The Prevention of Inflammation and the Maintenance of Iron and Hepcidin Homeostasis in the Gut, Liver, and Brain Pathologies

Abstract

The human gut microbiome consists of a variety of microorganisms that inhabit the intestinal tract. This flora has recently been shown to play an important role in human disease. The crosstalk between the gut and brain axis has been investigated through hepcidin, derived from both hepatocytes and dendritic cells. Hepcidin could potentially play an anti-inflammatory role in the process of gut dysbiosis through a means of either a localized approach of nutritional immunity, or a systemic approach. Like hepcidin, mBDNF and IL-6 are part of the gut-brain axis: gut microbiota affects their levels of expression, and this relationship is thought to play a role in cognitive function and decline, which could ultimately lead to a number of neurodegenerative diseases such as Alzheimer's disease. This review will focus on the interplay between gut dysbiosis and the crosstalk between the gut, liver, and brain and how this is mediated by hepcidin through different mechanisms including the vagus nerve and several different biomolecules. This overview will also focus on the gut microbiota-induced dysbiotic state on a systemic level, and how gut dysbiosis can contribute to beginnings and the progression of Alzheimer's disease and neuroinflammation.

Keywords: Brain; TMAO; Western diet; dysbiosis; hepcidin; high fat-high sugar diet; intestines; mBDNF; vagus nerve.

Fig. 1

A healthy microbiota consists of a balance of Gram-positive and Gram-negative bacteria; in which hepcidin, iron (Fe3+), IL-6, and TMAO levels express a normal state of balance. Whereas a dysbiosis state indicates an increase of gram-negative bacteria and elevated hepcidin levels resulting in excessive iron accumulation. This stimulates high ferritin levels which promotes less cognitive decline and therefore excess hepcidin production. The synthesis of hepcidin is rapidly increased by infection and inflammation in which elevated IL-6 levels initiate a pro-inflammatory cascade. With IL-6 upregulation occurring in the liver, the higher levels of TMA become oxidized to TMAO. Circulation of TMAO initiated in the small intestine initiates an inflammatory state.

Fig. 2

The liver in a healthy state contains baseline hepcidin, IL-6, and TMA levels which supports a balance of healthy and dysbiotic bacteria. Iron levels are slightly higher in the healthy state than a dysbiotic state as hepcidin is upregulated in a dysbiotic state. In the dysbiotic state, IL-6 is also upregulated in the liver, and higher levels of TMA are sent to the liver to be oxidized to TMAO. TMAO is sent to the small intestines which ultimately causes inflammation and the overgrowth of dysbiotic bacteria.

Fig. 3

In a state of a healthy microbiota, ferritin, hepcidin, IL-6, and iron are all at baseline levels. In a state of dysbiotic microbiota, the brain responds preventatively by upregulating ferritin and hepcidin levels, as well as IL-6. This is done via the astrocytes (purple) and microglia (red). In the neuron (dark yellow), iron is upregulated as well in the setting of neuroinflammation. Amyloid plaques can also be seen in the dysbiotic state as above.

Fig. 4

The endocrine summary of the gut-brain axis (GBA) involves an endocrine and neural communication between the brain, liver and intestines via several biomolecules and the vagus nerve. The arrows in this figure indicate the flow of each biomolecule. An overproduction of TMAO signifies overdevelopment of pathogenic gut bacteria and induces activation of macrophages, onsetting the secretion of IL-6, thus, initiating collective activation of microcascade inflammatory responses to absorb bacteria in attempt to mediate gut dysbiosis. IL-6 is unregulated in inflammation and involved in the regulation of neural processes. As the liver produces hepcidin, the sustained overproduction of hepcidin and IL-6 is stimulated throughout blood circulation. The hepcidin ascending to the brain is derived from circulation and further expressed through the production of iron-load and inflammation. The brain’s reactivity in response to overproduction sequesters iron to neurons. The activation of hepcidin results in the shutdown of ferroportin in neural cells. The increase of iron in neural cells activates an oxidative state in the brain. The brain is highly susceptible to oxidative damage. Imbalance of gut dysbiosis, thus, plays a major role in the pathophysiology and pathogenic mechanism for neurodegenerative diseases as a primary contributor.

Fig. 5

Normal mBDNF signaling pathway. mBDNF activates the TrkB signaling pathway which in turn activates the MAPK/ERK, PI3K/Akt, and PLC-γ pathways. These pathways work together to regulate important cognitive functions such as LTP formation and neurogenesis.

Fig. 6

mBDNF signaling pathway under HFHS diet conditions. This diet causes gut dysbiosis, which decreases levels of mBDNF. These decreased mBDNF levels downregulate the TrkB signaling pathway and ultimately the MAPK/ERK, PI3K/Akt, and PLC-γ pathways, causing a multitude of problems such as increased susceptibility to cell death, dysregulation of CREB and transcription factors, as well as a decrease in LTP and neurogenesis.

Fig. 7

The neural summary of the gut-brain axis. Gut endocrine cells are activated by mature mBDNF or inhibited by proBDNF, which in turn activate or inhibit vagal nerve communication to the brain respectively. Additionally, afferent vagal nerve fibers stimulate efferent vagal nerve fibers via the inflammatory reflex.

Fig. 8

Summary of healthy (left) and dysbiotic (right) states of the gut-brain axis. The left region of the figure depicts the brain, liver, and gut at optimal health whereas the right region represents the brain, liver, and gut in dysbiotic states. The brain, in a state of a healthy microbiota, ferritin, hepcidin, IL-6, and iron are all at baseline levels. The liver in a healthy state contains baseline hepcidin, IL-6, and TMA levels which supports a balance of healthy and dysbiotic bacteria. Iron levels are slightly higher in the healthy state than a dysbiotic state as hepcidin is upregulated in a dysbiotic state. In addition, a healthy microbiota consists of a balance of Gram-positive and Gram-negative bacteria; in which hepcidin, iron (Fe3+), IL-6, and TMAO levels express a normal state of balance. The right region of the figure depicts the brain in a state of dysbiotic microbiota. The brain responds preventatively by upregulating ferritin and hepcidin levels, as well as IL-6. This is done via the astrocytes (purple) and microglia (red). In the neuron (dark yellow), iron is upregulated as well in the setting of neuroinflammation. Amyloid plaques can also be seen in the dysbiotic state as above. Below, the liver is illustrated in a state of dysbiosis. IL-6 is upregulated, and higher levels of TMA are sent to the liver to be oxidized to TMAO. TMAO is sent to the small intestines which ultimately causes inflammation and the overgrowth of dysbiotic bacteria. Most importantly, the dysbiotic microbiota indicates an increase of gram-negative bacteria and elevated hepcidin. Whereas a dysbiosis state indicates an increase of gram-negative bacteria and elevated hepcidin levels resulting in excessive iron accumulation. This stimulates high ferritin levels which promotes less cognitive decline and therefore excess hepcidin production. The synthesis of hepcidin is rapidly increased by infection and inflammation in which elevated IL-6 levels initiate a pro-inflammatory cascade. With IL-6 upregulation occurring in the liver, the higher levels of TMA become oxidized to TMAO. Circulation of TMAO initiated in the small intestine initiates an inflammatory state.