysmotility, mucosal inflamma-

tion and intestinal microflora. Changes in the

intestinal microflora may explain, in part, the develop-

ment of symptoms in patients with colonic diverticulo-

sis. Stasis of luminal contents occurs in colonic

diverticula resulting in bacterial overgrowth.110 This in

turn may give rise to chronic low-grade mucosal

inflammation which sensitizes intrinsic primary affer-

ent neurones in the submucosal and myenteric

plexus,111, 112 resulting in visceral hypersensitivity and

changes in colonic motor function.95, 113 Such changes

may be mediated by alterations in neurochemical

transmitters. Increased levels of substance P, an exci-

tatory neurotransmitter that is important in visceral

nociception,114 have been reported in patients with DD

and abdominal pain, but without inflammation.115

Other authors have also described similar increases in

the level of substance P in patients with chronic right

iliac fossa pain in association with neuroproliferative

changes within the appendix, in the absence of

inflammation.116 Studies have also shown an increase

in the inhibitory neurotransmitter vasoactive intestinal

polypeptide (VIP) in patients with DD,117 which may

explain the alterations in colonic motility. Methane,

which is produced by gut bacteria, may also have an

effect by slowing intestinal transit and reducing post-

prandial plasma levels of serotonin.118

The most common symptom of uncomplicated DD is

abdominal pain,119 which may be exacerbated by eat-

ing and eased by defecation or the passage of flatus.

Other symptoms such as nausea, episodic diarrhoea,

constipation and bloating may also be present. How-

ever, a causal relationship of these non-specific symp-

toms with diverticulosis is sometimes difficult to

establish due to the high prevalence of IBS in western

countries.120 The symptoms of right-sided DD are sim-

ilar to those of left-sided DD with the exception of

symptom localization and age of onset.121, 122 How-

ever, the frequency of diverticula of the right colon

does not increase with age, suggesting that the condi-

tion might be self-limiting.16 Severe bleeding is also

more common in right-sided DD whereas diverticulitis

and fistulation are more frequent in left-sided DD.123

Many patients with DD present with symptoms at an

age when colorectal cancer is common124 and for this

reason colonoscopy is often the preferred investiga-

tion.125 However, the presence, localization and severity

of diverticulosis are better assessed with double contrast

barium enema.126–128 In contrast, barium enema has a

poor sensitivity for the detection of small colonic ade-

nomas and may miss up to 50% of large adenomas

(>1.0 cm diameter).129 This is more so in patients with

severe sigmoid diverticulosis in whom radiological

interpretation can be extremely difficult due to the pres-

ence of multiple ‘pockets’, luminal narrowing and colo-

nic spasm.128, 130 Colonoscopy may also be difficult in

such patients due to difficulty in visualization of the




colonic lumen as a result of luminal narrowing from

prominent enlarged folds, or fixation from previous

inflammation and pericolic fibrosis.131 The nature and

time course of symptoms may also help in deciding on

the most appropriate investigations. The indication for

an initial ultrasound examination is related to the diffi-

culty in attributing symptoms to the lower GI tract, and

its usefulness is related to the experience of the sonog-

rapher.132 In case of suspected complicated DD, ultraso-

nography, computerized tomography (CT) scan or

magnetic resonance imaging (MRI) are preferred133

because of the potential risk of perforation associated

with either colonoscopy or double-contrast barium

enema. Finally, there is insufficient data to support the

routine use of virtual colonography in patients with

severe diverticulosis.134

There are no good predictive factors for the develop-

ment of symptoms although it has been shown that

the involvement of a short segment of colon, a young

age (<50 years), and lack of physical activity may be

associated with an increased risk.135 A large prospect-

ive study found that a diet low in fibre and high in fat

and red meat carries a threefold risk of developing

symptomatic DD.136 The importance of low-grade coli-

tis in chronically symptomatic DD has been highligh-

ted by Horgan et al.94 In this study mild inflammatory

changes of the mucosa were found in 76% of patients

undergoing surgery and resolution of symptoms was

reported by over 75% of these patients.

TREATMENT

No treatment or follow-up needs to be offered to the

majority of patients with diverticulosis, and to those

with a single previous episode of symptoms of uncom-

plicated DD due to the low risk of recurrence.104 Treat-

ment of recurrent uncomplicated DD is aimed at relief

of symptoms and prevention of major complications,

but the standard approach is still debated. The principal

treatments are a fibre-rich diet and non-absorbable

antibiotics, but alternatives include mesalazine and pro-

biotics (Table 1). Anticholinergic and antispasmodics

agents may be effective in some cases of uncomplicated

DD, but their use remains to be confirmed by controlled

studies.

Fibre-supplementation

Dietary fibre consists of the structural and storage

polysaccharides and lignin in plants that are not

digested in the human stomach and small intestine.

These fibres are incompletely or slowly fermented by

microflora in the colon and promote normal laxation.

The recommended intake of fruit or vegetables is 20–

35 g/day for healthy adults, and age plus 5 g/day for

children.137 Fibre intake may be supplemented as sol-

uble and insoluble fibre. Soluble fibre (psyllium, ispag-

hula, calcium polycarbophil) dissolves in water,

forming a gel, and is fermented in the colon by bac-

teria to a greater extent than insoluble fibre. Short

chain fatty acids and gas are the active metabolites of

soluble fibre, both of which shorten the gut transit

time alleviating constipation and intracolonic pressure,

possibly resulting in a reduction of pain.138 In con-

trast, insoluble fibre (corn fibre, wheat bran) undergoes

minimal change causing an increase in the faecal

mass.

