Glucagon-like Peptide 2 (GLP-2) in Undernourished Women Improving From Histology-Confirmed Environmental Enteric Dysfunction (EED)

Background:

Burden: Recent studies indicated an association between undernutrition and Environmental Enteric Dysfunction (EED) with more than 90% of undernourished women in Dhaka slum having histo-pathological evidence of EED.

Knowledge gap: Currently, there is no available treatment for this condition. Teduglutide, a glucagon-like peptide-2 (GLP-2) analog, has been shown to improve damaged intestinal mucosa, improve villi height, absorptive capacity, and reduce mucosal inflammation. A recent study among children in Zambia and Zimbabwe with malnutrition enteropathy demonstrated significant improvement of EED features with no adverse effect following teduglutide treatment.

Relevance: Given the fundamental structural and functional alterations of the intestine due to EED, GLP-2 analogues such as teduglutide could significantly revolutionize treatment strategies. However, teduglutide has not yet been trialed in adults with EED.

Hypothesis: Daily treatment Glucagon-like Peptide 2 (GLP-2) Analog teduglutide for thirty days will improve histologic and biomarkers features of EED in undernourished women with biopsy-proven EED.

Objectives: To examine the efficacy of daily sub-cutaneous glucagon-like peptide 2 (GLP-2) analog teduglutide treatment for 30 days in undernourished women with histology-confirmed EED on improving histology features of EED (a continuous score on villus height, crypt depth, and immune infiltration) (Primary objective) and biomarkers of inflammation, intestinal permeability, enterocyte mass, and absorption (secondary objectives).

Methods: This is a community-based, single-arm, open-label, pilot intervention study. Undernourished women aged 18-35 years with a Body Mass Index (BMI) between 16 to 18.5 kg/m² will be enrolled from Bauniabadh and adjacent slum areas in Mirpur, Dhaka. Initially, participants will participate in a 60-day on-site nutrition intervention consisting of one egg (boiled or fried), 150 mL milk, two chapati/flat bread/bread with vegetable/lentil soup, and one tablet containing the 15-component UNIMMAP MMS (FullCare, SMC, Dhaka). Participants who do not respond adequately to this intervention (BMI < 18.5 and at least 10% improvement of baseline BMI) and who will not have any secondary causes of malnutrition will undergo an upper gastrointestinal (UGI) endoscopy and histologic evaluation for EED. Participants with histology-confirmed EED, who will provide consent will receive daily sub-cutaneous teduglutide (0.05 mg/kg/day) treatment for 30 days. A second UGI endoscopy will be done after the endoscopy and the biomarkers will assessed at different time points.

Sample Size: 55 participants will receive teduglutide treatment and at least 30 undernourished women with histology-confirmed EED will complete the study. To identify women with EED with a rationale to perform UGI endoscopies, and expected drop outs, we will enroll 500 low-BMI women for nutrition intervention. An additional 30 normal-BMI (20-24.9 kg/m² will be enrolled for aminoacid absorption studies.

Primary end point: A continuous measure, based on the presence of established histopathologic indicators of EED, including immune cell infiltration, reduced villus height, and increased crypt depth. Each feature present will contribute one point to the composite score, resulting in a total EED score ranging from 0 to 7 for participants undergoing EGD. A higher score indicates the presence of more severe EED.

Secondary end point: Histological recovery from EED, as indicated by reduced infiltration of immune cells, increased villus height, and reduced crypt depth. Recovery from EED will be assessed using a four-level ordinal outcome scale, ("no EED," "mild EED," "moderate EED," and "severe EED") at baseline and after treatment.

Inclusion criteria

Bangladeshi women, aged 18-35 years

• BMI between 16 kg/m2 to 18.5 kg/m2
• No antibiotics for 1 month
• Willing to sign the consent form
• Willing to receive food and multiple micronutrient supplementation for 2 months
• Willing to receive daily one-month sub-cutaneous GLP 2 analog, Teduglutide treatment
• Willing to undergo endoscopy and biopsy, twice, before and after intervention, if failed to respond to nutrition intervention and who did not have other chronic or acute diseases that may cause malnutrition
• Willing to provide biological samples during the study period of 4 months

Exclusion criteria

• Severe anemia (<8 g/dl), known case of TB, and other chronic diseases, including diabetes mellitus or any congenital disorder or deformity
• Pregnancy, lactation, drug abuse, known psychiatric disorders
• High clinical suspicion of cancer or other chronic or acute diseases that may cause malnutrition.
• Known allergy to any components of nutrition intervention or any GI polyp
• Ongoing episode of diarrhea, history of persistent diarrhea in the past month or history of acute diarrhea in the past 7 days