Accordingly, cross-organ sensitization has received mounting interest in the development and clinical diagnosis of chronic abdominal and pelvic pain states. This in turn has led to an expansion in preclinical research to delineate the mechanisms of such viscero-visceral interactions in disease. It also provides the tantalizing prospect of treating multiple syndromes concurrently, as well as avoiding debilitating side effects. This review will outline the current clinical evidence and experimental research for the existence of cross-organ sensitization between the colon and bladder. It will focus on how alterations in response to a colonic insult result in bladder dysfunction and provide insights into the mechanisms that have been hypothesized to mediate this phenomenon.

The subconscious coordination of sensory signals from the colon, bladder, and urethra is essential for synchronized defacatory and micturition responses ( 17 , 29 ). These sensory signals are conveyed via sensory afferents, which have peripheral endings within their host tissue, and travel via the splanchnic, pelvic, and pudendal nerves to the central nervous system. These sensory afferents have cell bodies located within the thoracolumbar (TL) and lumbosacral (LS) dorsal root ganglia (DRG) and central projections in the dorsal horn of the corresponding regions of spinal cord. It has recently become apparent that disease of one of these organs can result in the subsequent development of pathology in the otherwise unaffected adjacent organ. This process called “cross-organ sensitization” originates and is embedded within the physiological coordination of these organs. This pathological occurrence is believed to be responsible for the comorbidity of a number of lower urinary tract and colonic disorders, including, but not limited to, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), overactive bladder (OAB), and interstitial cystitis/painful bladder syndrome (IC/PBS), as well as both fecal and urinary incontinence ( 32 ).

Therefore, the defining symptoms of concurrent gastrointestinal and urological disorders, including abdominal/pelvic pain, urinary urgency, altered bowel habits, and urinary frequency, appear to be sensory driven. These are essentially replicated symptoms in separate, but closely located, organs that share similar primary roles (the collection, storage, and expulsion of waste products) ( 15 ). These findings suggest that coexisting comorbid conditions between the colon and bladder are a likely consequence of persistent pathological neuroplasticity to sensory pathways innervating these visceral organs ( 47 ). Because the sensory afferents from these different organs travel together within the same spinal nerves, it is likely that the neural pathways required for normal physiological function become sensitized in these disease states and are responsible for these phenotypic shifts. Experimental models of colitis in animals, particularly rodents, have provided valuable insight into these mechanisms

There are commonalities between IBS and IBD patients, with extraintestinal symptoms apparent in both patient cohorts. For example, bladder dysfunction is significantly more common among a cohort of IBS patients than in healthy control subjects ( 61 ). Correspondingly, patients with IBS are more likely to report OAB symptoms, including nocturia, urgency, and in some cases urge incontinence ( 14 ). Six years after once off giardiasis, which is a known risk factor for the development of IBS ( 25 ), the prevalence of OAB is significantly increased compared with healthy controls. On the flip side, patients with IC/PBS also present with both urological and gastrointestinal symptoms, including urinary frequency and urgency accompanied by persistent pelvic pain ( 1 ). These IC/PBS patients are 100 times more likely to have concurrent IBD than healthy controls ( 2 ). Patients visiting a gynecological clinic with combined or individual symptoms of urinary frequency and/or urgency are significantly more likely to have concurrent IBS symptoms than age-matched healthy controls ( 21 , 48 ). For those patients presenting with symptom-defined OAB, for which urgency is the only defining feature ( 60 ), ~30% also exhibit IBS symptoms ( 41 ). Furthermore, 20–30% of both men and women with IC/PBS report IBS as among their most common comorbidity ( 2 , 12 ).

Gastrointestinal disorders can be generally defined as being either “organic” or “functional” on the basis of their perceived underlying etiology. For instance, IBD, which includes both Crohn’s disease and ulcerative colitis, is an organic digestive disease. IBD is characterized by chronic remitting and relapsing inflammation of the intestine ( 3 ), resulting in abdominal pain, diarrhea, gastrointestinal bleeding, and malnutrition in ~0.5% of the Western population ( 31 ). Although the etiology of IBD is unknown, it is generally acknowledged that IBD development occurs through an exaggerated or inadequately suppressed immune response to luminal antigens, probably derived from intestinal microbiota, in genetically susceptible individuals ( 7 ). In contrast, IBS is a prevalent chronic functional gastrointestinal disorder that affects ~11% of the global population ( 19 ). While IBS is characterized by abdominal pain or discomfort associated with altered bowel habit (either diarrhea, constipation, or alternating between both), it differs from IBD in that these symptoms present in the absence of overt intestinal inflammation. Persistent neuroplasticity (structural, synaptic, or intrinsic changes that alter neuronal function) of the sensory afferent pathways innervating the colon contribute to these symptoms in the absence of inflammation and may arise following acute bouts of intestinal inflammation that resolve ( 7 ). This neuroplasticity may also be the result of low-grade inflammation not identified during routine clinical screening ( 7 ).