Painter139 was the first to advocate fibre-supplemen-

tation in symptomatic DD and the beneficial effects

were first reported in 1977 in two double-blind con-

trolled trials.139, 140 These studies showed significant

improvement in symptoms after a high-fibre regimen

over a 3-month period compared with placebo. Two

subsequent smaller randomized-controlled trials repor-

ted differing results. The first trial found no significant

difference between bran (7 g/day fibre), ispaghula husk

(9 g/day fibre) and placebo (2 g/day fibre) on symptom

relief after 4 months, although both active treatments

significantly reduced straining at stool, increased wet

stool weight and stool frequency, and significantly

softened the stools.141 The second study comparing

methylcellulose (1 g daily) and placebo also reached a

similar conclusion over a follow-up period of

3 months.142 Both studies did not assess complication

rates related to DD. Finally, previous observational

studies have reported that a high fibre diet prevents

the development of symptomatic DD143 and its com-

plications144, 145 despite a compliance rate of only

72% for fibre-supplementation. Therefore, there is lim-

ited evidence for the effectiveness of fibre in the treat-

ment of uncomplicated DD. From results of a

systematic review of fibre treatment in IBS, fibre-sup-

plementation showed a significant improvement of

global symptoms and constipation.146 Soluble and

insoluble fibres affected IBS differently: soluble fibre

was beneficial for global symptom improvement

whereas insoluble fibre resulted in worsening of

abdominal pain in some patients when compared with

a normal diet. Nowadays, a high-fibre diet is often

suggested for the prevention of DD, and insoluble




fibres from fruits and vegetables seem to be more pro-

tective than those from cereals.136, 137, 147

Non-absorbable antibiotics

Over the last decade, there has been much study on

the role of non-absorbable antibiotics in the manage-

ment of uncomplicated DD. Rifaximin is a broad spec-

trum poorly absorbable antibiotic which has been

evaluated in patients with DD. Rifaximin acts by bind-

ing to the b-subunit of bacterial DNA-dependent RNA

polymerase resulting in inhibition of bacterial RNA

synthesis. Pharmacokinetic studies have demonstrated

that 80–90% of orally administered rifaximin is con-

centrated in the gut with <0.2% in the liver and kid-

neys. The mode of action of rifaximin in reducing the

frequency of symptoms in patients with DD is

unknown, but rifaximin has been shown to influence

the metabolic activity of the gut flora, degradation of

dietary fibres and the production of gas, as confirmed

in patients with IBS.148 Furthermore, the cyclic admin-

istration of rifaximin may have an indirect effect on

mucosal inflammation by modulating the gut flora

responsible for low-grade, chronic mucosal inflamma-

tion.112 Currently, rifaximin is indicated in patients

with acute and chronic Gram-positive and Gram-neg-

ative bacterial bowel infections, travellers’ diarrhoea,

preoperative and post-operative prophylaxis in GI sur-

gery, but not for symptomatic DD although data on

the literature show that rifaximin is more effective

than fibre-supplementation alone. Two randomized-

controlled trials found that rifaximin plus dietary

fibre-supplementation improved symptoms compared

with fibre-supplementation alone after 12 months of

Table 1. Results of fibre-supplementation, rifaximin, mesalazine and probiotics in uncomplicated diverticular disease

TrialPatients(n)

Treatment

SymptomreductionDaily dose Duration

Fibre-supplementationPainter139 Open 62 Bran 12–14 g 8 weeks 89%

9 Bran 6.7 g <0.02�*Brodribb140 RCT 9 Placebo 0.6 g 12 weeks N.S.�

16 Methylcellulose 1 g <0.01�Hodgson142 RCT 11 Placebo 12 weeks N.S.�

Bran 7 g 40%Ornstein et al.141 RCT 56 Ispagula husk 9 g 16 weeks 41%

Placebo 2.3 g 45%Leahy et al.145 Open 31 High fibre diet >25 g 10 years 81%*

25 Free diet <25 g 56%Rifaximin

Papi et al.160 Open 107 Rifaximin 800 mg + glucomannan 2 g 1 week/month 64%*110 Glucomannan 2 g ·12 months 48%

Papi et al.149 RCT 84 Rifaximin 800 mg + glucomannan 2 g 1 week/month 69%*84 Placebo + glucomannan 2 g ·12 months 39%

Latella et al.150 RCT 595 Rifaximin 800 mg + glucomannan 4 g 1 week/month 57%*373 Placebo + glucomannan 4 g ·12 months 29%

MesalazineBrandimarte and Tursi152 Open 90 Mesalazine 1.6 g (after rifaximin 800 mg) 8 weeks 96%

ProbioticsFricu and Zavoral155 Open 15 Escherichia coli Nissle 5.0 · 1010

(after dichlorchinolinol)5 weeks 14 months�*

Dichlorchinolinol 750 mg + activecoal 960 mg

1 week 2.4 months�

* P < 0.05.� Mean symptom score variation from baseline to the end of treatment.� Remission length.




