Review
Infection, immune function, and functional gut disorders

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Basic mechanisms of disordered function after infection

The gut is a richly innervated organ and it is likely that most disorders of function involve disturbance of either efferent or afferent neural function. This can be either nonspecific neuronal damage caused by chronic inflammation or specific damage (e.g., caused by neurotrophic viruses) or to immune damage caused by cross-reacting antigens as seen in the Guillain-Barré syndrome after Campylobacter jejuni.1 Tissue damage usually is followed by repair in which nerve regrowth plays a vital role.

Acute inflammation

Damage to the barrier function of the gut or direct invasion of the tissue allows bacterial products such as lipopolysaccharide and chemotactic peptides to up-regulate key transcription factors such as nuclear factor κ B, inducing secretion of inflammatory cytokines including interleukins (IL-1β, IL-6, IL-8), tumor necrosis factor, and adhesion molecules. This is followed by recruitment of circulating polymorphonuclear leukocytes, lymphocytes, and monocytes. When these activated cells enter the

Long-term effects of inflammation

The later phases of the inflammatory response are characterized by infiltration with macrophages and lymphocytes. These have been shown to have profound effects on neural function,11, 12, 13 including impaired release of norepinephrine from inhibitory sympathetic nerves12, 13 together with enhanced muscular activity in response to cholinergic stimuli.13 Later still in the evolution of the condition prostaglandins appear important because cyclooxygenase-2 inhibitors can diminish the enhanced

Esophageal dysmotility

Dysphagia, with or without a dilated esophagus, is a common feature of Chagas’ disease, a systemic disorder caused by infection with Trypanosome cruzi. Although plainly not a functional disorder, it shares several features with other disorders of esophageal motility, is useful to consider as the mechanism, is well understood, and follows an acute inflammatory lesion. Amastigotes spread throughout the body causing inflammatory lesions in cardiac, skeletal, and gastrointestinal smooth muscle.

Mechanisms of acute symptoms

The acute anorexia and vomiting associated with infections likely are caused by many factors including effects of inflammatory cytokines such as IL-1, IL-6, and tumor necrosis factor-α, serotonin, and prostaglandins, and in the case of bacterial enteritis, lipopolysaccharide. Most of these mediators activate vagal afferents to induce altered gastric motility but they also act via the circumventricular organs where the blood brain barrier is weak or absent (e.g., pineal gland, median eminence,

Chronic effects

An autonomic neuropathy was shown in 3 of 3 patients tested in the Mayo series27 and antral hypomotility also was shown in several series.27, 34 The underlying pathology is rarely available, but in one individual who had an acute onset of vomiting 2 weeks after a flu-like illness who underwent surgery, mesenteric ganglionitis was reported. Full-thickness biopsy specimens of the stomach showed a marked T-lymphocyte infiltrate of the mesenteric plexus and a decrease in tachykinin immunoreactivity.

Prognosis

Prognosis is much better in those with postinfectious gastroparesis than in patients with an insidious-onset gastroparesis. There was resolution in 5 of 7 adult patients at a mean of 32 months,27 and complete recovery in all of the children reported by Sigurdsson.28 Similar results were observed in a series of 52 patients with idiopathic gastroparesis, of which 12 were thought to be postviral31 and 8 of whom were asymptomatic after a mean of 32 months follow-up evaluation. This survey found

Treatment

This is unsatisfactory and none so far have directed therapy specifically at postinfectious gastroparesis. A range of prokinetics has been evaluated including metoclopramide, domperidone, cisapride (now withdrawn, only limited availability), and erythromycin. All may benefit a few, especially milder, cases, but in severe cases no medications work and the main focus is on nutritional support with jejunostomy feeding. Gastric pacing can help relieve intractable nausea and vomiting and produces a

Postinfective functional dyspepsia

This encompasses a larger group of patients with acute-onset dyspepsia, not all of whom have delayed gastric emptying. These cases are presumed to be postinfectious, although there was no microbiologic proof in the cases reported in one large series.39 When compared with those not thought to be postinfective, these patients showed more early satiety and weight loss and were found to be more likely to show impaired gastric accommodation to a meal.39 Pharmacologic studies suggest that this is

Postinfective irritable bowel syndrome

This disorder is much more common and, hence, better documented than gastric dysfunction with several well-designed prospective as well as cross-sectional studies using appropriate controls to guide conclusions.

Clinical features

Clinicians looking after patients with proven IBD will be familiar with patients who experience IBS-type symptoms, particularly pain and diarrhea, but in whom there is no sign of relapse of inflammation.76 A more recent study confirmed this with IBS-like symptoms of at least moderate severity being reported by 33% of ulcerative colitis patients and 57% of Crohn’s patients thought to be in remission.77 Interestingly, the extent of colitis did not predict symptoms whereas a longer history of IBD

Guillain-barré syndrome complicated by prolonged ileus

Although not usually considered a functional disease, this exemplifies an interesting mechanism that may be relevant. A minority of patients affected by this acute ascending paralytic syndrome showed evidence of recent prior infection with C. jejuni.1 These patients showed a more severe atypical illness with an acute motor neuropathy, often without sensory loss.86 Autonomic dysfunction may be associated with a profound ileus affecting the whole gut, which can last many months.87 Sera from

Neuroimmune appendicitis

The removal of noninflamed appendices from patients with recurrent, right, iliac fossa pain is an everyday occurrence. A recent study suggested that these patients have suffered previous missed appendiceal inflammation and developed a postinflammatory hypersensitivity that then mimics true appendicitis. Several studies have examined these noninflamed appendices and showed increased expression of substance P,89, 90 and evidence of previous inflammation with increased expression of

Symptoms in diverticulosis after acute inflammation

Although the cause of diverticulosis is disputed, this aging change of the colon is associated with weakness of collagen associated with changes in its cross-linking,93 which may well be owing to a lack of dietary factors found in fruit and vegetables. It is much more common in regions of the world where dietary fiber intake has been traditionally low, but its relation to symptoms is controversial.94 Given that one third of the population over 65 in some Western countries have diverticulosis,

Summary and a look to the future

Functional diseases have, in the past, been synonymous with a lack of sufficient understanding and therapeutic failure. This article has attempted to show that when these conditions begin after a bout of inflammation, there is good reason to be optimistic that further studies will yield conceptual and therapeutic advances. Underlying mechanisms that are being identified include continued low-grade inflammation, increased availability of serotonin, altered nerve structure, and expression of

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