Unravelling the structure and function of the ‘brain in the gut’ – Fellows’ seminar by Ulrika Marklund

9 February 2023

“The gastrointestinal tract is unique in having its own intrinsic nervous system. The enteric nervous system (ENS) is equal in size to the spinal cord, and controls bowel movement, fluid balance and blood flow independently of the brain. It’s therefore sometimes referred to as the ‘brain in the gut’ or ‘second brain’,” said Ulrika Marklund of the Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Sweden. “While a wide range of inflammatory, congenital and degenerative disorders affect the ENS, it’s still understudied. My team has used novel technologies to introduce a molecular classification of enteric neuronal cell types. The new classification brings new ways to study enteric neurons, which could lead to the discovery of new roles for the ENS in physiology and disease.”

STIAS Fellow Ulrika Marklund during her seminar on 2 February 2023

Explaining her career path into this area, Marklund highlighted an early interest in understanding how two cells (sperm and egg) become a complex organism – how cells within the early foetus read signals to know where they fit and what their function eventually should be, i.e. acquire identities.

Work on the central nervous system (CNS), which includes the brain and spinal cord, has shown that different brain functions require different types of cells – for example the dopamine producers in the midbrain, the serotonin producers in the hindbrain and the motor neurons in the spinal cord. It’s also looked at how signalling molecules are recognised by receptor proteins, how they are transcribed, which genes express and translate into proteins, and which don’t.

But why do we need to understand in detail what occurs? “Because we believe you can use the transcription codes to produce specific types of neurons – to regenerate neurons lost due to illness and to study disease mechanisms on a cellular level,” explained Marklund. Motor neurons are linked with diseases like ALS – amyotrophic lateral sclerosis, serotonin neurons are linked with addiction-related disorders and dopamine neurons are linked with Parkinson’s.

“If we can unlock the key we could convert stem cells into the different types of neurons offering possible treatments for these conditions,” said Marklund. “Cell-replacement therapies are being tested in clinical trials currently for Parkinson’s.”

Into the unknown

Her PhD and post-doc experience encouraged Marklund to expand her interest to the less-known field of looking at the ‘brain’ in the gastrointestinal tract to see if what we know about the CNS also applies.

The ENS is an eight-metre long, autonomous nervous system containing 168 million neurons – equal to the spinal cord. It’s divided into two layers – the outer layer controlling peristalsis and the inner controlling fluid balance and blood flow.

Although Marklund admits she isn’t fond of the brain metaphor, it emphasises the autonomy of the system. “The ENS is not as complicated as the CNS but does function autonomously. Also, from an evolutionary perspective, the gut was controlled by a nervous system before a brain developed, so in some ways, it’s the first brain.”

“The ENS also consists of multiple neuron subtypes that organise into full neuronal circuits and communicate with the same signalling mechanisms as in the CNS but we don’t know all their functions,” she said.

What we do know is that there is a clear link to disease – including Hirschsprung disease in infants and inflammatory bowel disease. It’s believed that as many as 30% of the general population suffer from some form of gut ailment so “more studies are definitely needed and novel therapies especially stem-cell based,” said Marklund.

Her research group is looking at understanding the cell composition and how the different neuronal subtypes form during development of the ENS.

But it’s no easy task. “The system is scattered along the gut wall and the different neuron types are arranged in irregular groups of cells,” she explained. “Until recently we could not distinguish neuron types in a consistent manner but with new sequencing technologies and visualisation tools, we can assess 1000s of genes in single cells and visualise particular neuron types directly in native tissue.”

They have already found about 12 neuronal types – some of which can be linked to already known neuron types, for instance up to six motor neuron types, while others are completely novel. By identifying unique marker genes and assessing the protein contents we will learn more about each neuron type.

“We can now visualise particular neuron types and determine their positions in the gut wall to try to understand who they are ‘talking’ to and their functions. They could be communicating with other gut neurons and also non-ENS cells like immune-system cells, blood vessels, etc.”

Although the two nervous systems use the same neurotransmitters to communicate there are distinct differences in how the two systems arise in the foetus. In the developing CNS, the stem cells don’t move much and there is a clear spatial patterning. They occupy typical positions which determine their identity and function, making them easy to find. Underlying this ‘spatial patterning’ are graded signalling molecules that regulate gene expression, and therefore the protein content of the developing cells. “Stem cells read the signalling molecules to know what to develop into,” explained Marklund. “Cell identity is the sum of the produced proteins.”

The ENS stem cells are more motile – you can’t know their identity and function just based on their position – they intermingle in random patterns and the system is less anatomically segmented. How stem cells in the ENS acquire different identities has therefore been an enigma. However, Marklund’s team has discovered a new principle for enteric cell diversification that relies on stepwise maturation and temporal, rather than spatial, control mechanisms.

As for the CNS, understanding these mechanisms may make it possible to direct stem cells to form specific neuron types which could be used in therapy.

“Several gastrointestinal disorders that are not currently satisfactory treated involve specific enteric neuron subtypes or ENS segments. This work should make it possible to derive specific types of enteric neurons from stem cells and lead the way to future therapies that can replace missing neurons in gut disorders.”

“I believe that a new era for ENS research has opened and that the next decade will uncover new roles for the ENS in health and disease,” said Marklund. “We need more-refined experiments but it’s an exciting time due to technological developments. We will learn much more in the next few years.”


Michelle Galloway: Part-time media officer at STIAS
Photograph: Noloyiso Mtembu

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