treatment. The first study randomized 168 patients

with uncomplicated DD to fibre-supplementation (glu-

comannan 2 g/day) plus rifaximin (400 mg b.d.) or

fibre-supplementation plus placebo for 1 week out of

every month over a period of 1 year.149 Fibre-supple-

mentation plus rifaximin was associated with a signifi-

cant increase in the proportion of patients with no or

only mild symptoms (69% with rifaximin vs. 39% with

placebo), but did not result in a significant improve-

ment in the severity of diarrhoea, tenesmus, or abdom-

inal pain. The second multicentre study enrolled a

larger population (968 patients) and compared fibre-

supplementation (glucomannan 4 g/day) plus rifaximin

(400 mg b.d.) with glucomannan alone.150 Dietary

fibre-supplementation plus rifaximin was shown to

significantly improve global symptom score compared

with fibre-supplementation alone. Approximately 30%

therapeutic gain compared with fibre-supplementation

alone may be expected after 1 year of intermittent

treatment with rifaximin, and considering its safety

and tolerability, rifaximin may be useful in patients

with symptomatic uncomplicated DD. Finally, a recent

study showed that patients with DD treated with

rifaximin over a period of 10 years experienced a

5% relapse rate of symptoms and a 1% rate of

complications.151

Mesalazine

Mesalazine, an anti-inflammatory drug that is typically

used in patients with inflammatory bowel disease, has

recently been reported to be a possible alternative treat-

ment option in patients with uncomplicated DD. Mesal-

azine was discovered to be therapeutically active in

ulcerative colitis through a mechanism of action that

appears to be topical rather than systemic, reducing

inflammation by blocking cyclo-oxygenase and inhibit-

ing prostaglandin (PG) production in the colon. Accord-

ing to the hypothesis that the symptoms of DD might be

secondary to chronic mucosal inflammation, Brandim-

arte and Tursi152 treated 90 patients with rifaximin

(400 mg b.d.) plus mesalazine (800 mg t.d.s.) for

10 days followed by mesalazine (800 mg b.d.) for a fur-

ther 8 weeks. At the end of the treatment period, 81% of

patients were asymptomatic suggesting that mesalazine

might be beneficial in maintaining clinical remission.

Although the results of this study are encouraging, fur-

ther studies are needed with longer follow-up before

mesalazine can be considered a valid alternative for the

prevention of recurrent symptoms in patients with DD.

Probiotics and prebiotics

Probiotics are a preparation of, or a product contain-

ing viable defined micro-organisms in sufficient num-

bers, which alter the host microflora by implantation

or colonization in a compartment of the host, exerting

beneficial health effects.76, 153 The strains with benefi-

cial properties most frequently belong to the genera

Bifidobacterium and Lactobacillus, but other bacterial

strains have been used including certain strains of

Escherichia coli and non-bacterial organisms such as

Saccaromyces boulardii. The rationale for the use of

probiotics is to re-establish the normal bacterial flora,

which in the presence of DD may be altered by the

reduced colonic transit time and stasis of faecal mater-

ial within the diverticula. There is little data on the

treatment of uncomplicated DD with probiotics. The

first report on the use of probiotics in DD comes from

a prospective observational trial on the prevention of

complications after acute diverticulitis. All patients

with a postdiverticular stenosis of the colon were trea-

ted sequentially with rifaximin and lactobacilli for a

period of 12 months. This treatment proved to be

effective in preventing symptom recurrence and com-

plications.154 The efficacy of probiotic treatment as a

single therapy for uncomplicated DD has been assessed

in only one study comprising a very small group of

patients. A non-pathogenic E. coli strain was given for

a mean period of 5 weeks after a course of treatment

with an intestinal antimicrobial and absorbent, result-

ing in a significantly prolonged remission period and

significant improvement of all abdominal symp-

toms.155 In DD, probiotics may not only relieve func-

tional symptoms but also alleviate intestinal

inflammation, normalize gut mucosal dysfunction and

downregulate hypersensitivity reactions.156

Prebiotics are dietary substances, usually indigestible

complex carbohydrates, which stimulate the growth

and metabolic activity of beneficial enteric bacteria,

especially Lactobacillus and Bifidobacterium species.157

Bacterial fermentation of poorly absorbed carbohy-

drates results in a decrease in luminal pH, which sup-

presses growth of harmful bacteria and production of

butyrate (SCFAs), which is a key substrate for colonic

cell and mucosal barrier function.158 Inulin, fructose

oligosaccharides, lactulose, germinated barley extracts

and psyllium fibre have been shown to promote the

growth of luminal Lactobacillus and Bifidobacterium

species and butyrate production.159 Thus, the optimal

treatment of uncomplicated DD might be an initial




course of antibiotics to normalize the gut flora fol-

lowed by a combination of a probiotic to prevent

relapse, and prebiotic to maintain growth of protective

bacteria.

In conclusion, western diets should be modified

by increasing fibre intake and decreasing fat and

red meat. This ‘easternization’ of the diet should be

the first-line preventative measure for DD as well

colorectal cancer. The therapeutic management of

uncomplicated DD should include non-absorbable

antibiotics such as rifaximin and probiotics, which

may also be beneficial in reducing the complications

from DD. Treatment of diverticular-associated colitis

should include a short course of antibiotics and/or a

trial of mesalazine. Future studies should assess not

only symptom improvement, but also long-term

remission rates, cost of treatment and impact on

quality of life.

REFERENCES

1 Stollman N, Raskin JB. Diverticular dis-

ease of the colon. Lancet 2004; 363:

631–9.

2 Custer TJ, Blevins DV, Vara TM. Giant

colonic diverticulum: a rare manifesta-

tion of a common disease. J Gastroin-

test Surg 1999; 3: 543–8.

3 Kohler L, Sauerland S, Neugebauer E.

Diagnosis and treatment of diverticular

disease: results of a consensus develop-

ment conference. The Scientific Com-

mittee of the European Association for

Endoscopic Surgery. Surg Endosc 1999;

13: 430–6.

4 Sandler RS, Everhart JE, Donowitz M,

et al. The burden of selected digestive

diseases in the United States. Gastroen-

terology 2002; 122: 1500–11.

5 Manousos ON, Truelove SC, Lumsden

K. Prevalence of colonic diverticulosis

in general population of Oxford area.

BMJ 1967; 3: 762–3.

6 Hughes LE. Post mortem survey of

diverticular disease of the colon: I.

Diverticulosis and diverticulitis. Gut

1969; 10: 336–44.

7 Painter NS, Burkitt DP. Diverticular

disease of the colon: a deficiency dis-

ease of western civilization. BMJ 1971;

2: 450–4.

8 Almy TP, Howell DA. Diverticular dis-

ease of the colon. N Engl J Med 1980;

302: 324–31.

9 Painter NS, Burkitt DP. Diverticular

disease of the colon, a 20th century

problem. Clin Gastroenterol 1975; 4:

3–22.

10 Schoetz DJ. Diverticular disease of the

colon: a century-old problem. Dis

Colon Rectum 1999; 42: 703–9.

