Diverticular disease (DD) is an age-related disorder of the large bowel which may affect half of the population over the age of 65 in the UK. This high prevalence ranks it as one of the most common bowel disorders in western nations. The majority of patients remain asymptomatic but there are associated life-threatening co-morbidities, which, given the large numbers of people with DD, translates into a considerable number of deaths per annum. Despite this public health burden, relatively little seems to be known about either the mechanisms of development or causality. In the 1970s, a model of DD formulated the concept that diverticula occur as a consequence of pressure-induced damage to the colon wall amongst those with a low intake of dietary fiber. In this review, we have examined the evidence regarding the influence of ageing, diet, inflammation and genetics on DD development. We argue that the evidence supporting the barotrauma hypothesis is largely anecdotal. We have also identified several gaps in the knowledge base which need to be filled before we can complete a model for the etiology of diverticular disease.

Diverticular disease (DD) is characterized by out-pouching in the wall of the colon; though generally benign, a minority of individuals develop associated morbidities, ranging from excessive flatulence and minor Irritable Bowel Syndrome (IBS)-like symptoms, through to inflammation of these out-pouchings (diverticulitis)[1]. Diverticulitis can lead to potentially life-threatening complications (i.e. abscess formation, colonic perforation, and bowel obstruction) in up to a quarter of sufferers[2] and one estimate puts European DD associated mortality at 23 600 deaths per annum[3].

Necropsy-based studies implicate ageing as the primary risk factor for DD. Two studies in separate Northern European populations, dating from 1968 and 1979, indicate a prevalence of around 13% up to 54 years of age and rising to 40%-50% in individuals over 75 years old[45] (Figure 1A). Age-standardized mortality rates for DD in the UK have not changed considerably since 1979[6], so we can assume that these figures are a reasonable estimate of the current prevalence. As an age-related phenomenon we can expect the burden of DD upon society to rise with the continuing increases in life expectancy throughout the developed world (data from the UK Office of National Statistics show continued increases in life expectancy in the UK[7]).

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Figure 1 Prevalence of DD in intestines obtained at necropsy by age, gender and region. A: Increasing prevalence of DD with age in western populations. In contrast DD peaked amongst individuals in their late fifties and early sixties in Singapore. The Singapore study however is based on diverse ethnic populations which may be confounding these observations; B: Percentages of intestine shown to have DD present at necropsy by gender. Data obtained on individuals from the Trømso region of northern Norway between 1974 and 1976, Northern Irish subjects in 1968, Cretan subjects 1997-1999, and Singapore prior to 1986. Note: The data presented for the Cretan-, Belfast- and Singapore-based studies are adjusted for age groups used by the Norwegian study using slopes obtained from the published data. Figures adapted from reference[1–4].

Diverticular disease has been described as a 20th century phenomenon[8], however there are cases in the European literature dating from well before 1900 as evidenced by Jun and Stollman[9]. In addition, evidence of an increase in the death rate from diverticulitis between 1923 and 1966 in England and Wales has been noted[10], and this probably reflects the increasing percentage of elderly people in the population over the same period[7]. The age-standardized mortality rates for DD in the UK have not changed considerably since 1979[3]; it follows that advances in medical practices coupled with increased lifespan may help explain in part the increased diagnosis of DD in the 20th century.

Necropsy data from Northern Europe, Southern Europe and Asia indicate wide geographic disparities in DD prevalence, i.e. it is more common in Northern Europe than in Crete or Singapore (Figure 1A). These studies also show an east-west divide in the nature of disease presentation, with right-sided diverticula being more prevalent in Asian populations; this hints at distinct etiologies[11]. Finally, the necropsy data also indicate that DD is more prevalent in women than men (Figure 1B). It is not yet clear as to whether this gender effect is related to hormonal or anthropometric risk factors, although Manousos et al[12] report a relationship with parity.

