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 ).
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 (more ...)
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[18,21
] 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.
Colonic transit times
Studies of colonic transit times (performed by adding radiological markers to the diet) in DD, by both Evans et al[27
] and Manousos et al[28
], showed faster colonic transit in individuals with DD. This is perhaps in contrast to what we might expect, given that DD is an age-related phenomenon, and studies of transit time in the aged show either a slower rate of passage through the colon amongst the elderly[29–31
], or no differences with ageing[27,32–34
]. In addition, Evans et al[27
] observed longer transit times in females, in whom the evidence points towards a higher risk for developing DD. We might question the potential confounding effects of habitual diet and physical activity in these studies. In particular, upon diagnosis, patients with DD are generally recommended a high fiber diet, which could account for accelerated transit time amongst cases. Nevertheless this interesting counter-intuitive observation is worthy of follow up.
Intra-luminal pressure and colonic motility
Classically, researchers interested in colonic motility in DD performed endoscopy-based manometry studies to measure changes in luminal pressure in the evacuated colon. The main findings of these studies are that there are similar resting luminal pressures between DD cases and controls[35
], but higher luminal pressures in segments of colon with diverticula in response to pharmaceutical stimulus[36,37
] and an increase in post-prandial colonic motility[38
]. Paradoxically, inflating a balloon in the colon of individuals with DD induces the musculature of the colonic wall to yield to the increasing luminal pressure more quickly than in controls[38,39
]. In addition, these and later studies indicate increased colonic motility (as assessed by number and amplitude of bowel wall contractions) in the sigmoid colon of individuals with left-sided DD[40,41
], and also in the ascending colon of patients with right-sided diverticulosis[42
]. These classical studies were generally performed with low numbers and failed to account for age, gender, physical activity or body fat percentage; the physiological observations were made under artificial conditions, i.e. in the evacuated bowel during endoscopy. Furthermore, they were performed over one or two hours, with the subject at rest, whilst in reality one would expect variation in bowel pressures throughout the day. More recently however, Bassotti et al[41
] made recordings over a 24 h period, and observed higher colonic motility in DD cases throughout the recording period than in a younger control group (cases 42-65 mmHg, controls 37-55 mmHg). It is unclear whether or not failing to control for age confounds these studies; Firth and Prather[43
] suggest that colonic motility is not altered in the normal ageing colon, but this warrants further investigation, ideally utilizing pressure-sensitive transducers which can be swallowed and allowed to pass through the GI tract to provide more representative measures of colonic physiology[44
]. That said, the evidence described points towards a neuromuscular dysfunction in DD; although it remains uncertain whether this is a cause or effect of the condition.
Electrophysiology and neuromuscular dysfunction
Electrophysiological examinations of the bowel wall have been used to investigate neuromuscular dysfunction in DD in several studies. Shafik et al[45
] identified two distinct types of neuromuscular dysfunction by transcutaneously measuring electrophysiological activity in the sigmoid colons of DD subjects and comparing with age- and sex-matched controls; (1) elevated electrophysiological activity in early stage diverticulosis, and (2) a silent or low electrophysiological tone in advanced DD. This finding is supported by the ex vivo observation of Guagnini et al[46
] who failed to induce an electrical field twitch response in resected longitudinal muscle from 30% of DD patients, but observed similar responses to electrical field stimulation in the remaining 70% of the samples compared with resected smooth muscle from slightly younger colorectal cancer patients.
Similar ex vivo electrophysiological studies of this type on DD specimens are summarized in Table . Typically they also show aberrant responses to relaxatory and contractionary stimuli in colonic smooth muscle in DD. On a cautionary note, the weaknesses of these studies include: (1) a lack of power due to the small numbers of subjects; (2) the use of colorectal cancer patients as controls; (3) the focus on complicated/advanced DD specimens.
Summary of electrophysiology studies in diverticular disease (DD)
Evidence from recent histological studies of neurones in the ageing human gut suggests that there is a natural decrease in nerve density with ageing[47,48
], a finding supported in animal models[49
]. Age-related neurone loss is intuitively attractive as an explanation for the impaired colorectal motility in DD; however, data concerning this remains relatively sparse. An early study by Macbeth and Hawthorne[50
] suggested the opposite, i.e. an increase in the number of intramural ganglia but with disorganized distribution of ganglia in DD tissues. Fortunately, recent studies contradict this finding[21
], and this work may have been confounded by the morphological distortions associated with the colon shortening in DD. Golder et al[51
] show histological evidence for decreased nerve content of longitudinal muscle in DD as evidenced by reduced prostaglandin immunoreactivity. They have also found that individual nerve fibers were smaller in cases vs
controls and were less likely to stain positively for choline acetyltransferase[52
] and NOS 1[51
], suggestive of cholinergic and nitrergic denervation in these samples. Again the primary potential confounder to these studies is the fact that the colon shortens, and that the muscle layers become thicker (due to elastin and collagen deposition), in DD; it is not clear as to how the authors have controlled for this. In contrast, Bassotti et al[53
] found no difference in the number of enteric nerves, but a significantly lower number of glial cells in DD. In an interesting take on the same principal, they also found a significant decrease in the number of interstitial cells of Cajal in the myenteric plexus, the sub-mucosa and within the muscle. These cells are emerging as potential colonic pacemaker cells and, like neural cells, their loss might explain poor bowel motility, but yet again we are left with a cause or effect type question. Simpson et al[54
] have argued (though not evidenced) that nerve damage results from periods of acute inflammation which arise as a consequence of the presence of diverticulosis, whilst others argue that age-related nerve withdrawal induces smooth muscle dysfunction, which thus predisposes to diverticulosis formation[55