11 Parks TG. Natural history of diverticu-

lar disease of the colon. Clin Gastroen-

terol 1975; 4: 53–69.

12 Gear JS, Ware A, Fursdon P, et al.

Symptomless diverticular disease and

intake of dietary fiber. Lancet 1976; 1:

511–4.

13 Vajrabukka T, Saksornchai K, Jimakorn

P. Diverticular disease of the colon in a

far-eastern community. Dis Colon Rec-

tum 1980; 23: 151–4.

14 Chia JG, Wilde CC, Ngoi SS, Goh PM,

Ong CL. Trends of diverticular disease

of the large bowel in a newly devel-

oped country. Dis Colon Rectum 1991;

34: 498–501.

15 Nakada I, Ubukata H, Goto Y. Diverti-

cular disease of the colon at a regional

general hospital in Japan. Dis Colon

Rectum 1995; 38: 755–9.

16 Miura S, Kodaira S, Shatari T. Recent

trends in diverticulosis of the right

colon in Japan: retrospective review in

a regional hospital. Dis Colon Rectum

2000; 43: 1383–9.

17 Chan CC, Lo KKL, Chung CH. Colonic

diverticulosis in Hong Kong: distribu-

tion pattern and clinical significance.

Clin Radiol 1998; 53: 842–4.

18 Fearnhead NS, Mortensen NJ. Clinical

features and differential diagnosis of

diverticular disease. Best Pract Res Clin

Gastroenterol 2002; 16: 577–93.

19 Lee YS. Diverticular disease of the large

bowel in Singapore: an autopsy study.

Dis Colon Rectum 1986; 29: 330–5.

20 Segal I, Solomon A, Hunt JA. Emer-

gence of diverticular disease in the

urban South African black. Gastroen-

terology 1977; 72: 215–9.

21 Levy N, Stermer E, Simon J. The chan-

ging epidemiology of diverticular dis-

ease in Israel. Dis Colon Rectum 1985;

28: 416–8.

22 Position of the American Dietetic

Association: health implications of

dietary fiber. J Am Diet Assoc 1997;

97: 1157–9.

23 Mimura T, Emanuel A, Kamm MA.

Pathophysiology of diverticular disease.

Best Pract Res Clin Gastroenterol 2002;

16: 563–76.

24 Smith AN. Colonic muscle in diverticu-

lar disease. Clin Gastroenterol 1986;

15: 917–35.

25 Painter NS, Truelove SC, Ardran GM.

Segmentation and the localisation of

intraluminal pressures in the human

colon, with special reference to the

pathogenesis of colonic diverticula.

Gastroenterology 1965; 49: 169–77.

26 Burkitt DP, Walker AR, Painter NS.

Effect of dietary fiber on stools and the

transit-times, and its role in the causa-

tion of disease. Lancet 1972; 2: 1408–12.

27 Painter NS, Trowell H, Burkitt DP.

Diverticular disease of the colon. In:

Trowell H, Burkitt D, Heaton K, eds.

Dietary Fiber, Fiber-Depleted Foods and

Disease. London, UK: Academic Press,

1985: 145–60.

28 Watters DA, Smith AN, Eastwood MA,

Anderson KC, Elton RA, Mugerwa JW.

Mechanical properties of the colon:

comparison of the features of the Afri-

can and European colon in vitro. Gut

1985; 26: 384–92.

29 Parks T. Rectal and colonic studies

after resection of the sigmoid for diver-

ticular disease. Gut 1970; 11: 121–5.

30 Thomson HJ, Busuttil A, Eastwood MA,

Smith AN, Elton RA. Submucosal colla-

gen changes in the normal colon and

in diverticular disease. Int J Colorectal

Dis 1987; 2: 208–13.

31 Wess L, Eastwood MA, Wess TJ, Busut-

til A, Miller A. Cross linking of colla-

gen is increased in colonic

diverticulosis. Gut 1995; 37: 91–4.

32 Thomson HJ, Busuttil A, Eastwood MA,

Smith AN, Elton RA. The submucosa of

the human colon. J Ultrastruct Mol

Struct Res 1986; 96: 22–30.




33 Tanner MS, Smith B, Lloyd JK. Func-

tional intestinal obstruction due to

deficiency of argyrophil neurones in

the myenteric plexus. Familial syn-

drome presenting with short small

bowel, malrotation, and pyloric hyper-

trophy. Arch Dis Child 1976; 51:

837–41.

34 Bassotti G, Chistolini F, Morelli A.

Pathophysiological aspects of diverticu-

lar disease of colon and role of large

bowel motility. World J Gastroenterol

2003; 9: 2140–2.

35 Sandberg LB, Soskel NT, Leslie JG.

Elastin structure, biosynthesis, and

relation to disease states. N Engl J Med

1981; 304: 566–79.

36 West AB, Losada M. The pathology of

diverticulosis coli. J Clin Gastroenterol

2004; 38 (Suppl. 5): S11–6.

37 Simpson J, Scholefield JH, Spiller RC.

Pathogenesis of colonic diverticula.

Br J Surg 2002; 89: 546–54.

38 Mimura T, Bateman AC, Lee RL, et al.

Up-regulation of collagen and tissue

inhibitors of matrix metalloproteinase

in colonic diverticular disease. Dis

Colon Rectum 2004; 47: 371–8.

39 Nagase H, Woessner JF. Matrix metal-

loproteinases. J Biol Chem 1999; 274:

21491–4.

40 Pender SLF, MacDonald TT. Matrix

metalloproteinases and the gut-new

roles for old enzymes. Curr Opin Phar-

macol 2004; 4: 546–50.

41 Gomez DE, Alonso DF, Yoshiji H, Thor-

geirsson UP. Tissue inhibitors of metal-

loproteinases: structure, regulation and

biological functions. Eur J Cell Biol

1997; 74: 111–22.

