Lactoferrin and lysozyme to reduce environmental enteric dysfunction and stunting in Malawian children: study protocol for a randomized controlled trial.

BACKGROUND: Chronic childhood malnutrition, as manifested by stunted linear growth, remains a persistent barrier to optimal child growth and societal development. Environmental enteric dysfunction (EED) is a significant underlying factor in the causal pathway to stunting, delayed cognitive development, and ultimately morbidity and mortality. Effective therapies against EED and stunting are lacking and further clinical trials are warranted to effectively identify and operationalize interventions. METHODS/DESIGN: A prospective randomized placebo-controlled parallel-group randomized controlled trial will be conducted to determine if a daily supplement of lactoferrin and lysozyme, two important proteins found in breast milk, can decrease the burden of EED and stunting in rural Malawian children aged 12-23 months old. The intervention and control groups will have a sample size of 86 subjects each. All field and laboratory researchers will be blinded to the assigned intervention group, as will the subjects and their caregivers. The percentage of ingested lactulose excreted in the urine (Δ%L) after 4 h will be used as the biomarker for EED and linear growth as the measure of chronic malnutrition (stunting). The primary outcomes of interest will be change in Δ%L from baseline to 8 weeks and to 16 weeks. Intention-to-treat analyses will be used. DISCUSSION: A rigorous clinical trial design will be used to assess the biologically plausible use of lactoferrin and lysozyme as dietary supplements for children at high risk for EED. If proven effective, these safe proteins may serve to markedly reduce the burden of childhood malnutrition and improve survival. TRIAL REGISTRATION: Clinicaltrials.gov, NCT02925026 . Registered on 4 October 2016.

Pathogenesis of tropical sprue: a pilot study of antroduodenal manometry, duodenocaecal transit time & fat-induced ileal brake.

BACKGROUND & OBJECTIVES: Small intestinal bacterial overgrowth (SIBO) due to ileal brake-induced hypomotility may cause tropical sprue (TS). We evaluated effect of infusion of fat or placebo in duodenum randomly in patients with TS and healthy controls on antroduodenal manometry (ADM) and mediators of ileal brake, and duodenocaecal transit time (DCTT). METHODS: ADM and DCTT (lactulose hydrogen breath test, HBT) were evaluated with placebo and fat in eight controls and 13 patients with TS (diagnostic criteria: tests showing malabsorption of two unrelated substances, abnormal duodenal histology, absence of other causes, response to antibiotics and folate). RESULTS: Patients with TS (6 had SIBO by glucose HBT) were similar in age and gender with controls. After fat infusion, proximal gut motility index (MI) was reduced compared to fasting state in TS, and DCTT was longer in TS than controls (200 min, 120-380 vs. 130, 70-160, P=0.001), though comparable after placebo (70 min, 30-140 vs. 60, 40-90). TS patients had higher PYY and neurotensin than controls after fat infusion. DCTT after fat infusion correlated with plasma level of PYY in TS but not in controls. Post-fat PYY and neurotensin levels were higher in TS with lower BMI (<16 kg/m [2] ) than those with higher BMI. Parameters of ileal brake (post-fat DCTT, PYY and neurotensin) were higher in patients with than without SIBO. INTERPRETATION & CONCLUSIONS: Fat infusion reduced proximal gut MI, increased DCTT, PYY, and neurotensin among patients with TS. Malabsorbed fat might cause exaggerated ileal brake reducing gut motility, promoting SIBO and bacterial colonization and malabsorption in TS.

13C-sucrose breath test: novel use of a noninvasive biomarker of environmental gut health.