Together these data provide evidence that colonic hypersensitivity is able to cause acute changes in bladder sensation that persist following the resolution of experimental colitis. Furthermore, it is this enhanced bladder sensitivity that correlates to symptoms analogous to those observed in OAB and IC/PBS states. The questions that remain are: 1 ) by what mechanisms does this sensitization occur, and, more importantly; 2 ) if we understand the mechanisms, can we reverse afferent sensitization and cross-organ sensitization?

Other studies have shown that as little as 1 h after intracolonic TNBS administration, bladder afferent responses to noxious bladder distension, as well as capsaicin, bradykinin, and substance P application, are all enhanced ( 56 ). Furthermore, at 3 days post-TNBS, bladder-innervating LS DRG neurons display hyperexcitability ( 36 , 40 ). These changes following acute colitis are accompanied by a twofold increase in the peak Na + current amplitude in bladder-innervating DRG neurons, which may be due in part to upregulation of the voltage-gated Na + (Na V ) channels Na V 1.7 and Na V 1.8 ( 36 , 37 , 40 ). These acute changes in the excitability of bladder-innervating DRG neurons provide a basis for the long-term changes in neuronal excitability of the bladder that occur following the resolution of experimental colitis, as discussed below. At 10 days postintracolonic TNBS, exaggerated bladder afferent responses to bladder distension pressures above 30 mmHg are maintained, as well as enhanced chemosensitive responses to intravesical capsaicin ( 57 , 66 ). At 30 days postintracolonic TNBS, the peak amplitude of total Na + current remains enhanced, with a leftward shift in the steady-state activation of the total Na + current and a significantly higher Na + current density ( Fig. 1 ) ( 36 ).

The detection and transmission of mechanical and chemical stimuli by extrinsic sensory afferents play a key role in modulating autonomic reflexes and maintaining the homeostasis of visceral organs. Therefore, recent research into the mechanisms underlying OAB and IC/PBS have focused on the function of the peripheral endings of sensory afferents ( 67 ). There is a clear correlation between increased bladder afferent sensitization and changes in bladder voiding parameters ( 59 ), while the extent of bladder afferent sensitization is linked to the transition of symptoms from urgency and frequency, through to pain ( 68 ). Accordingly, bladder afferent sensitization to bladder distension is essential for symptom progression. Such sensory afferent sensitization is also hypothesized to be responsible for establishing cross-organ sensitization between the colon and bladder. For example, rats with dextran sodium sulfate (DSS)-induced colitis have spinal neurons within the dorsal horn of the LS spinal cord that exhibit greater excitatory responses compared with those in healthy control animals ( 52 ). Correspondingly, these rats with DSS-induced colitis also display hyperalgesia to bladder distension compared with healthy control animals ( 52 ). Furthermore, colitis induced by intracolonic TNBS administration results in mechanical hypersensitivity of high-threshold afferents in both the splanchnic and pelvic pathways. This corresponds with hyperexcitability of retrogradely traced colon-innervating DRG neurons, in addition to hyperalgesia and allodynia to colorectal distension ( Fig. 1 ) ( 5 , 44 ).

As an immediate comparison with the clinical symptoms of OAB and IC/PBS, there have been a number of well-documented studies into the effects of transient colitis on bladder voiding. During the acute phase of trinitrobenzesulfonic acid (TNBS)-induced colitis in rodents, when colonic inflammation is pronounced, there are consistent changes in bladder voiding parameters. This includes deceased micturition intervals, decreased voided volumes, and decreased bladder capacity, as well as increased micturition frequency ( 37 , 65 ). By 7 days post-TNBS administration, colonic inflammation has begun to spontaneously resolve, with a corresponding increase in the integrity of the colonic wall. By 28 days post-TNBS, there are no observable histological changes in the colon compared with healthy control mice ( 9 , 10 , 16 , 27 ). However, changes in bladder micturition parameters remain altered at 10 and 12 days post-TNBS ( 20 , 57 ) and may persist long term ( 24 ). Accordingly, these studies indicate that transient experimental colitis can have profound acute and long-term effects on bladder function following resolution of the initial inflammatory stimuli. This provides us with the closest possible analogy to the symptoms of urgency, urge incontinence, and frequency observed in humans with OAB and IC/PBS ( Table 1 ).