42 von Lampe B, Barthel B, Coupland SE,

Riecken EO, Rosewicz S. Differential

expression of matrix metalloproteinases

and their tissue inhibitors in colon mu-

cosa of patients with inflammatory

bowel disease. Gut 2000; 47: 63–73.

43 Schuppan D, Hahn EG. MMPs in the

gut: inflammation hits the matrix. Gut

2000; 47: 12–4.

44 Gordon JN, Di Sabatino A, MacDonald

TT. The pathophysiologic rationale for

biological therapies in inflammatory

bowel disease. Curr Opin Gastroenterol

2005; 21: 431–7.

45 Gunther U, Schuppan D, Bauer M. Fibr-

ogenesis and fibrolysis in collagenous

colitis. Patterns of procollagen types I

and IV, matrix-metalloproteinase-1 and

-13, and TIMP-1 gene expression. Am

J Pathol 1999; 155: 493–503.

46 Stumpf M, Cao W, Klinge U, Kloster-

halfen B, Kasperk R, Schumpelick V.

Increased distribution of collagen type

III and reduced expression of matrix

metalloproteinase 1 in patients with

diverticular disease. Int J Colorectal Dis

2001; 16: 271–5.

47 Weinreich J, Moller SH, Andersen D.

Colonic haustral pattern in relation to

pressure activity and presence of diver-

ticula. Scand J Gastroenterol 1977; 12:

857–64.

48 Trotman IF, Misiewicz JJ. Sigmoid

motility in diverticular disease and the

irritable bowel syndrome. Gut 1988;

29: 218–22.

49 Christopher K, Sadeghi P, Rao S. Inves-

tigation of the pathophysiology of

diverticular disease. Gastroenterology

2000; 118: A833.

50 Bassotti G, Battaglia E, Spinozzi F.

Twenty-four recordings of colonic

motility in patients with diverticular

disease. Evidence for abnormal motility

and propulsive activity. Dis Colon Rec-

tum 2001; 44: 1814–20.

51 Painter NS, Truelove SC. The intralumi-

nal pressure patterns in diverticulosis

of the colon. Gut 1964; 5: 365–9.

52 Arfwidsson S. Pathogenesis of multiple

diverticular of the sigmoid colon in

diverticular disease. Acta Chirurg

Scand 1964; 342 (Suppl.): 1–68.

53 Parks T, Connell A. Motility studies in

diverticular disease of the colon. Gut

1969; 10: 538–42.

54 Hyland JM, Darby CF, Hammond P,

Taylor I. Myoelectrical activity of the

sigmoid colon in patients with diverti-

cular disease and the irritable colon

syndrome suffering from diarrhoea.

Digestion 1980; 20: 293–9.

55 Huizinga JD, Waterfall WE, Stern HS.

Abnormal response to cholinergic sti-

mulation in the circular muscle layer

of the human colon in diverticular dis-

ease. Scand J Gastroenterol 1999; 34:

683–8.

56 Simpson J, Scholefield JH, Spiller RC.

Origin of symptoms in diverticular dis-

ease. Br J Surg 2003; 90: 899–908.

57 Hanani M, Freund HR. Interstitial cells

of Cajal – their role in pacing and sig-

nal transmission in the digestive sys-

tem. Acta Physiol Scand 2000; 170:

177–90.

58 Thomsen L, Robinson TL, Lee JC, et al.

Interstitial cells of Cajal generate a

rhythmic pacemaker current. Nat Med

1998; 4: 848–51.

59 Huizinga JD, Thuneberg L, Vanderwin-

den JM, Rumessen JJ. Interstitial cells

of Cajal as targets for pharmacological

intervention in gastrointestinal motor

disorders. Trends Pharmacol Sci 1997;

18: 393–403.

60 Lyford GL, He CL, Soffer EE. Pan-colo-

nic decrease in interstitial cells of Cajal

in patients with slow transit constipa-

tion. Gut 2002; 51: 496–501.

61 Ward SM, Sanders KM. Interstitial cells

of Cajal: primary targets of enteric

motor innervation. Anat Rec 2001;

262: 125–35.

62 Ward SM, Beckett EA, Wang X. Inter-

stitial cells of Cajal mediate cholinergic

neurotransmission from enteric motor

neurones. J Neurosci 2000; 20: 1393–

403.

63 Boeckxstaens GE. Understanding and

controlling the enteric nervous system.

Best Pract Res Clin Gastroenterol 2002;

16: 1013–23.

64 Ward SM, Burns AJ, Torihashi S, Sand-

ers KM. Mutation of the proto-onco-

gene c-kit blocks development of

interstitial cells and electrical rhyth-

micity in murine intestine. J Physiol

1994; 480: 91–7.

65 Huizinga JD, Thuneberg L, Kluppel M.

W/kit gene required for interstitial cells

of Cajal and for intestinal pacemaker

activity. Nature 1995; 373: 347–9.

66 Vanderwinden JM, De Liu H, Laet MH,

Vanderhaeghen JJ. Study of the

interstitial cells of Cajal in infantile

hypertrophic pyloric stenosis. Gastro-

enterology 1996; 111: 279–88.

67 He CL, Soffer EE, Ferris CD, Walsh RM,

Szurszewski JH, Farrugia G. Loss of

interstitial cells of Cajal and inhibitory

innervation in insulin-dependent dia-

betes. Gastroenterology 2001; 121:

427–34.

68 Schuffler MD, Bird TD, Sumi SM, Cook

A. A familial neuronal disease present-

ing as intestinal pseudo-obstruction.


69 Tong WD, Liu BH, Zhang LY. Decreased

interstitial cells of Cajal in the sigmoid

colon of patients with slow transit con-

stipation. Int J Colorectal Dis 2004; 19:

467–73.

70 He CL, Burgart L, Wang L. Decreased

interstitial cells of Cajal volume in

patients with slow transit constipation.


