Familial Hemophagocytic Lymphohystiocytosis and Digestive Malabsorption

Familial Hemophagocytic Lymphohistiocytosis (FHL) is a rare genetic disorder characterized by an exaggerated and impaired immune system response. It causes persistent fever, fatigue and irritability, accompanied by enlargement of the liver and spleen, and sometimes neurological or digestive disorders. Dr. Nadine Cerf-Bensussan, laboratory director at the Imagine Institute, and Dr. Grégoire Michaux, research director at the Institute of Genetics and Development in Rennes (CNRS), provide an update on these digestive symptoms and the genetic mutations involved.

Published on 17.03.2021

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Can you recall the main functions of the of the intestine?

NCB: The intestine is the organ that allows digestion and absorption of nutrients. It is also a barrier that protects the body from the many microbes and food allergens present in its lumen.

Can you explain the mechanism of absorption in the gut?

NCB: It is a complex process through which nutrients from the digestion of food in the lumen of the intestine are transported into the blood or lymph to be made available to the various tissues of the body and to the digestion of food in the lumen of the intestine are transported in the blood or lymph to be made available to the various tissues of the body for their functioning. The absorption of nutrients takes place in the proximal part of the intestine (or small intestine). Water reabsorption, which is important to avoid diarrhea, takes place mainly in the distal part of the intestine (or colon).

What role do epithelial cells play in this absorption mechanism? absorption mechanism?

NCB: The epithelial cells form a monolayer on the surface of the intestine. They are the first to come into contact with nutrients, water and minerals, but also with the many microbes present in the lumen of the intestine.

Their apical pole is specialized to promote the entry of nutrients and precisely regulate the flow of water and electrolytes. This pole has a "brush border" made of multiple folds of the membrane that bounds each cell. These folds called microvilli allow to increase in a significant way the efficiency of absorption. Indeed, these folds/microvilli contain transporters specialized in the entry of different nutrients as well as "pumps" that regulate the movement of water and electrolytes (sodium, potassium, chlorine...).

Once nutrients enter the epithelial cells, they can be transported to the basal pole of the epithelial cells and then enter the bloodstream through the many blood and lymphatic vessels present in the supporting tissue on which the epithelial cells rest. 

How does the STXBP2 gene mutation (linked to the Munc 18-2 protein) affect this absorption mechanism?

NCB: STXPB2 is the gene that codes for the Munc 18-2 protein. The mutation in STXPB2 prevents the targeting of molecules necessary for the formation of the apical pole of epithelial cells. It thus hinders the formation of the brush border and the insertion into this border of several of the transporters and "pumps" necessary for the absorption of nutrients and the regulation of water and electrolyte movements. Alterations in the brush border lacking certain transporters and pumps explain the intractable diarrhea and severe malabsorption induced by STXPB2 gene mutations associated with LHF disease.

What other diseases have absorption deficiency? How are they similar or different from the STXBP2 (Munc 18-2) gene mutation?

NCB and GM: There are many, many diseases that can lead to a lack of absorption.

These include:

  • Gastrointestinal infections with bacteria or viruses.
  • Diseases related to excessive activation of the immune system associated with the intestine. The immune system plays a key role in reinforcing the barrier role of the epithelial cells and preventing the entry of micro-organisms. Conversely, excessive activation of the immune system can lead to the destruction of the epithelial cells and, as a result, to severe chronic malabsorption. This is the case, for example, of celiac disease induced by the ingestion of gluten in predisposed individuals.
  • Absorption defects can be observed in several rare genetic diseases: some diseases affect the expression or function of one of the transporters present in the brush border, and thus cause selective malabsorption of the transported molecule and congenital chloride diarrhea. These diseases can usually be controlled by diet adjustment.

Some mutations profoundly affect the differentiation of epithelial cells epithelial cell differentiation and cause severe absorption defects that are difficult to treat.

  • This is particularly the case for mutations that prevent the formation of the brush border and cause "microvillous inclusion disease".

  • Among these mutations, some affect the STXBP2 gene which is necessary for the expression of the Munc 18-2 protein.) These mutations are also the cause of Familial Lymphohistiocytosis type 5 disease also observed in patients

  • Mutations have also been described in three other genes:  

    - the Myo5B gene which codes for a motor molecule that allows the transport of vesicles carrying components of the brush border to the apical pole of epithelial cells

    - the STX3 gene which codes for a moleculei working in tandem with STXBP2 to allow the fusion of vesicles with the brush border and thus its formation.

    - a new gene is being characterized by the teams of N. Cerf-Bensussan and G. Michaux.