Experimental studies demonstrate that LS spinal dorsal horn neurons receiving input from the colon display sensitization to colorectal distension during colitis ( 53 ). Thus every level of the peripheral sensory pathway, from the afferent ending to the spinal cord, is hyperexcitable following experimental colitis ( 7 , 53 ). Interestingly, ~12% of spinal neurons within the superficial and deeper regions of the LS dorsal horn that respond to noxious colorectal distension also respond to urinary bladder distension. Notably, this proportion of spinal dorsal horn neurons is similar to the proportion of DRG showing dichotomizing afferents ( 11 , 36 , 37 , 40 , 51 , 52 , 66 ). Hyperexcitability of LS spinal dorsal horn neurons in rats with DSS-induced colitis show concurrent hypersensitivity of colon/bladder convergent neurons but also in neurons with inputs only from the urinary bladder ( 52 ). Therefore, it is unlikely that direct sensitization of colonic spinal neurons is able to provide general sensitization of the bladder distension pathway without further structural plasticity. In this regard, there is evidence for the central terminals of colonic afferents sprouting into other regions of the dorsal horn following recovery from TNBS-induced colitis ( 26 ). This increased density and sprouting of colonic afferent central terminals correlates with increased numbers of activated dorsal horn neurons in response to colorectal distension, showing that transient colitis is able to induce long-term rewiring of the nociceptive input within the spinal cord ( 26 ). Whether this increased sprouting is in areas associated with bladder spinal signaling has yet to be determined but is an intriguing possibility because of the close proximity of bladder and colon central endings within the dorsal horn of the spinal cord ( 17 ). Although not specifically studied within visceral pathways, the somatosensory literature suggests that interneurons and satellite cells within the central nervous system may be an essential component in the development of neuropathic pain ( 70 ). Therefore, continued activation of these pathways has the potential to induce chronic cross-sensitization and could be an important component in the transition to a more complete sensitization of the entire visceral network.

The visceral sensory input from the bladder and colon converges into similar areas of the spinal cord and is essential for the coordinated function of these organs ( 17 , 29 ). It is hypothesized that sensitization of spinal cord dorsal horn neurons receiving input from colonic afferents may subsequently sensitize a proportion of convergent bladder afferents whose autonomic regulation occurs in similar regions.

Although these dichotomizing dual-labeled DRG neurons are hyperexcitable during and following TNBS colitis ( 40 ), the proportion of dichotomizing afferents remains small compared with the total population of bladder or colonic afferents. Therefore, dichotomizing afferents are unlikely to be the sole explanation for the large cross-sensitization effects observed in both colitis and postcolitis animals. This is supported by data showing that, following TNBS colitis, LS DRG with axons innervating only the bladder also display increased total Na + currents and a corresponding neuronal hyperexcitability, much like those with dichotomizing axons to both the bladder and colon ( 36 , 37 , 40 ).

Dichotomizing afferents are a subpopulation of DRG neurons that have a single cell soma but axons that project to multiple visceral organs. Retrograde tracing from both the colon and bladder reveal that dual-labeled bladder/colon innervating DRG neurons in TL and LS regions represent ~10% (range 5–25%) of the total number of DRG neurons. There is also a greater proportion of dual-labeled bladder/colon innervating neurons in the LS DRG relative to the TL DRG ( 11 , 37 , 40 , 66 ). The significance of this disproportion, and the relative contribution of LS and TL regions to nociceptive signaling in relation to the establishment of cross-organ sensitization, has yet to be determined ( 11 , 37 , 40 , 52 , 66 ). However, these dichotomizing afferents are hypothesized to directly translate the sensitization of peripheral afferents from one organ to another ( Fig. 1 ). For example, following colitis this allows hypersensitivity of the colon-innervating axon to induce hypersensitivity of the convergent bladder-innervating axon ( 5 , 9 , 27 ). This is evident in LS DRG retrogradely labeled from both the bladder and colon of rats with colitis. These neurons display lower voltage and current thresholds for action potential generation and an increased upstroke velocity, which is accompanied by enhanced capsaicin responses and a significant increase in peak amplitudes of tetrodotoxin-resistant (TTX-R) Na + currents ( 39 , 40 ).

