Researchers at Johns Hopkins Children’s Center have discovered a gene pathway linked to zinc in mice that could pave the way for the use of zinc-based supplements to assist individuals with a rare condition known as short bowel syndrome (SBS).
Researchers at Johns Hopkins Children’s Center have pinpointed a gene pathway in mice that involves the mineral zinc, which may eventually lead to the use of zinc supplements to aid those affected by the rare condition called short bowel syndrome (SBS).
The study, published on October 7 in Nature Communications, represents a step forward in creating more effective treatment options for both children and adults suffering from this challenging health issue.
SBS impacts between 10,000 to 20,000 patients in the United States, leading to damage and shortening of the small intestine. While some children can be born with SBS, it is more commonly a result of conditions such as necrotizing enterocolitis, which affects premature infants’ intestines.
Patients with SBS struggle to absorb necessary nutrients from their food, often requiring intravenous nutritional support, and face significant complications including malnutrition, dehydration, involuntary weight loss, and even death. Standard treatment strategies—like specialized diets, surgeries, and occasionally small bowel transplants—provide only partial relief and can lead to side effects such as infections and lengthy hospitalizations.
“Short bowel syndrome is a significant issue and profoundly affects the lives of those diagnosed and their families,” explains David Hackam, surgeon-in-chief and co-director of Johns Hopkins Children’s Center, as well as the lead author of the study. The aim of the research was to explore new potential treatment options for SBS patients. Interestingly, they uncovered a previously unknown function for zinc that could help protect and promote the growth of the remaining bowel tissue in SBS patients.
Initially, the researchers utilized a mouse model of SBS that exhibited traits akin to those seen in humans. They investigated the changes in the structure of the shortened bowel over time and found that the villi—tiny, hair-like structures in the small intestine vital for nutrient absorption—began to grow longer as a natural response.
“The villi were adapting, as if they were reaching out for more nourishment,” notes Hackam. However, he mentioned that these villi were unable to fully “recover” or repair themselves.
The team then considered how the healing process might function in human patients with SBS, discovering potential gene pathways that could aid in the intestines’ adaptation and healing. To investigate this, they transplanted human-induced stem cells into mice, enabling the growth of human-like intestinal structures.
Using single-cell RNA sequencing, the researchers assessed the expression of specific genes in the mice’s intestines. This analysis allowed them to map out multiple gene pathways and see which genes influenced recovery, according to Hackam.
After a month of recovery, they examined which genes were activated or deactivated as the intestines attempted to adapt and heal. They found that zinc transport genes, SLC39A4 and SLC39A5, located in the small intestine and critical for zinc transportation in the body, were significantly upregulated, indicating their role in bowel recovery. Through quantitative polymerase chain reaction (qPCR), a method for quantifying gene expression, they noted that these zinc transporter gene levels in the experimental subjects were up to 4 or 5 times greater than those in control subjects.
To evaluate whether zinc supplementation could enhance intestinal function and healing, they administered a high-zinc liquid diet (65 milligrams per kilogram per day of zinc acetate) to some SBS-afflicted mice. Those on the high-zinc diet not only gained weight more effectively than those on standard or zinc-deficient diets but also showed a partial reversal of typical SBS symptoms. By the end of the first week, mice on the standard zinc-depleted diet had lost 13.38 ± 1.11% of their weight, whereas mice receiving the additional zinc lost only 7.1 ± 1.19%. Importantly, the high-zinc diet led to improved survival rates—85.7% compared to 66.67%—and allowed the intestines to better absorb nutrients and fluids due to healthier and longer villi. “In summary, we found that increasing zinc intake supported better recovery in the mice and enhanced their survival prospects,” states Maame Sampah, a research fellow and surgical trainee involved in the study.
To validate these observations in human samples, the researchers analyzed tissues from 26 individuals (14 with SBS) who underwent endoscopic or surgical treatments from 2008 to 2020 at Washington University in St. Louis. Their analysis revealed that individuals with SBS exhibited notably higher RNA levels of the SLC39A5 gene, while the levels of another key zinc gene, SLC39A4, were consistent between both groups. However, the proteins produced by these genes—the zinc transporter proteins ZIP4 and ZIP5—appeared in different locations within the intestinal cells of SBS patients compared to the control group. These findings suggest that SBS patients are actively working to absorb as much zinc as possible and indicate the therapeutic potential of zinc supplementation for managing SBS.
Although researchers stress the need for additional studies, including animal trials and clinical research, to confirm the safety and effectiveness of zinc supplements for human therapy, they believe these findings provide valuable insights into short bowel syndrome.
“Our study results give hope to patients and families dealing with SBS,” remarks Hackam. “There may be new, safe, and effective treatment options on the horizon.”
In addition to Hackam and Sampah, the study’s authors from Johns Hopkins include Hannah Moore, Raheel Ahmad, Johannes Duess, Peng Lu, Carla Lopez, Steve Steinway, Daniel Scheese, Zachariah Raouf, Koichi Tsuboi, Jeffrey Ding, Connor Caputo, Madison McFarland, William Fulton, Sanxia Wang, Meghan Wang, Thomas Prindle, Samuel Alaish, and Chhinder Sodhi. Authors from Washington University School of Medicine in St. Louis include Vered Gazit and Deborah Rubin.
This research was funded by grants from the National Institutes of Health, specifically the R35GM141956 and T32DK007713 awards.
No authors reported any conflicts of interest as per Johns Hopkins University School of Medicine policies.
