Food contains macronutrients, namely carbohydrates, protein, and fat. A balanced intake of these macronutrients is essential for the well-being of organisms. Protein, a crucial nutrient, is comprised of essential amino acids (EAAs) and non-essential amino acids (NEAAs). EAAs are not produced by our bodies and must be acquired from external food sources, whereas NEAAs are synthesized by our bodies. As such, our bodies must have a system to meticulously monitor EAA levels and induce a specific appetite for EAAs or protein, ensuring the maintenance of proper EAA homeostasis. In our laboratory, we have recently identified and characterized specific populations of the gut cells and the brain cells responsible for detecting and responding to the deprivation (or absence) of EAAs in Drosophila (Kim et al., 2021 Nature) and are currently investigating how these cells selectively direct the intake of protein or EAAs and not necessarily sugar or fat. Furthermore, we aim to identify and characterize the molecules and cells that directly detect each EAAs in the gut, and respond to the presence of EAAs. We are extending the line of studies to rodents.

Another goal of our laboratory is to identify glucose sensors or glucose-sensing neurons, and characterize the physiological roles mediated by these molecules and cells. Glucose-sensing neurons respond to glucose or its metabolites, which act as signaling cues to regulate their neuronal activity. According to the glucostatic hypothesis proposed in 1953, feeding and related behaviors are regulated by neurons in the brain that sense changes in glucose levels in the blood (Mayer, 1953 NEJM). Despite the discovery of glucose-sensing neurons in the hypothalamus through electrophysiological methods more than ten years later (Oomura et al., 1964 Science), the physiological role of these neurons remained unclear until recently, when a population of DH44-expressing glucose-excited neurons in the Drosophila brain, which our laboratory identified and characterized, were determined to function as an internal nutrient sensor to mediate the intake of sugar in animals (Parton et al., 2007 Nature; Levin, 2007 Cell Metabolism; Dus et al., 2015 Neuron; Oh et al., 2021 Neuron). In addition to the glucose-sensing neurons that mediate sugar consumption, we identified a pair of glucose-excited neurons that promote the release of insulin and, at the same time, inhibit the release of glucagon during a period of hyperglycemia, thereby maintaining glucose homeostasis (Oh et al., 2019 Nature).

There are a large number of glucose-excited and glucose-inhibited neurons in animals. Our laboratory would like to understand distinct physiological functions mediated by different populations of glucose-sensing neurons in the brain and enteric system.

Micronutrient is essential for the well-being of organism. Salt (sodium chloride) is a key micronutrient that mediates important functions in a variety of physiological processes. It was one of the most sought-after commodities until a hundred year ago, likely because humans were frequently deprived of sodium. Indeed, the human desire for salt led to the establishment of trade routes and cities, provoked and financed wars, and controlled the citizens of empires. This significance had also transpired as religious symbolism. Despite the widely-recognized research on taste sensation of salt, we have little understanding of whether animals are capable of detecting and responding to sodium independently of taste system. Our laboratory recently demonstrated that animals were able to respond to sodium without taste input during a period of salt deprivation. Using the Drosophila model, we have identified a discrete population of enteric neurons, termed INSO (Internal Sodium Sensing) neurons that function as a taste-independent, postprandial sodium sensor that directly detects sodium ions and mediates sodium intake (Kim et al., Nature Metabolism in press). Intriguingly, these neurons innervate their dendrites to the anterior portion of the intestine and project their axons to the brain. We therefore hypothesize that these neurons detect ingested sodium in the intestine and transmit signals to the brain, which subsequently regulates the appetite for salt. This study of the deprivation-induced sodium sensing mediated by INSO neurons might provide insights into the fervent human activities triggered by our carving for salt.

Vitamin C is another micronutrient that is essential for animals and humans, but our body does not produce it. As an antioxidant, vitamin C plays a key role in scavenging ROS that is often generated during a period of stress. We have inquired whether fruit flies or mice develop an appetite for vitamin C and other antioxidants under stress. In nature, many animals search for and consume a specific plant enriched in certain nutrients and metabolites when they are sick or deprived, or are in need of particular chemical compounds. Apparently, animals exhibit this behavior to alleviate the sickness. This phenomenon was coined “self-medication”, which was observed in insects such as butterflies and fruit flies, and even in primates such as chimpanzees. However, few studies have addressed this phenomenon, and its mechanism is poorly understood. Our laboratory is currently investigating whether fruit flies select antioxidants when stressed and elucidating the mechanism by which flies are attracted to the needed antioxidants, possibly through the action of interoceptive sensors present throughout the gut-brain axis.

Neurological disorders of the microbiome-gut-brain axis

Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the most common neurodegenerative disorders characterized by a progressive degeneration of the central nervous system. Aggregates of the tau and α-synuclein (α-syn) proteins are major hallmarks of these diseases, respectively, and likely involved in their etiologies. In addition, these proteins are the key culprits in various other tauopathies and synucleinopathies. The tau protein gradually forms neurofibrillary tangles inside neurons causing the disintegration of cytoskeletal structure and neuronal death that eventually results in severe cognitive, memory, and functional impairments in AD. Similar to AD, PD is triggered by insoluble α-syn-derived inclusions, known as Lewy bodies, that selectively destruct dopaminergic neurons in the substantial nigra. PD patients with the loss of dopaminergic neurons suffer from movement related symptoms including tremor, rigidity, bradykinesia, as well as autonomic dysfunction and neuropsychiatric problems in later stages. In addition to these insoluble entities, soluble forms of tau and α-syn aggregates are also likely involved in the cell type specific neurotoxicity seen in these diseases. Notably, the pathogenesis of PD in particular and possibly AD have been proposed to initiate largely in the gastrointestinal tract of these patients where tau and α-syn aggregates may originate and spread to the brain through the gut-brain axis such as vagal nerves. Importantly, there are no effective therapies approved for targeting and eliminating tau or α-synuclein aggregates or cures for these diseases by other means.

Our laboratory recently embarked on a study to understand the pathophysiology of these neurological diseases that were initiated in the gut possibly through the injurious interactions with gut microbiome and investigate the mechanisms by which Lewy bodies (and neurofibrillary tangles) spread to the brain through the gut-brain axis using the rodent and Drosophila models.