Updated: Feb 21
Why there’s no “off” switch in obesity.
The connection between the health of our gut and the health of our brain has been well established, with a decade of scientific research showing that the gut microbiota can influence many facets of brain function, such as mood, cognition, sleep, the stress response, appetite and energy balance.
Signals from the gut are transmitted either through the bloodstream or via the Vagus nerve, a nerve that originates in the brain and innervates the entire length of the gastrointestinal tract.
This communication works both ways.
The Vagus nerve detects changes in the gut and relays this information to the brain. These signals are integrated in the hypothalamus, a region of the brain responsible for appetite and energy balance. The hypothalamus then responds by influencing the production of hormones and neurotransmitters that go on to produce an effect in the brain and the rest of the body.
There are several signalling pathways by which the gut and gut microbiota can communicate with the brain to influence weight management.
The gut microbiota produces metabolites that regulate the production of gut peptides.
Gut peptides, such as glucagon-like peptide, gastric inhibitory peptide and peptide YY, are hormones released from enteroendocrine cells that line the gut wall. These peptides play a key role in appetite and energy balance.
A new study published in The Journal of Clinical Investigationlooked at one mechanism that links a high-fat diet with peptide levels that led to overeating and weight gain.
Researchers found that mice with high-fat diet-induced obesity had increased levels of Gastric Inhibitory Peptide (GIP). GIP travels to the hypothalamus where it attaches to GIP receptors and inhibits the action of Leptin. Leptin is a hormone that is released from fat cells as they enlarge,and it normally sends signals of satiety to the hypothalamus. However, with the increase in GIP in a high-fat diet, these signals were inhibited resulting in over-eating and weight gain in the studied mice.
The researchers then infused the mice with an antibody that inhibits the binding of GIP to its receptor in the hypothalamus and this resulted in reduced food intake and weight loss.
It is important to note that studies into the effects of high-fat diets use animal-derived saturated fat such as lard. Healthy fats, such as omega-3 fatty acids from fish or plant sources have been shown to have a beneficial effect on the gut microbiota, immune function, brain health and body fat.
Gut microbiota produce neurotransmitters that influence brain function
The gut microbiota produces a number of neurotransmitters such as serotonin, dopamine, gamma-aminobutyric acid (GABA)and noradrenaline - involved in mood/sleep, reward, a sense of calm and the stress response respectively.
They also produce metabolites, known as short-chain fatty acids, that stimulate the production of these neurotransmitters by enterochromaffiin cells, another type of cell that lines the gut wall.
It was initially believed that neurotransmitters produced in the gut have little to no effect on the brain as they are unable to cross the blood-brain-barrier. However, it is now known that the Vagus nerve is able to detect changes in neurotransmitter levels in the gut and transmit signals that produce an effect in the brain. For example, studies show that alterations in serotonin levels in the gut have been associated with disruptions in mood, sleep and appetite.
The composition and relative proportions microbial species present in the gut microbiota influences the level of specific neurotransmitters. This is in part due to the fact that certain microbial species are known to produce specific neurotransmitters. Therefore, a disruption in the gut microbiota can disrupt the neurotransmitter balance in the gut. For example, E. coli is a normal component of the gut microbiota and is beneficial when present at low levels. E. coli produce noradrenaline which acts locally in the gut to increase gut secretions and control movement through the gastrointestinal tract. If E. coli numbers increase, as is the case in dysbiosis, noradrenaline levels also increase, and this can lead to diarrhoea as well as impaired digestion and absorption.
Gut microbiota influence immune function
The gut microbiota is a major regulator of immune function. Eighty percent of the body’s immune cells are located along the length of the gastrointestinal tract and the function of these cells is largely under the control of the gut microbiota.
In a healthy gut, the gut microbiota stimulates the immune system to produce a low-level anti-inflammatory response that can quickly neutralise any antigens it may come in contact with.
In dysbiosis, where there is altered composition of the gut microbiota, usually with a predominance of pathogenic species, a pro-inflammatory response is initiated.
Pathogenic bacterial species such as E. coli contain a molecule in their cell wall called lipopolysaccharide (LPS) which is released when they die. LPS is known to disrupt tight junctions between gut cells and increase intestinal permeability, commonly known as leaky gut. This then allows LPS (and other pro-inflammatory molecules) to enter the blood stream. Once in the blood stream, LPS initiates a potent pro-inflammatory response eventually leading to inflammation within fat cells and various regions in the brain. This inflammation disrupts hormonal balance, appetite and energy balance.
Inflammation within fat cells changes their hormonal output which ultimately leads to leptin resistance in the brain. This means that, regardless of how much leptin is produced from enlarging fat cells, the brain cannot detect it. This is why there is no “off” switch when it comes to food in obese individuals.
A high level of circulating LPS has also been associated with inflammation within the brain, termed neuroinflammation. Many studies have shown that neuroinflammation leads to alterations in the production of neurotransmitters and appetite-regulating peptides. It also alters the function of brain regions that are responsible for emotional control and cognitive restraint over food (or other addictions).
Ultimately, dysbiosis leads to changes in the brain that set the stage for weight gain.
Nutrients in the gut transmit signals to the brain
When food is digested in the gut, it is broken down into glucose, amino acids and fats. These macronutrients influence appetite and energy balance through three mechanisms.