71 Rumessen JJ. Ultrastructure of intersti-

tial cells of Cajal at the colonic sub-

mucosal border in patients with




ulcerative colitis. Gastroenterology

1996; 111: 1447–55.

72 Reddy SN, Bazzochi G, Chan S. Colonic

motility and transit in health and

ulcerative colitis. Gastroenterology

1991; 93: 934–40.

73 Sanders KM. A case for interstitial cells

of Cajal as pacemakers and mediators

of neurotransmission in the gastroin-

testinal tract. Gastroenterology 1996;

111: 492–515.

74 Ward SM, Sanders KM, Hirst GD. Role

of interstitial cells of Cajal in neural

control of gastrointestinal smooth mus-

cles. Neurogastroenterol Motil 2004; 16

(Suppl. 1): 112–7.

75 Liu LWC, Thuneberg L, Huizinga JD.

Selective lesioning of interstitial cells

of Cajal by methylene blue and light

leads to loss of slow waves. Am J

Physiol 1994; 266: G485–96.

76 Sanders KM, Ordog T, Koh SD, Toriha-

shi S, Ward SM. Development and

plasticity of interstitial cells of Cajal.

Neurogastroenterol Motil 1999; 11:

311–38.

77 Bassotti G, Battaglia E, Bellone G, et al.

Interstitial cells of Cajal, enteric nerves,

and glial cells in colonic diverticular

disease. J Clin Pathol 2005; 58: 973–7.

78 Golden M, Burleigh DE, Belai A.

Smooth muscle cholinergic denervation

hypersensitivity in diverticular disease.

Lancet 2003; 361: 1945–51.

79 Mayer EA, Gebhart GF. Basic and clin-

ical aspects of visceral hyperalgesia.


80 Whitehead WE, Holtkatter B, Enk P.

Tolerance for rectosigmoid distension

in irritable bowel syndrome. Gastroen-

terology 1990; 98: 1187–92.

81 Trimble KC, Farouk R, Pryde A. Heigh-

tened visceral sensation in functional

gastrointestinal disease is not site-spe-

cific. Evidence for a generalized disor-

der of gut sensitivity. Dig Dis Sci 195;

40: 1607–13.

82 Mertz H, Naliboff BD, Munakata J.

Altered rectal perception is a biological

marker of patients with irritable bowel

syndrome. Gastroenterology 1995; 109:

40–52.

83 Bradette M, Delvaux M, Stoumont G.

Evaluation of colonic sensory thresh-

olds in IBS patients using a barostat.

Dig Dis Sci 1994; 39: 449–57.

84 Clemens CH, Samsom M, Roelofs J,

Berge Henegouwen GP, Smout AJ.

Colorectal visceral perception in diver-

ticular disease. Gut 2004; 53: 717–22.

85 Bueno L. Neuroimmune alterations of

ENS functioning. Gut 2000; 47 (Suppl.

4): 63–5.

86 Collins SM. The immunomodulation of

enteric neuromuscular function: impli-

cations for motility and inflammatory

disorders. Gastroenterology 1996; 111:

1683–99.

87 Gebhart GF. Pathobiology of visceral

pain: molecular mechanisms and thera-

peutic implications: IV. Visceral affer-

ent contributions to the pathobiology

of visceral pain. Am J Physiol Gastro-

intest Liver Physiol 2000; 278: G834–8.

88 De Giorgio R, Stanghellini V, Barbara

G, et al. Primary enteric neuropathies

underlying gastrointestinal motor dys-

function. Scand J Gastroenterol 2000;

35: 114–22.

89 Dvorak AM, Osage JE, Monahan RA,

Dickersin GR. Crohn’s disease: trans-

mission electron microscopic studies:

III. Target tissues. Proliferation of and

injury to smooth muscle and the auto-

nomic nervous system. Human Pathol

1980; 11: 620–34.

90 Jacobson K, McHugh K, Collins SM.

Experimental colitis alters myenteric

nerve function at inflamed and nonin-

flamed sites in the rat. Gastroenterology

1995; 109: 718–22.

91 Barbara G, Vallance BA, Collins SM.

Persistent intestinal neuromuscular

dysfunction after acute nematode

infection in mice. Gastroenterology

1997; 113: 1224–32.

92 Bueno L, Fioramonti J. Visceral percep-

tion: inflammatory and non-inflamma-

tory mediators. Gut 2002; 51: 19–23.

93 Collins SM. Irritable bowel syndrome

could be an inflammatory disorder. Eur

J Gastroenterol Hepatol 1994; 6: 478–82.

94 Horgan AF, McConnell EJ, Wolff BG.

Atypical diverticular disease: surgical

results. Dis Colon Rectum 2001; 44:

1315–8.

95 Sanovic S, Lamb DP, Blennerhassett

MG. Damage to the enteric nervous

system in experimental colitis. Am J

Pathol 1999; 155: 1051–7.

96 Simpson J, Haji-Suyoi A, Jenkins D,

Scholefield JH, Stach W. Quantification

of neurological changes in resection

specimens with complicated and

uncomplicated diverticular disease.

Gastroenterology 2002; 122: A314.

97 Suster SM, Ronnen M, Bubis JJ.

Diverticulosis coli in association with

Marfan’s syndrome. Arch Intern Med

1984; 144: 203.

98 Beighton PH, Murdoch JL, Votteler T.

Gastrointestinal complications of the

Ehlers-Danlos syndrome. Gut 1969; 10:

1004–8.

99 Omojola MF, Mangete E. Diverticula of

the colon in three Nigerian siblings.

Trop Geogr Med 1988; 40: 54–7.

100 Wess L, Eastwood MA, Edwards CA,

Busuttil A, Miller A. Collagen alteration

in an animal model of colonic diverti-

culosis. Gut 1996; 38: 701–6.

