What is tropical sprue?

See article in J. Gastroenterol. Hepatol. 2003; 18: 540–7. A simple definition of tropical sprue (TS) is ‘an acquired disease of unknown etiology characterized by malabsorption, multiple nutritional deficiencies, and mucosal abnormalities in the small bowel’.1 There are few recent studies on this entity and considerable confusion regarding the relationship of TS to tropical enteropathy and traveller's diarrhea. In issue 5 of the Journal, Ghoshal et al.2 define a group of patients with TS by strict clinical and pathological criteria and show that aerobic bacteria contaminate the small bowel in patients with TS and that these patients have a prolonged orocecal transit time (OCTT) compared with healthy control subjects. It is speculated that bacterial contamination worsens steatorrhea and activates the ‘ileal brake’, which is reversible in the majority of patients on treatment with tetracycline and folic acid. The etiology of TS is presumed to be infective; however, attempts have failed to isolate a single organism and it might therefore be the result of an unfortunate coincidence of circumstances. Most likely ‘hit and run’ bacteria damage enterocytes, resulting in a cascade of events leading to small bowel stasis, bacterial overgrowth, disturbances in gut motility, malabsorption and loss of folate with further damage to the enterocyte, and a vicious cycle results. Elimination of bacterial overgrowth by tetracycline and mucosal repair by folate supplements results in the restoration of mucosal integrity.3 The overlap of tropical enteropathy and TS corresponds to the particular geographical distribution of these conditions and a link is purely speculative. More studies are needed to unravel the nature of the enterocyte response in this spectrum of enteropathies resulting from antigen or pathogen insult. Although the pathogenesis of TS is unknown, speculation has centered around infection leading to bacterial overgrowth and disturbance of motility, but other factors such as genetic susceptibility, local environment, bacteria and food practices should be considered in the etiology. In bacterial overgrowth syndromes of the small intestine (e.g. blind loop syndrome), enterocyte brush-border motility is altered.4 Bacteria recovered in this syndrome are anaerobes that actively deconjugate bile acids5 preventing proper bile acid function by reducing enterohepatic circulation. As deconjugated bile acids cannot form chylomicrons, fatty acid absorption is impaired. Deconjugated bile acids also directly inhibit carbohydrate transporters, reduce intraluminal pH, and further damage intestinal enterocytes creating a self-perpetuating cycle. In bacterial overgrowth syndromes, there is an alteration of duodenal morphology similar to that seen in TS, namely villous atrophy and an increase in intra-epithelial lymphocytes, that returns to normal on antibiotic treatment.6 The difference between these two enteropathies appears to be caused by the bacterial population. In TS, many different bacteria have been isolated including Escherichia coli, Klebsiella pneumoniae and Enterobacter cloace, and patients can harbor one or more highly toxigenic strains. In contrast, patients with blind loop syndrome did not have toxigenic strains.7 Overgrowth of bacteria and damage to enterocytes with subsequent increased fat in the lumen of the small intestine cause release of gut hormones that regulate motility and mucosal integrity.8-10 Recently described glucagon-like peptides (GLP) play a major role in this process. Both GLP1 and GLP2 are proglucagon-derived peptides secreted from gut endocrine cells in response to nutrient ingestion. They promote nutrient absorption through distinct mechanisms, and GLP2 regulates gastric motility, gastric acid secretion, intestinal hexose transport and increases the barrier function of the gut epithelium. It also promotes nutrient absorption via expansion of the mucosal epithelium by stimulation of crypt cell proliferation and inhibition of apoptosis in the small intestine, thereby acting as a repair mechanism. No studies have been performed on TS to identify these peptides. This might be a fruitful avenue to explore because these substances could be subject to therapeutic manipulation. It is thought that GLP1 might be a candidate mediator for the ileal brake mechanism.11 The ileal brake is an inhibitory intestinal control mechanism, whereby ileal fat perfusion inhibits jejunal motility and delays caudal transit of jejunal contents.12, 13 In celiac disease, an immune-mediated enteropathy, the OCTT is also reduced but returns to normal on a gluten-free diet with restoration of mucosal integrity.14 The study by Ghoshal et al. has similarly shown a prolonged OCTT in TS that will leave pathogenic bacteria in contact with enterocytes for a longer time and thus compound damage, but the OCTT returns to normal on treatment.2 This suggests that the prime motivator for the ‘ileal brake’ is enterocyte integrity. Tropical sprue occurs in distinct geographical locations within 30° of either side of the equator. The condition is not limited to indigenous populations but also affects European or American expatriates living in the tropical regions. The first description of TS was attributed to Hillary in 1759.15 In the 1950s, it was reported that intestinal malabsorption as a result of TS is widespread among the indigenous population of south India.16 It is more common in India, Haiti, Cuba, Puerto Rico and the Dominican