There have been several studies of DD risk in migrant populations. For example, “non western” immigrants showed a lower risk of DD-related hospital admissions and death but after adjusting for age, risk increased with years of residence in Sweden[13]. In contrast, other studies found no changes in DD incidence amongst migrant communities following periods of naturalization in countries with high or low risk DD in the native population. For example, evidence gathered from endoscopy reports suggests that the predominantly Turkish migrant community in the Zaanstreek region of the Netherlands have a significantly lower incidence of DD than the native Dutch population. Just 7.5% of 387 immigrants examined were shown to have DD, in contrast to 50% of the 5973 “native Dutch”. Unfortunately, no information is available on the subjects’ diet, how long they had been in the Netherlands or whether the subjects were first, second or third generation immigrants[14]. A UK study observed a lower incidence of DD amongst patients defined as “Indian subcontinent Asian males and females” compared with other ethnic groups. This study showed no difference in DD incidence between first and second generation Asians although numbers were limited[15]. In addition, an autopsy-based study of 1014 cadavers in Singapore showed a significantly higher risk of DD amongst the ethnically Chinese population when compared to the ethnically Malay and Indian populations[16]. The epidemiological data described suggests environmental and genetic components to DD etiology.

DD presents as pockets within the colon wall, often around points of penetration of the vasa recta through to the luminal side of the muscularis propria[11], possibly because these sites are inherently weak. In western nations diverticula are most common in, though not confined to, the descending and sigmoid colon (left colon). This is in contrast to Asian nations where they occur primarily in the cecum and ascending colon (right colon)[17]. This difference suggests a role for genetic, environmental or lifestyle factors in the etiology of the condition.

At a functional level, the cecum and ascending colon are the primary sites of bacterial fermentation of carbohydrates and proteins which escape small bowel digestion. Microbial action, coupled with anti-peristaltic mixing, maintains a large digestive mass in this segment of the colon; thereby maintaining distention in the longitudinal and circular muscles of this region of the bowel for significant periods. In contrast, the descending colon serves primarily as a holding reservoir for fecal matter prior to excretion. Fecal matter reaching this stage of the colon is significantly reduced in bulk owing to the re-absorption of water and electrolytes, and the depletion of substrate for microbial activity. In addition, movement of bolus through this phase of the colon is subject to increasing voluntary control with variation in intra-luminal pressures throughout the length of the colon (Figure 2).

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Figure 2 Physiological activity within the large bowel. Schematic of the human colon highlighting functional roles; the right colon is associated with high microbial activity, larger fecal volume and parasympathetic control. DD in the right colon is infrequently observed in western populations but commonly found in Asian populations. The left colon is the primary site of diverticula in western populations and has lower microbial activity, decreased fecal volume and is more responsive to voluntary control.

At a structural level, the mechanical characteristics of the bowel are maintained via circular and longitudinal muscle layers. The circular muscle thickens in regular bands of contraction (plicae circulares) which control peristalsis. The longitudinal muscle also condenses in thick bands (the teniae coli) which serve to pull the colon to a relatively short functional length. In DD, the circular muscle layer is thicker and the longitudinal muscle is shorter[1], although a similar thickening of the colon wall may be a natural feature of the normal ageing bowel[18] and seems to occur at an accelerated rate in inflammatory bowel disease (IBD)[19]. Comparing the DNA to nitrogen ratio in DD tissue confirms that the muscle thickening is not due to hypertrophy[20] whilst individual muscle fiber cells and their organelles appear normal on histological examination[18]. Instead, histological studies suggest that the accumulation and aberrant deposition of connective tissue fibers (elastin[1821] and collagen[22]) underlie the altered muscle morphology. Furthermore, in diverticulitis the ratio of type I to type III collagen is altered in both the serosa and sub-mucosa, indicative of scarring[23]. This effect may be attributable to aberrant activity of matrix metalloproteinases (MMPs) and tissue inhibitors of the matrix metalloproteinases (TIMPs). In one small DD study (11 cases, 6 of which were uncomplicated, vs 11 controls) increases in TIMP-1 and -2 expression were associated with disease severity i.e. expression was higher in symptomatic disease[24]. Separately, in a small study of patients with clinical diverticulitis (n = 13), Stumpf et al[23] found decreased expression of MMP1. In contrast, Rosemar et al[25] found an up-regulation of the expression of MMP1, in addition to increased expression of MMP2 and TIMP1, in DD affected tissues compared to unaffected bowel specimens from the same patients (who were undergoing sigmoid colectomy to treat complicated DD). Whether or not the MMPs and TIMPs play an important role in the tissue organisation observed in asymptomatic DD remains to be seen; the findings reported thus far may be due to acute inflammation rather than DD per se[26].

