Methods to utilize microbial organisms in the gut to modulate neurological responses

Unmet Need

The gut is home to dynamic bacterial communities that shape the behavior of the host. The food we eat, our changes in mood, and even some of our social behaviors correlate with shifts in our microbiome. The brain is constantly being modulated by signals from the gut. For instance, studies have shown that humans have an innate preference for caloric sugars over non-caloric sugars. Signals like these arise from the intestine and are transmitted to the brain. Our knowledge about which gut bacteria modulate brain behaviors related to appetite and mood, the underlying mechanisms, and their impact on health conditions like obesity is limited. Some of these health conditions are common among the population today. For instance, nearly 1 in 3 adults are overweight, and more than 2 in 5 adults are obese. Better understanding of these gut-brain circuits will aid in therapeutic advancements for obesity and other health conditions. Because of this, there is a need to understand how the intestinal wall senses and transduces signals about caloric content of nutrients to the brain.

Technology

Duke inventors have discovered a link between neuronal activity and gut microbiota. They have also discerned the importance of calorie addiction in humans, its link to obesity, and potential drug therapies to target the circuit between gut sensory cells and the brain. This is intended to serve as vital foundational information for future research focused on gut microbiota and its specific affects on brain behavior related to appetite and mood. Specifically, the authors show that colonic neuropod cells use a pattern recognition receptor, toll like receptor 5 (TLR5) to signal changes in bacterial flagellin onto the vagus nerve to alter feeding behavior. They found that a microbial protein was directly sensed by an epithelial cell prior to activating neuronal circuits. Furthermore, they demonstrate that neuroepithelial cells are critical channels for communication across the gut and brain, and these cells provide a target for therapeutic interventions. Duke researchers also disclose a mechanism by which neuropod cells drive the preference for caloric sugars which involves activation of sodium glucose transporter 1 channels. This has been demonstrated in vitro showing a general mechanism for how host colonic sensory systems detect changes in microbial communities. They have also demonstrated how neuropod cells drive the preference for caloric sugars in mouse models where animals choose sucrose over sucralose. Future work involves continuing to identify therapeutic targets with the knowledge gained thus far.

Other Applications

This technology could also lead to the development of drug therapies for mood regulation in patients with depression or anxiety. The technology could also lead to the development of novel therapeutics for cancer, metabolic diseases, and other gut-brain disease states. The authors provide a foundation that could lead to greater understanding of how to manipulate the gut microbiota and use it to our advantage therapeutically.

Advantages

• Mechanism linking gut sensory molecules and gut microbiota with the nervous system and brain
• Modulation of the gut-brain axis can provide novel therapeutics for a wide range of disease states
• Understanding of gut microbiota preference for caloric sugars and its link to obesity