OBJECTIVE: Environmental enteropathy syndrome may compromise growth and predispose to infectious diseases in children in the developing world, including Australian Aboriginal children from remote communities of the Northern Territory. In this study, we described the use of a biomarker (13)C-sucrose breath test (SBT) to measure enterocyte sucrase activity as a marker of small intestinal villus integrity and function. METHODS: This was a hospital-based prospective case-control study of Aboriginal and non-Aboriginal children with and without acute diarrheal disease. Using the SBT, we compared 36 Aboriginal case subjects admitted to a hospital (18 diarrheal and 18 nondiarrheal disease), with 7 healthy non-Aboriginal control subjects. Intestinal permeability using the lactulose/rhamnose (L/R) ratio on a timed 90-minute blood test was performed simultaneously with the SBT. The SBT results are expressed as a cumulative percentage of the dose recovered at 90 minutes. RESULTS: Aboriginal children with acute diarrheal disease have a significantly decreased absorptive capacity, as determined by the SBT, with a mean of 1.9% compared with either Aboriginal children without diarrhea (4.1%) or non-Aboriginal (6.1%) control subjects. The mean L/R ratio in the diarrhea group was 31.8 compared with 11.4 in Aboriginal children without diarrhea. There was a significant inverse correlation between the SBT and the L/R ratio. CONCLUSIONS: The SBT was able to discriminate among Aboriginal children with diarrhea, asymptomatic Aboriginal children with an underlying environmental enteropathy, and healthy non-Aboriginal controls. This test provides a noninvasive, easy-to-use, integrated marker of the absorptive capacity and integrity of the small intestine and could be a valuable tool in evaluating the efficacy of interventions aimed at improving gut health.

[Tropical sprue]. / Sprue tropicale.

Tropical sprue associates prolonged diarrhea, a malabsorption syndrome, and nutritional deficiency in patients who live in or have visited tropical areas. Pathogenesis is still unknown but an infectious cause is suspected. Macrocytic anemia and hypoalbuminemia are present, together with progressive villus atrophy of the small intestine. Treatment with tetracycline, folic acid and proper nutritional support generally results in full recovery.

Tropical sprue.

Tropical sprue (TS) is a clinical entity of unknown etiology characterized by an acquired chronic diarrheal illness and malabsorption that affects indigenous inhabitants and expatriates, either long-term residents or short-term visitors, in the tropical countries. The exact pathogenetic sequence of TS remains incompletely characterized. Bacterial overgrowth, disturbed gut motility, and hormonal and histopathologic abnormalities contribute to the development of TS in a susceptible host. Treatment with tetracycline and folate is effective in some patients, although relapses after treatment are common. Research in the areas of microbial factors, pathogenesis, immunogenetics, and hormonal and immune regulation, using modern diagnostic techniques, may be able to settle some of the unanswered issues and open new venues for diagnosis, prevention, and treatment of tropical sprue.

Tropical sprue is associated with contamination of small bowel with aerobic bacteria and reversible prolongation of orocecal transit time.

BACKGROUND: In tropical sprue (TS), response to antibiotics may suggest a role for bacterial contamination of the small bowel, which is known in diseases with prolonged orocecal transit time (OCTT). METHODS: We studied 13 patients with TS (diagnosed by standard criteria) for frequency, nature and degree of bacterial contamination of the small bowel by quantitative culture of jejunal aspirate, glucose hydrogen breath test (GHBT), and OCTT by lactulose hydrogen breath test before and after treatment. Twelve patients with constipation-predominant irritable bowel syndrome (IBS) and 12 healthy subjects served as controls. RESULTS: Ten of 13 patients with TS had bacterial contamination compared with 3/12 with IBS (all aerobic, P < 0.05). Median colony count in TS (36 000 CFU/mL, 400 to > 100 000) was higher than IBS (700 CFU/mL, 100-1000, P < 0.05). Gram-negative aerobic bacilli were commonly isolated in TS but not in IBS. Median OCTT was longer in TS (180 m, 40 - 240) than IBS (110 m, 70 - 150, P = 0.008) and healthy subjects (65 m, 40 - 110, P = 0.0007, Wilcoxon rank sum test). Orocecal transit time in TS correlated with fecal fat (Spearman's rank correlation coefficient 0.69, P < 0.05). Orocecal transit time and fecal fat, repeated in 8/13 patients, decreased with treatment for TS (195 m, 130-240 vs 125 m, 90-200, P = 0.02; 8 g/24 h, 6.8-19.6 vs 7 g/24 h, 4.2-9, P = 0.04, respectively). CONCLUSION: Aerobic bacterial contamination of the small bowel is common in patients with TS. Prolonged OCTT in TS correlated with fecal fat and normalized in a subset of patients after treatment.

Tropical enteritis: nutritional consequences and connections with the riddle of cholera.