What treatment exists today to alleviate intestinal malabsorption related to genetic diseases that affect the differentiation of epithelial cells and their brush border (STXBP2, Myo5B, STX3...)?

NCB and GM: The therapeutic solutions are very limited and unsatisfactory.

  • The first is parenteral nutrition, which consists of using the intravenous route to compensate for water and electrolyte losses (often massive) and to provide nutrients that cannot be absorbed. This solution, which is essential for the survival of patients, is very restrictive and can be incompatible with a normal life. It is complicated in the long term because of the risk of infection and the difficulty of keeping veins accessible for infusions.
  • These difficulties have led to the development of intestinal transplantation to replace the diseased intestine with that of a donor. This transplantation remains very difficult to date, in particular because of the frequency of rejections linked to the presence of a very abundant immune system in the intestine.
  • Research is underway to try to correct the mutations by pharmacological approaches (or drug molecules). This is the objective of the research work being done on the STXBP2 gene.
  • Other long-term approaches aim at correcting the genetic defect in epithelial cells and using these corrected cells to reconstruct the intestine.

How research has led to a better understanding and definition of abnormalities leading to absorption deficits in the digestive system? digestive system?

Fundamental work on the mechanisms controlling epithelial cell differentiation and nutrient absorption has been an essential basis for understanding the consequences of mutations.

Conversely, the analysis of the consequences of mutations on cell differentiation and differentiation and function of epithelial cells provide new information on the role of new information on the role of the molecules affected by the mutations.

This work allows to better define therapeutic options and to set up tools to identify therapeutic targets:

  • intestinal organoids (constitution of mini-intestines from pluripotent or adult stem cells) that allow recapitulation (in vitro) of the abnormalities observed (in vivo) in patients
  • animal models that allow to test therapeutic solutions (mouse ? nematode ?)

Can you explain when and how the research identified the Munc 18-2?

GM: Munc 18-2 was first linked to a disease of the immune system. In some patients, in addition to the immune system, the intestinal absorption function is also affected. It was thought that this absorption defect would disappear after correction of the immune system by a bone marrow transplant, but unfortunately this has not been the case.

Doctors from the Necker Hospital and the Imagine Institute (Geneviève de Saint-Basile's team) then started to look into this particular aspect of the diagnosis.

If correction of the immune system does not improve intestinal absorption, what is the cause of this defect? How does the absence of Munc 18-2 in the gut affect absorption?

Can you give more details about the work you want to do on the STXPB2 (Munc 18-2) genetic mutation?

During a collaboration with Dr Geneviève de Saint Basile, a specialist in LHF-type diseases who works at the Imagine Institute, we were able to help show that intestinal damage due to the loss of the STXBP2 gene (and the absence of the Munc 18-2 protein) is very similar to that of another rare disease, microvillous inclusion disease, due to the loss of the MYO5B or STX3 genes. We also participated in the characterization of some defects of this disease in collaboration with Prof. Frank Ruemmele from Necker Hospital.

We would like to build on the results obtained on microvillous inclusion disease in different animal or cell culture models, to better understand what happens at the brush border of intestinal cells. We will culture organoids (mini intestines formed from adult stem cells) from control mice or mice not expressing the Munc 18-2 protein.

We will then try to correct the defects observed in the absence of Munc18-2, using a phamacological approach, by adding different candidate molecules, which are either already known for microvillous inclusion disease or identified as potential drug molecules in animal models. These molecules will be validated if they can restore the function of the brush border in nutrient uptake, a function that cannot be provided due to the absence of the Munc 18-2 protein.

How will this research improve the quality of life of patients affected by the STXPB2 / Munc 18-2 genetic mutation?

GM: If we identify molecules that can correct the brush border defects observed in cultured organoids, the first step will be to validate these results in vivo in mice and in cultured human intestinal organoids with the support of Nadine Cerf-Bensussan and Geneviève de Saint Basile's groups at the Imagine Institute.

If the results are positive, we could then consider setting up a trial in patients, but for the time being, this remains dependent on the success of each of the steps listed above.

In the long term, such a treatment could improve food absorption and thus reduce the need for parenteral nutrition.

Will the results of this work benefit other rare digestive diseases with the same disorders as Munc 18-2 ?

GM: Since the intestinal phenotype is very similar in microvillous inclusion disease, regardless of the mutated gene, it is hoped that treatment will benefit all patients. More broadly, such an approach could be beneficial for other diseases with intestinal absorption defects due at least in part to a deficient brush border. 


This interview was conducted by LHF espoir, a patient association that aims to support patients with Familial Hemophagocytic Lymphohistiocytosis (FHL), as well as their families, and to fund research on this rare immune deficiency disease.