The Lachman Lab at Albert Einstein College of Medicine is interested in the role of the intestinal (gut) microbiome in psychiatric and neurodevelopmental disorders, in particular, autism and PANS (Pediatric Acute-Onset Neuropsychiatric Syndrome). Dr. Lachman is a professor in the Departments of Psychiatry, Medicine, Genetics, and Neuroscience. His lab has had continuous funding by the NIH, foundations, and private donors since 1985.

The gut microbiome is the community of bacteria in our intestines that play an important role in human health. There is evidence that “gut dysbiosis”, an imbalance in intestinal bacteria, can contribute to the development of depression, autism spectrum disorders, Alzheimer’s disease, Parkinson’s disease, and a host of other conditions. Dysbiosis, it has been postulated, can activate the immune system through the leakage of bacterial components into the circulation via an abnormal permeability of the intestinal wall, a process commonly referred to as “leaky gut syndrome.” This can cause an inflammatory response in the brain mediated by the immune system; the so-called gut-immune-brain axis.

Despite hundreds of studies, primarily carried out in animal models, the underlying biological basis for these phenomena in humans is not known. The Lachman lab has been studying the genetic underpinnings of acute, infection-induced changes in behavior in children with autism spectrum disorders and other neurodevelopmental disorders (NDDs). During our studies, we identified mutations in several genes known to play a role in gut dysbiosis and intestinal permeability, providing a unique opportunity to investigate and elucidate underlying biological pathways. One of the genes is called DUOX2, which plays a key role in inflammatory responses in the intestines. We propose to study the effect of pathogenic DUOX2 mutations we identified on intestinal physiology in “intestinal organoids,” which are small, 3-dimensional structures that resemble human intestines, using a technique developed more than 10 years ago by another investigator. Intestinal organoids are derived from “induced pluripotent stem cells” (iPSCs). iPSCs are made from skin and white blood cells using a technique that led to a Nobel Prize in Physiology or Medicine for the inventor, Shinya Yamanaka. iPSCs have the unique capacity to be turned into essentially any cell type in the body, including neurons (brain cells) and intestinal organoids using different cocktails of growth factors.

The Lachman lab has been using iPSCs to grow neurons that contain mutations in genes implicated in autism and other NDDs. In the proposed study, we will introduce pathogenic DUOX2 mutations into iPSCs using CRISPR-Cas9-mediated genetic engineering from which intestinal organoids will be developed. We will then study the effect on gut permeability and various molecular pathways using state-of-the-art techniques, such as single cell RNA sequencing. Our study will identify potential therapeutic targets. Studies relating intestinal permeability and neuropsychiatric disorders to specific genetic mutations have never been carried out. Given the difficulties in obtaining funding from the National Institutes of Health (NIH) for new, high-risk, high-reward research, we set up this JustGiving campaign to initiate our groundbreaking experiments. The data we obtain will be publishable and serve as background material to eventually apply for NIH funding to study other genes and to test the effects of medications directed against molecular targets identified in this study.