INDIRECT MECHANISMS FOR CROSS-SENSITIZATION

Inflammation Postinflammatory afferent hyperexcitability is a hallmark of chronic pain syndromes. However, there is scant evidence to suggest that colitis results in significant inflammation within the bladder. In the numerous studies detailed above that have observed changes in bladder function following colitis, there has been little corresponding observable change in 1) the histology of the bladder, 2) myeloperoxidase activity, 3) hypertrophy, nor 4) changes in bladder weight that, if present, would be suggestive of active inflammation (23, 35, 37, 38, 40, 43, 45, 46, 49, 57, 65, 66). Assessments from day 1 through day 30 postintracolonic TNBS administration fail to show neutrophil infiltration within the bladder. However, some studies have shown increased mast cell numbers within the bladder at 10 and 12 days postintracolonic TNBS administration (20, 57). Interestingly, other studies show that depletion of C-fiber neuropeptides, with systemic capsaicin pretreatment, not only significantly reduces mast cell numbers within the bladder but also restores natural voiding intervals and afferent excitability to distension (57), suggesting a key mechanism in this process. Along similar lines of evidence, an increase in the number of activated mast cells, as well as the mast cell growth factor, stem cell factor, have also been reported within the bladder wall following colitis (38). Notably, the contractile response of the bladder to the mast cell activating agent 48/80 is significantly greater in mice at 12 days postintracolonic TNBS administration (20). Treatment with the mast cell stabilizer ketotifen for 5–7 days, or desensitization of the protease-activated receptor 2, significantly reduces 48/80-induced contractions observed in rats with TNBS-induced colitis (20). Moreover, oral administration of ketitofen restores normal voiding parameters, while TNBS treatment in KitaWa/KitaW-va mast cell-deficient mice fails to induce changes in voiding interval (20). These findings provide compelling evidence that mast cells are essential components mediating alterations in bladder function following colitis (20). However, both this study and that of Ustinova (57) did not reveal if the degree of colitis, nor if the sensitivity of the colon, was altered following manipulation of mast cells. This is important, since mast cells have also been suggested to play key roles in the development of colonic hypersensitivity relevant to IBS (4). Therefore, the precise mechanism of mast cell-induced bladder hypersensitivity following colitis remains currently unresolved. Although the origins of bladder inflammation as a result of a colonic insult remain unknown, there are a number of recent studies showing intracolonic TNBS is associated with changes in bladder permeability. This increased permeability of the bladder may lead to a localized mild inflammation of the bladder, as discussed below.

Bladder Permeability The urothelium’s major role is to act as a barrier; however, when this barrier is compromised, its breakdown allows the passage of urine contents into underlying structures. Recent studies have demonstrated that disruption of the urothelium can alter the balance of mediator release, resulting in bladder afferent hypersensitivity either directly or indirectly through the induction of localized inflammation (13, 18). Studies demonstrate that, following intracolonic TNBS administration, the permeability of the bladder urothelium is altered. For example, there is a significant increase in the concentration of sodium fluorescein in plasma 15 min after infusion in the bladder at 12 days postintracolonic TNBS administration (20). Because sodium fluorescein should be predominantly contained within the bladder following this route of administration, these findings suggest colitis causes long-term alterations in urothelial barrier function. Systemic inflammation has been implicated in the development of OAB and IC/PBS (22, 34), and changes in bladder permeability could be a consequence of low-level systemic inflammation during and following colitis. IBS, and to greater extent IBD, patients show altered innate and adaptive immune responses and corresponding changes in circulating cytokine/chemokine profiles (28, 54). These same proinflammatory mediators are also increased in the serum of patients with IC/PBS and, to a lesser extent, the urine of OAB patients (22, 30, 34, 55). In ovariectomized rats, which are known to exhibit an OAB phenotype (63), there is a significant decrease in transepithelial electrical resistance, indicative of increased urothelial permeability in the bladder at 1, 3, and 5 days postintracolonic TNBS administration (23). Furthermore, the transfer of the 4-kDa fluorescent molecule FITC-4 through the bladder wall is significantly increased 1 and 3 days postintracolonic TNBS compared with saline-treated controls (23). In these studies, the time course of urothelial permeability and subsequent barrier recovery correlate more closely with the time course of inflammation than afferent hypersensitivity, which, although not measured directly in these studies, often persists beyond the resolution of inflammation. Earlier reports showed that, in proestrous, but not metestrous, acute colonic inflammation with mustard oil (a known TRPA1 agonist) significantly increased extravasation in the uninflamed bladder (62). These results lead to the hypothesis that estrogen may play an essential role in this mechanism and could be related to the increased prevalence of urological disorders in females (62). This effect was blocked by transection of the hypogastric nerve before colonic inflammation, implicating sensory spinal nerves innervating both the colon and bladder in driving these changes in permeability. Furthermore, intrabladder infusion of protamine sulfate, which permeabilizes the urothelium, but does not induce inflammation, increases colonic permeability (23), suggesting a direct link between the two organs that is not dependent on inflammation. It remains to be determined if changes in bladder afferent physiology following colitis result in changes to urothelial permeability or if urothelial permeability determines bladder afferent sensitivity and bladder function.