There have been a number of physiological studies of the diverticular diseased colon, focusing primarily on colonic transit times, intra-luminal pressure, colonic motility and electrophysiology. In the main, inference from these studies about DD specific events or processes is difficult because of the limited data on changes in normal colonic function with ageing, but they offer some insight into the disease process.

It is tempting to postulate that inflammation plays a role in the etiology of DD for several reasons; (1) An increase in plasma inflammatory markers correlates with ageing in man and rats[7778] as does the prevalence of DD; (2) Bowel wall thickness increases in both IBD[19] and DD[1]; (3) Inflammation could explain neuronal cell death in DD[54]; (4) In a small minority of DD cases the bowel becomes acutely inflamed; (5) Narayan and Floch observed non-specific inflammation in biopsy specimens from non-inflamed DD cases vs controls[79]; (6) Kealy observed significantly higher numbers of lymph nodes in disease-free portions of necropsied colon from subjects with DD vs controls[80]; (7) Inflammation could be a common factor linking diet and DD.

In contrast, Pezzilli et al[81] did not observe differences in fecal calprotectin concentrations between subjects with DD vs controls, though the study size was rather small (17 cases). More importantly, recent case-control studies of IBD suggest that chronic acute inflammation actually protects against DD[8283]. The mechanisms by which this protection occurs are not yet understood, but may involve alterations to the luminal bolus, i.e. the loose watery stool associated with IBD may lower luminal pressures and help prevent DD, or through the impact of intestinal inflammation on the colonic flora. In either case, these findings do not rule out a role for mild non-acute inflammation, with a less pronounced effect on the fecal stream, in DD etiology. However, any mild non-specific inflammation in DD remains poorly evidenced.

Clinical observations associate a number of rare genetic disorders with a strong predisposition towards diverticula formation. Notably, patients with Ehlers-Danlos syndrome[8485], Williams-Beuren syndrome[86], polycystic kidney disease[87] and Coffin-Lowry syndrome[88] are often afflicted with diverticula of the colon and other internal organs. The etiology of diverticula formation in these syndromes may be unrelated to sporadic age-related DD, but they may offer insight into mechanisms of disease in that at least three of these syndromes are associated with a connective tissue disorder. Ehlers-Danlos syndrome is an inherited connective tissue disorder arising through mutations in either the COL5A1 or COL5A2 genes encoding part of the type V collagen protein or through mutations in the gene for the extra cellular matrix (ECM) protein, tenascin-X[89]. Williams-Beuren syndrome affects 1:10 000 of the population and is due to a deletion of about 20 genes on chromosome 7. Although the genetic basis of this syndrome has not been elucidated fully, it appears to result in elastin haplo-insufficiency[90]. Coffin-Lowry syndrome is a maternally inheritable disorder that may also be related to disrupted collagen metabolism[88]. Scheff et al[91] observed colonic diverticulae in 83% of patients with end stage polycystic kidney disease (PKD). PKD is due to mutations in the PKD1 or PKD2 genes coding for the cell membrane-bound polycystin proteins. Whilst the function of these proteins is uncertain, it has been suggested that they interact with the ECM and with extra-cellular signaling pathways regulating cell migration and differentiation[92]. Collectively, these syndromes linked by an ECM defect might suggest that the accumulation of collagen and elastin in the smooth muscle of sporadic DD specimens[2021] is a prerequisite to diverticula formation.

Separately, clinical observations of poor colonic motility also feature in a significant subset of individuals with mitochondrial diseases[93]. Perez-Atayde et al[94] observed a duodenal diverticulum in a 14-year-old with mitochondrial neurogastrointestinal encephalomyopathy which suggests that mitochondrial neuromuscular dysfunction may be associated with DD.