101 Mortensen PB, Clausen MR. Short-

chain fatty acids in the human colon:

relation to gastrointestinal health and

disease. Scand J Gastroenterol 1996;

216 (Suppl.): 132–48.

102 Wess L, Eastwood M, Busuttil A,

Edwards C, Miller A. An association

between maternal diet and colonic

diverticulosis in an animal model. Gut

1996; 39: 423–7.

103 Bode MK, Karttunen TJ, Makela J, Rist-

eli L, Risteli J. Type I and III collagens

in human colon cancer and diverticulo-

sis. Scand J Gastroenterol 2000; 35:

747–52.

104 Ludeman L, Shepherd NA. What is

diverticular colitis? Pathology 2002;

34: 568–72.

105 Shepherd NA. Diverticular disease and

chronic idiopathic inflammatory bowel

disease: associations and masquerades.

Gut 1996; 38: 801–2.

106 Peppercorn MA. Drug-responsive chro-

nic segmental colitis associated with

diverticula: a clinical syndrome in the

elderly. Am J Gastroenterol 1992; 87:

609–12.

107 Imperiali G, Meucci G, Alvisi C. Seg-

mental colitis associated with diverti-

cula: a prospective study. Am J


108 Peppercorn MA. The overlap of inflam-

matory bowel disease and diverticular

disease. J Clin Gastroenterol 2004; 38:

S8–S10.

109 Stollman NH, Raskin JB. Diagnosis and

management of diverticular disease of

the colon in adults. Ad Hoc Practice

Parameters Committee of the American

College of Gastroenterology. Am J


110 Ventrucci M, Ferrieri A, Bergami R,

Roda E. Evaluation of the effect of rif-

aximin in colon diverticular disease by

means of lactulose hydrogen breath

test. Curr Med Res Opin 1994; 13:

202–6.

111 Barbara G, De Giorgio R, Stanghellini

V, Cremon C, Corinaldesi R. A role for




inflammation in irritable bowel syn-

drome? Gut 2002; 51 (Suppl. 1): 41–4.

112 Colecchia A, Sandri L, Capodicasa S,

et al. Diverticular disease of the colon:

new perspectives in symptom develop-

ment and treatment. World J Gastroen-

terol 2003; 9: 1385–9.

113 Premysl F, Miroslav Z. The effect of

non-pathogeneic Escherichia coli in

symptomatic uncomplicated diverticu-

lar disease of the colon. Eur J Gast-

roenterol Hepatol 2003; 15: 313–5.

114 Goyal RK, Hirano I. The enteric ner-

vous system. N Engl J Med 1996; 334:

1106–15.

115 Watanabe T, Kubota Y, Muto T. Sub-

stance P containing nerve fibers in rec-

tal mucosa of ulcerative colitis. Dis

Colon Rectum 1997; 40: 718–25.

116 Di Sebastiano P, Fink T, Di Mola FF.

Neuroimmune appendicitis. Lancet

1999; 354: 461–6.

117 Milner P, Crowe R, Kamm MA, Len-

nard-Jones JE, Burnstock G. Vasoactive

intestinal polypeptide levels in sigmoid

colon in idiopathic constipation and

diverticular disease. Gastroenterology

1990; 99: 666–75.

118 Lin HC. Small intestinal bacterial over-

growth – a framework for understand-

ing irritable bowel syndrome. JAMA

2004; 292: 852–8.

119 Zollinger RW. The prognosis in diverti-

culitis of the colon. Arch Surg 1968;

97: 418–22.

120 Thompson WG, Longstreth GF, Dross-

man DA, Heaton KW, Irvine EJ, Mul-

ler-Lissner SA. Functional bowel

disorders and functional abdominal

pain. Gut 1999; 45 (Suppl. 2): 43–7.

121 Sugihara K, Muto T, Morioka Y, Asano

A, Yamamoto T. Diverticular disease of

the colon in Japan. A review of 615

cases. Dis Colon Rectum 1984; 27:

531–7.

122 Markham NI, Li AK. Diverticulitis of

the right colon: experience from Hong

Kong. Gut 1992; 33: 547–9.

123 Wong SK, Ho YH, Leong AP, Seow-

Choen F. Clinical behavior of com-

plicated right-sided and left-sided

diverticulosis. Dis Colon Rectum 1997;

40: 344–8.

124 Zagnoon A. Appropriateness of colon-

oscopy. Gastrointest Endosc 1999; 49:

412–3.

125 Place RJ, Simmang CL. Diverticular

disease. Best Pract Res Clin Gastroen-

terol 2002; 16: 135–48.

126 Schnyder P, Moss AA, Thoeni RF,

Margulis AR. A double-blind study

of radiologic accuracy in diverticulitis,

diverticulosis, and carcinoma of the

sigmoid colon. J Clin Gastroenterol

1979; 1: 55–66.

127 Boulos PB, Cowin AP, Karamanolis DG,

Clark CG. Diverticula, neoplasia, or

both? Early detection of carcinoma in

sigmoid diverticular disease. Ann Surg

1985; 202: 607–9.

128 Rockey DC, Kock J. Prospective com-

parison of air-contrast barium enema

and colonoscopy in patients with fecal

occult blood: a pilot study. Gastrointest

Endosc 2005; 60: 953–8.

129 Winawer SJ, Stewart ET, Zauber AG,

Bond JH, Ansel H. The National Polyp

Study Work Group. A comparison of

colonoscopy and double-contrast bar-

ium enema for surveillance after polyp-

ectomy. N Engl J Med 2000; 342:

1766–72.

130 Boulos PB, Karamanolis DG. Is colon-

oscopy necessary in diverticular dis-

ease? Lancet 1984; 1: 95–6.

131 Kozarek RA, Botoman VA, Patterson

DJ. Prospective evaluation of a small

caliber upper endoscope for colonos-

copy after unsuccessful standard exam-

ination. Gastrointest Endosc 1989; 35:

333–5.