One of the important consequences of the infection-nutrition interaction is mediated by malabsorption associated with chronic inflammation in the intestine, enteritis. Studies made possible after development of the peroral intestinal biopsy technique in the 1950s indicated the wide prevalence of enteropathy, particularly in tropical developing countries with poor levels of sanitation. Some consider this so-called subclinical tropical malabsorption to be the base of an iceberg, whose tip is tropical sprue, a severe form of malabsorption leading to nutritional deficiency that had been reported in colonial expatriates in tropical countries for 200 y. Some of the first demonstrations of the prevalence of tropical enteritis in Asia were made in quest of the pathologic lesion of cholera, and further examination of the water and electrolyte, as well as nutrient, malabsorption in cholera led serendipitously to the discovery of the oral rehydration solution for the treatment of diarrheal disease.

Age-related association of small intestinal mucosal enteropathy with nutritional status in rural Gambian children.

Small bowel enteropathy (assessed by the lactulose (L) : mannitol (M) permeability test) is a major factor in infant growth faltering and malnutrition in The Gambia. However, little is known about its persistence and nutritional effect beyond 2 years of age. This was addressed by two cross-sectional studies of intestinal permeability and nutritional status in 162 residents, aged 2-60 years, living in three villages in rural Gambia. L:M ratio was found to be highest in the youngest children and although there was a significant improvement with age (P<0.0001), values were always greater than the range found in UK counterparts. M recovery (mean value 5.68 (se 0.12) %) was at all times between one-third and one-half of expected UK values and showed no improvement with age. Gut barrier function, assessed by L uptake, improved with age (P<0.001) and fell within the UK normal range beyond age 10 years. Both the L:M permeability ratio and L recovery were significantly associated with height-for-age z-scores and -0.22 respectively, P<0.001), a relationship that persisted throughout childhood and into adulthood. Change in height-for-age z-score between the two visits was also related to the L:M ratio P=0.018). The close within-subject correlation of permeability variabilities between the two visits suggests a long-term persistence of enteropathy within individuals. It appears that the small bowel enteropathy previously described in Gambian infants persists through to adulthood. Although the lesion improves with age, the relationship between attained height and L:M permeability raises the possibility that enteropathy may continue to limit growth throughout childhood and puberty.

[Chronic diarrhea since returning from Black Africa. "Think of tropical sprue"!]. / Diarrhée chronique au retour d'Afrique noire "penser à la sprue tropicale"!

Tropical sprue is a diagnosis about which we have to think when we are confronted to a patient back from overseas. We examined a young man back from Central African Republic where he got diarrhoea which keeps going on in France, with alteration of his general condition and stigmata of malabsorption. Taking advantage of such observation, the authors report on the present knowledge about that disease peculiar to tropical zone. Biological elements of malabsorption are associated to partial emaciation of villi of small intestine. As a matter of fact, diagnosis is made by elimination. Its pathogenesis remains unknown and is linked to some troubles of intestinal microbism of which exact causes has not been yet put into evidence. An easy treatment by tetracycline and folic acid is a true diagnosis test, as general condition is set up again, as well as villi intestinalis.

Intestinal transit in healthy southern Indian subjects and in patients with tropical sprue.

Whole gut transit was measured in a group of 21 healthy volunteers and 21 patients with tropical sprue by radio-opaque marker technique, using mean transit time single (MTTS) and single stool transit (SST) method. Mean SST in controls was 25.8 (1.4) (SE) hours, which is considerably shorter than in controls in temperate zones. Mean SST (23.7 (0.6) h) correlated significantly with average MTTS (24.9 (1.6) h) (r = 0.88; p less than 0.001) confirming that SST is a valid method to measure intestinal transit in the tropics. Patients with tropical sprue had a mean SST similar to controls (24.4 (1.1) h), in spite of significantly higher faecal weights (580 (41.2) g v 252 (17.2) g; p less than 0.001).

Tropical sprue in southern India.

Tropical sprue, a primary malabsorption syndrome affecting residents and visitors to several tropical regions, occurs in southern India in endemic and epidemic forms. The stomach, the small intestine and colon are affected and malabsorption results in nutrient deficiency. Enterocyte damage, the primary lesion in southern Indian tropical sprue, is the result of a persistent lesion of the stem cell compartment. This lesion occurs on a background of tropical enteropathy and the available evidence suggests that an immunity conferring agent may be responsible for initiating the damage.