On a different note, clinical case reports hint at familial risk factors for DD in the general population; Schlotthauer reported DD in seven American brothers (aged 40-70), but not in their two sisters (ages not given)[95]; Omojola and Mangete[96] observed DD in three siblings in a Nigerian population with a traditionally low incidence of DD and Claassen et al[97] observed DD in two teenage siblings in Holland, in whom they also noted joint hypermobility, perhaps indicating a collagen disorder. Siblings share similar environmental exposure which may help explain familial clustering of DD but does not account for observations in populations where the prevalence is low or in the very young. These observations may simply be statistical anomalies, but taken together with the ethnic variations in both the site and age of onset of DD (Figure 1) they do suggest a genetic component. Unfortunately there is no published literature on attempts to quantify the hereditary component of this condition. Of note, our own preliminary epigenetic data have shown unusual DNA methylation patterns in the colonic mucosa of patients with DD[9899].

A number of questions still remain regarding the biology and etiology of DD. Perhaps the most pressing amongst these relate to the role of diet and lifestyle, as these factors offer strategies for prevention. The two approaches which have been most successful in illuminating the role of diet and lifestyle in DD prevalence thus far are epidemiology and observational studies in man. The epidemiological approach is currently confounded by the lack of available up-to-date data on DD prevalence in different populations. A priority for future research should therefore be the collection of recent necropsy data to indicate current regional prevalence.

There have been no true prospective case-control cohort studies into DD and diet performed to date. For validity, any such study would require a prospective colonic examination to exclude DD patients at baseline, a follow up period of some years and a subsequent exam; this may be unfeasible given the time taken for diverticula to develop and demands on research budgets. In considering a low budget approach, it could be possible to append this type of study to the back of any new prospective colorectal cancer cohorts or to future polyp recurrence trials.

Other clinical and biological questions concern the mechanisms underlying the disease process. Gaps in the knowledge base on the natural changes in bowel physiology, inflammation and composition with ageing impede our understanding of DD. Less invasive methods for measuring physiological activity in the GI tract are under development[44], which may allow for the measurement of colonic motility under more natural physiological conditions and could be employed to study the effects of diet and ageing on normal bowel function and specifically changes related to DD.

Diverticulosis is ultimately a disease of ageing; recent studies show increasing mitochondrial dysfunction in the ageing colonic epithelia and this data correlates well with DD prevalence (Figure 4)[100]. We have been conducting preliminary investigations into the accumulation of mitochondrial deficiencies in the colonic epithelia in DD[101], Studies of mitochondrial deficiency or other age-associated changes in the colonic muscle might further illuminate the pathology of this condition. Similarly, we should further examine what phenomenon (if apparently not inflammation) drives excess ECM deposition in ageing and DD.

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Figure 4 Graph showing the relationship of age with mitochondrial DNA damage and risk of hospital admissions for DD. Graph showing the correlation between the percentage accumulation mitochondrial (mt) DNA damage in the colonic mucosa - right hand y axis whilst left hand y axis shows hospital admissions for DD/10⁵ in the UK. Ageing is expressed on the x axis in decades. The incidence of asymptomatic disease is considerably higher but the rate of hospital admissions may mirror DD incidence in the population as a whole. Mitochondrial DNA mutations are inferred from level of deficiency/inactivity in the respiratory chain mitochondrial protein Cytochrome C oxidase[102].

Animal models of DD hint at a role for the colonic microflora in the disease process, especially when one considers the differences in microflora composition between high and low risk populations[60102]. A direct comparison of the fecal and colonic mucosal flora between cases and controls might simply reveal differences associated with the altered luminal environment; a better approach would be to characterize the microflora of volunteers prior to any prospective study.

Finally, it remains to be established as to whether right- and left-sided DD have different etiologies and to what extent genetics, environmental and lifestyle factors contribute to this difference. Ageing is the primary risk factor in DD, but the condition is not an inevitable consequence of the ageing process. It seems probable that dietary or environmental factors protect against diverticula formation but further evidence is needed to fully define these factors. The high prevalence of DD within our increasingly elderly population translates into significant morbidity. We feel therefore that the investment of research funds in this area is justified.