Firstly, they trigger enteroendocrine cells to produce the gut peptides mentioned above. Secondly, nutrients can enter the bloodstream and travel to the brain where they exert an effect on the hypothalamus. And finally, the Vagus nerve transmits information regarding nutrient status to the brain.
A clean and balanced diet that supports gut health and provides sufficient nutrients will lead to the production of signals that convey a sense of satiety to the brain.
Conversely, diets high in saturated fats from animal sources, processed foods, refined sugars/carbohydrates, gluten and food additives convey signals of hunger to the brain.
These foods alter the composition of gut bacteria, therefore changing the production of microbial metabolites, gut peptides and neurotransmitters. They also increase the number of pathogenic bacterial species, thereby increasing LPS-induced leaky gut and altering nutrient processing and absorption.
Faulty Gut-Brain = Weight Gain
Any alterations in the composition of the gut microbiota can lead to faulty signals to the brain and ultimately weight gain.
Obese individuals and people who struggle with cravings and weight gain are likely to have faulty signalling in both directions.
Reversing the damage
When there is a healthy composition in the gut microbiota and inflammation is reduced, appropriate signalling to the brain can be restored.
The Biome Protocol aims to reverse the damage by managing two key factors; dysbiosis and inflammation.
Dysbiosis is corrected by:
Avoiding all foods that cause dysbiosis (as noted above)
Including foods that contain prebiotics and have gut-healing properties
Adding supplements that support the growth of healthy gut bacteria and assist with regeneration of the gut wall.
Inflammation is reduced by:
Avoiding foods that cause inflammation (as noted above)
Including foods that contain omega-3 fatty acids and polyphenols
Adding supplements that reduce inflammation, assist with the processing of toxins and support brain function.
The Biome Protocol includes compounded nutrient formulations containing a supplements that are known to support gut health, replenish nutrients, improve mitochondrial function, assist with detoxification, rebalance hormones and improve appetite regulation and brain health.
To participate in The Biome Protocol or find a provider near you, please
1. Kentaro Kaneko, Yukiko Fu, Hsiao-Yun Lin, Elizabeth L. Cordonier, Qianxing Mo, Yong Gao, Ting Yao, Jacqueline Naylor, Victor Howard, Kenji Saito, Pingwen Xu, Siyu S. Chen, Miao-Hsueh Chen, Yong Xu, Kevin W. Williams, Peter Ravn, Makoto Fukuda. Gut-derived GIP activates central Rap1 to impair neural leptin sensitivity during overnutrition. Journal of Clinical Investigation, 2019; DOI: 10.1172/JCI126107
2. Bonaz B, Bazin T, Pellissier S. “The Vagus Nerve at the Interface of the Microbiota-Gut-Brain Axis.” Frontiers in neuroscience vol. 12 49. 7 Feb. 2018, doi:10.3389/fnins.2018.00049
3. Strandwitz, Philip. “Neurotransmitter modulation by the gut microbiota.” Brain research vol. 1693,Pt B (2018): 128-133. doi:10.1016/j.brainres.2018.03.015
4. Covasa M, Stephens RW, Toderean R, Cobuz C. “Intestinal Sensing by Gut Microbiota: Targeting Gut Peptides.” Frontiers in endocrinology vol. 10 82. 19 Feb. 2019, doi:10.3389/fendo.2019.00082
5. Rooks, Michelle G, and Wendy S Garrett. “Gut microbiota, metabolites and host immunity.” Nature reviews. Immunology vol. 16,6 (2016): 341-52. doi:10.1038/nri.2016.42
6. Guo S, Al-Sadi R, Said HM, Ma TY. “Lipopolysaccharide causes an increase in intestinal tight junction permeability in vitro and in vivo by inducing enterocyte membrane expression and localization of TLR-4 and CD14.” The American journal of pathology vol. 182,2 (2013): 375-87. doi:10.1016/j.ajpath.2012.10.014
7. Hersoug, Lars-Georg & Møller, Peter & Loft, Steffen. (2018). Role of microbiota-derived lipopolysaccharide in adipose tissue inflammation, adipocyte size and pyroptosis during obesity. Nutrition Research Reviews. 31. 1-11. 10.1017/S0954422417000269.
8. Sandiego CM, Gallezot JD, Pittman B, Nabulsi N, Lim K, Lin SF, Matuskey D, Lee JY, O'Connor KC, Huang Y, Carson RE, Hannestad J, Cosgrove KP. “Imaging robust microglial activation after lipopolysaccharide administration in humans with PET.” Proceedings of the National Academy of Sciences of the United States of America vol. 112,40 (2015): 12468-73. doi:10.1073/pnas.1511003112
9. Francisco, Vera, Francisco V, Pino J, Campos-Cabaleiro V, Ruiz-Fernández C, Mera A, Gonzalez-Gay MA, Gómez R, Gualillo O. “Obesity, Fat Mass and Immune System: Role for Leptin.” Frontiers in physiology vol. 9 640. 1 Jun. 2018, doi:10.3389/fphys.2018.00640
10. Kwon, O., Kim, K.W. & Kim, MS. Leptin signalling pathways in hypothalamic neurons Cellular and Molecular Life Sciences (2016) 73: 1457. https://doi.org/10.1007/s00018-016-2133-1