Revolutionary Biological Discovery Challenges Established Notions Regarding the “Second Brain”

The enteric nervous system (ENS), commonly referred to as the “second brain,” has long been recognized for its pivotal role in processes such as digestion, immunity, and communication with the central nervous system. Recent breakthroughs in research have unveiled a paradigm-shifting revelation: ENS development persists beyond birth and encompasses neurons originating from mesodermal tissue. This revelation challenges deeply entrenched scientific beliefs and holds promise for innovative approaches to combat aging-related and gastrointestinal disorders.

This groundbreaking discovery may pave the way for advanced therapies targeting gastrointestinal ailments.

Often, we regard the gut merely as an organ responsible for digestion. However, commonplace expressions such as “following your gut,” “losing your appetite,” and “making a gutsy move” underscore the broader spectrum of critical functions that the gut performs.

The entire digestive tract is ensconced by the enteric nervous system (ENS), an extensive network comprising millions of neurons and glial cells, akin to the cell types found in the central nervous system. While colloquially dubbed the “second brain,” the ENS not only produces the same neurotransmitters as the central nervous system but also predates the evolution of the brain’s central nervous system.

The functions executed by the ENS are pivotal for sustaining life and extend far beyond digestion. This intricate system regulates immunity, orchestrates gut secretions, and enables intricate two-way communication between the gut and the brain. Consequently, the state of the gut and its functionality intimately influences one’s mood and behavior, elucidating the profound connection between a healthy gut and a sound mind.

Until recently, the prevailing scientific consensus since the mid-20th century posited that the ENS originates from the neural crest before birth and remains unaltered thereafter. However, in a seminal paper published in the esteemed journal eLife, scientists from the Beth Israel Deaconess Medical Center (BIDMC) have introduced an entirely novel perspective. They have unveiled a developmental trajectory whereby ENS development persists postnatally, as evidenced in both mouse models and human tissue samples.

This groundbreaking revelation upends decades of scientific dogma pertaining to the fundamental principles of neuroscience and the ENS. It marks the first instance of compelling evidence supporting the existence of a significant population of enteric neurons born after birth, originating not from ectodermal tissue but from mesodermal tissue. These findings underscore the relevance of these neurons to the maturation and aging of the ENS, impacting both health and disease.

Dr. Subhash Kulkarni, a staff scientist at BIDMC and an assistant professor in the Division of Medical Sciences at Harvard Medical School, elucidated, “These results indicate for the first time that the mesoderm is an important source of neurons in the second largest nervous system of the body. Understanding how we mature and age is central to our comprehension of health and disease in our rapidly aging population. The increasing proportion of neurons of mesodermal lineage is a natural consequence of maturation and aging, and this lineage is expected to exhibit distinct susceptibilities to disease.”

The research team employed transgenic mouse models, high-resolution microscopy, and genetic analyses to scrutinize the populations of ENS neurons in adult mice and human tissues. Their investigation revealed a fascinating transformation. While early postnatal ENS cells adhered to the anticipated neural crest lineage, this pattern swiftly evolved as the animals matured. Kulkarni and his colleagues meticulously documented the arrival and continual proliferation of a novel cohort of enteric neurons stemming from mesodermal tissue—the same lineage responsible for generating muscle and heart cells.

This newfound population of mesoderm-derived neurons expanded with age, ultimately constituting a substantial portion of all enteric neurons in adolescent and adult mice, even surpassing the original neural crest-derived population in aging mice.

By deciphering the molecular signature of these neurons, the research team identified novel cellular markers. These markers not only facilitated the identification of mesoderm-derived neurons in human gut tissue but also presented potential pharmacological targets. Utilizing these targets, the researchers were able to manipulate the proportions of mesodermal neurons in adolescent mice and mitigate their dominance in the aging mouse gut, alleviating age-related declines in gut motility.

Dr. Kulkarni added, “These findings empower us to explore their translation into human systems, potentially offering disease-modifying treatments to aging patients who frequently grapple with gastrointestinal disorders. By challenging a cornerstone belief in neuroscience, we now stand at the precipice of uncharted territory, armed with a significant opportunity to delve into the concealed realms of basic, translational, and clinical neuronal biology. The discovery of this new lineage of neurons presents us with promising targets for drug development that could benefit vast populations of patients.”

Reference: “Age-associated changes in lineage composition of the enteric nervous system regulate gut health and disease” by Subhash Kulkarni, Monalee Saha, Jared Slosberg, Alpana Singh, Sushma Nagaraj, Laren Becker, Chengxiu Zhang, Alicia Bukowski, Zhuolun Wang, Guosheng Liu, Jenna Leser, Mithra Kumar, Shriya Bakhshi, Matthew Anderson, Mark Lewandoski, Elizabeth Vincent, and Loyal A. Goff and Pankaj Jay Pasricha, 7 August 2023, eLife. DOI: 10.7554/eLife.88051.1

Co-authors: Monalee Saha, Jared Slosberg, Alpana Singh, Sushma Nagaraj, Chengxiu Zhang, Alicia Bukowski, Zhuolun Wang, Guosheng Liu, Jenna Leser, Mithra Kumar, Shriya Bakhshi, Elizabeth Vincent, and Loyal A. Goff of Johns Hopkins University School of Medicine; Laren Becker of Stanford University School of Medicine; Matthew Anderson and Mark Lewandoski of Center for Cancer Research, National Cancer Institute; and Pankaj Jay Pasricha of the Mayo Clinic.

Acknowledgments: The microscopy was performed at the Ross Imaging Core at the Hopkins Conte Digestive Disease Center at the Johns Hopkins University (P30DK089502) using the Olympus FV 3000rs (procured with the NIH-NIDDK S10 OD025244 grant). The 10X Genomics Chromium processing for scRNAseq was conducted at the GRCF Core, and the sequencing was carried out at the CIDR core at the Johns Hopkins University. This work received support through grants from the Ludwig Foundation, the NIA (R01AG066768), a pilot award from the Hopkins Digestive Diseases Basic & Translational Research Core Center grant (P30DK089502), a pilot award from the Diacomp initiative through Augusta University; a Johns Hopkins Catalyst Award; the Maryland Genetics, Epidemiology, and Medicine training program sponsored by the Burroughs Welcome Fund; the Hopkins Conte Digestive Disease Center at the Johns Hopkins University (P30DK089502); NIDDK (R01DK080920); the Maryland Stem Cell Research Foundation (MSCRF130005), and a grant from the AMOS family.

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More about Enteric Nervous System Development

• eLife Journal Article
• Beth Israel Deaconess Medical Center
• Harvard Medical School
• Johns Hopkins University School of Medicine
• Stanford University School of Medicine
• Center for Cancer Research, National Cancer Institute
• Mayo Clinic
• National Institute on Aging (NIA)
• Ludwig Foundation
• Maryland Stem Cell Research Foundation
• Diacomp Initiative
• Hopkins Digestive Diseases Basic & Translational Research Core Center
• Maryland Genetics, Epidemiology, and Medicine Training Program
• NIH-NIDDK S10 OD025244 Grant
• AMOS Family