132 Wilson SR, Toi A. The value of sonog-

raphy in the diagnosis of acute dive-

ticulitis of the colon. Am J Roentgenol

1990; 154: 1183–99.

133 Ambrosetti P, Jenny A, Becker C. Acute

left colonic diverticulitis: compared

performance of computed tomography

and water-soluble contrast enema:

prospective evaluation of 420 patients.

Dis Colon Rectum 2000; 43: 1363–7.

134 van Dam J, Cotton P, Johnson C, et al.

AGA future trends report: CT colono-

graphy. Gastroenterology 2004; 127:

970–84.

135 Farrell RJ, Farrell JJ, Morrin MM.

Diverticular disease in the elderly.

Gastroenterol Clin North Am 2001; 30:

475–96.

136 Aldoori WH, Giovannucci EL, Rockett

HR, Sampson L, Rimm EB, Willett WC.

A prospective study of dietary fiber

types and symptomatic diverticular dis-

ease in men. J Nutr 1998; 128: 714–9.

137 Marlett J. Position of the American

Dietetic Association: health implica-

tions of dietary fiber. J Am Diet Assoc

2002; 102: 993–1000.

138 Thorburn HA, Carter KB, Goldberg JA,

Finlay IG. Does ispaghula husk stimu-

late the entire colon in diverticular dis-

ease? Gut 1992; 33: 352–6.

139 Painter NS. The high fiber diet in the

treatment of diverticular disease of the

colon. Postgrad Med J 1974; 50: 629–

35.

140 Brodribb AJ. Treatment of symptomatic

diverticular disease with a high-fiber

diet. Lancet 1977; 1: 664–6.

141 Ornstein MH, Littlewood ER, Baird IM,

Fowler J, North WR, Cox AG. Are fiber

supplements really necessary in diverti-

cular disease of the colon? A controlled

clinical trial. Br Med J 1981; 282:

1353–6.

142 Hodgson WJ. The placebo effect. Is it

important in diverticular disease? Am J


143 Aldoori WH, Giovannucci EL, Rimm

EB, Ascherio A, Stampfer MJ. Prospect-

ive study of physical activity and the

risk of symptomatic diverticular disease

in men. Gut 1995; 36: 276–82.

144 Hyland JM, Taylor I. Does a high fiber

diet prevent the complications of diver-

ticular disease? Br J Surg 1980; 67:

77–9.

145 Leahy AL, Ellis RM, Quill DS, Peel AL.

High fiber diet in symptomatic diverti-

cular disease of the colon. Ann R Coll

Surg Engl 1985; 67: 173–4.

146 Bijkerk CJ, Muris JW, Knottnerus JA,

Hoes AW, de Wit NJ. Systematic

review: the role of different types of

fibre in the treatment of irritable bowel

syndrome. Aliment Pharmacol Ther

2004; 19: 245–51.

147 Aldoori W, Ryan-Harshman M. Pre-

venting diverticular disease. Review of

recent evidence on high-fiber diets.

Can Fam Physician 2002; 48: 1632–

7.

148 Di Stefano M, Strocchi A, Malservisi S,

Veneto G, Ferrieri A. Non absorbable

antibiotics for managing intestinal gas

production and gas-related symptoms.

Aliment Pharmacol Ther 2000; 14:

1001–8.

149 Papi C, Ciaco A, Koch M, Capurso L.

Efficacy of rifaximin in the treatment

of symptomatic diverticular disease of

the colon. A multicentre double-blind

placebo-controlled trial. Aliment Phar-

macol Ther 1995; 9: 33–9.

150 Latella G, Pimpo MT, Sottili S, et al.

Rifaximin improves symptoms of

acquired uncomplicated diverticular

disease of the colon. Int J Colorectal

Dis 2003; 18: 55–62.

151 Khan A, Piris J, Truelove SC. An

experiment to determine the active

therapeutic moiety of sulphasalazine.

Lancet 1977; 2: 892–5.




152 Brandimarte G, Tursi A. Rifaximin plus

mesalazine followed by mesalazine

alone is highly effective in obtaining

remission of symptomatic uncompli-

cated diverticular disease. Med Sci

Monit 2004; 10: 170–3.

153 Schrezenmeir J, de Vrese M. Probiotics,

prebiotics, and synbiotics-approaching

a definition. Am J Clin Nutr 2001; 73

(Suppl. 2): 316S–64.

154 Giaccari S, Tronci S, Falconieri M,

Ferrieri A. Long-term treatment with

rifaximin and lactobacilli in post-diver-

ticulitic stenoses of the colon. Riv Eur

Sci Med Farmacol 1993; 15: 29–34.

155 Fricu P, Zavoral M. The effect of

non-pathogenic Escherichia coli in

symptomatic uncomplicated diverticu-

lar disease of the colon. Eur J Gast-

roenterol Hepatol 2003; 15: 313–5.

156 Shanahan F. Turbo probiotics for IBD.


157 Sartor RB. Targeting enteric bacteria in

treatment of inflammatory bowel dis-

ease: why, how, and when. Curr Opin


158 Bocker U, Nebe T, Herweck F. Butyrate

modulates intestinal epithelial cell-

mediated neutrophil migration. Clin

Exp Immunol 2003; 131: 53–60.

159 Kleessen B, Hartmann L, Blaut M.

Oligofructose and long-chain inulin:

influence on the gut microbial ecology

of rats associated with a human faecal

flora. Br J Nutr 2001; 86: 291–300.

160 Papi C, Ciaco A, Koch M, Capurso L.

Efficacy of rifaximin on symptoms of

uncomplicated diverticular disease of

the colon. A pilot multicentre open

trial. Diverticular Disease Study Group.

Ital J Gastroenterol 1992; 24: 452–6.




Review article: uncomplicated diverticular disease of the colon

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