Republic, but is rare or absent in Africa, the Bahamas and Jamaica.17 This particular geographical distribution suggests a genetic link in TS. While celiac disease is associated with certain HLA haplotypes,18 this is not the case in TS, nor in a study in Puerto Rico where the absence of a B-locus or haplotype effect suggested a marker association rather than an immune association.19 Other environmental factors appear to be more important. A dietary link to cultural culinary practices such as high fat consumption and bacterial exposure have been postulated.17 Tropical sprue can either be a disease in its own right or part of a spectrum including tropical enteropathy and traveller's diarrhea. Tropical enteropathy refers to morphological differences in small intestinal mucosa of those residing in the tropics compared with temperate regions,20 and thus has some geographical and histopathological overlap with TS. These morphological differences in small intestinal biopsies from different ethnic groups are also described in populations migrating to and from that region. A study of Asian, Caucasian and Afro-Caribbean subjects in the UK showed decreased villous height and villous : crypt ratios in both migrant groups, but no differences in biochemical, hematological indices or body habitus, indicating no clinical effect.21 Tropical enteropathy has also been noted in all races in Zimbabwe, which precludes a genetic link.22 Tropical enteropathy was present in a healthy Zambian population. In this group, tropical enteropathy was associated with mucosal T-cell activation and crypt hyperplasia; however, subjects were asymptomatic. From the observation that tropical enteropathy appeared to be the ‘normal’ state of the small intestine in the majority of Zambian inhabitants, it was concluded that ‘enteropathy’ is a misnomer and that exposure to an increased enteric pathogen load upregulates mucosal T cells with resultant enteric morphological change.23 An alternative hypothesis is that tropical enteropathy can be triggered by antigens similar to celiac disease, as suggested by the lack of response to antibiotics in this condition. Characterization of the T-cell population in TS has not been elucidated and it would be of interest to compare it with that of tropical enteropathy. Despite the pathological similarity, there are marked clinical differences between tropical enteropathy and TS. Tropical enteropathy does not respond to treatment with tetracycline and folic acid, and occurs in Africa where TS is uncommon. In contrast, traveller's diarrhea is a self-limiting illness that usually has a defined or recognizable microbial etiology. Morphological abnormalities can be minimal or directly related to a visible pathogen, for example, giardia.24 Other pathological mimics of TS are cow's milk protein sensitivity25 and immunoglobulin A deficiency.26 There are pathological similarities in these enteropathies, but there is likely a profound difference in host response to environmental insults and immune profiling, and the response to treatment often characterizes the disease. Tetracycline is well established in the treatment of TS and exerts bacteriostatic properties by inhibiting amino acid uptake by bacteria from the host and inhibiting replication. These nutrients are captured from the surrounding environment at the expense of the host and contribute to malnutrition. This drug binds to 30S ribosomal ribonucleic acid of bacteria, which is responsible for amino acid uptake and blocks protein biosynthesis. This leads to the inability to replicate, death and neutrophil activation.27 However, tetracycline also has indirect effects on inflammation. In acne of the skin, in vitro and in vivo studies have shown that when administered systemically and topically, it can suppress neutrophil chemotaxis.28, 29 The antioxidant effect of tetracycline on the generation of reactive oxidant species (ROS) is shown to be not as a scavenger of ROS but by direct action on neutrophil function with resultant anti-inflammatory effects.30 In chronic diarrhea and malabsorption, the antioxidant defence system in the gut is impaired.31 Tetracycline might also act as an anti-inflammatory agent to restore function of the enterocyte in combination with the mucosal repair agent, folic acid. This action has not been investigated in gut infection and it is interesting to speculate that this drug might be anti-inflammatory as well as bacteriostatic in TS. Folic acid is both depleted by damage to the host epithelium in malabsorption in infection32 and is also ultilized and taken up by bacteria for essential biosynthesis of cellular components,33 thus, in bacterial overgrowth, further depleting the available folate pool. This might be the reason that folic acid supplements are necessary in effective therapy for TS. Other antibiotics and therapies are poorly documented, but with the ready availability of antibiotics for self-medication in travellers’ diarrhea, these might have been unknowingly tried and tested and might be why TS appears to be decreasing in incidence. Probiotics might play a role, but a recent review showed these to be limited in efficacy and availability in travellers’ diarrhea.34 Intestinal hormone manipulation mighty hold promise in stubborn cases. More studies are needed to unravel the complex relationship between these curious enteropathies and to comprehend the pathogenesis, immunogenetics, explore the role of small intestinal motility and investigate novel treatments of TS.