Gut microbiome, SCFAs, mood disorders, ketogenic diet and seizures

Evidence for regulation of the immune system by the gut microbiome, especially through the effect of short-chain fatty acids (SCFCAs) produced by bacterial metabolism (‘postbiotics‘) is exploding in the scientific community. A trio of recent papers highlights the great importance of the gut microbiome for inflammation and brain health.

Short-chain fatty acids promote IL-10 production

Gut microbiome, SCFAs, IL-10Interleukin-10 (IL-10) is an anti-inflammatory cytokine crucial for immune system regulation. A recent paper published in Nature Communications reveals how SCFAs produced by the gut microbiome promote the IL-10 production necessary for immune balance in the intestines. The authors state:

“The host immune system coordinates the balance of effector and regulatory immune cells, as well as anti- and pro-inflammatory cytokines in the physical condition through interaction with microbiota. Accumulating evidence suggests that host immune system senses the gut bacteria not only through recognition of the pathogen-associated molecular patterns (PAMP)1, but in addition by sensing microbial metabolites, which influence the host immune response in the gut and beyond2,3. Bacterial fermentation products, particularly short-chain fatty acids (SCFAs) including acetate (C2), propionate (C3), and butyrate (C4), mediate the effects on host physiology and immunity, regulating the function and differentiation of virtually all immune cell repertoire of gut4,5.”

SFCAs confer multiple benefits:

“SCFAs have been shown to maintain intestinal homeostasis through protecting epithelial barrier integrity10,12, promoting B-cell IgA production13, and regulating T-cell differentiation8,14.”

It’s through its effect on T-cell differentiation to IL-10 producing regulatory and effector cells that the gut microbiome production of SFCAs promote an important immune-regulating anti-inflammatory effect.

IL-10 prevention of autoimmune disease

When IL-10 production is deficient there is increased risk of inflammatory bowel disease (IBD) and other autoimmune conditions.

“T-effector cell production of IL-10 has been considered as a self-limiting mechanism to prevent an exaggerated T-cell response in the intestines as well as in other autoimmune diseases, which otherwise would be detrimental20. Polymorphisms in the IL10 locus confer a risk for IBD, including both ulcerative colitis (UC) and Crohn’s disease (CD)21,22,23,…”

SCFA production by the gut microbiome, IL-10 and autoimmunity

Through generation of Th1 cells treated with butyrate, propionate and acetate; contrasting the effect of butyrate with HDAC inhibition; and exploring the effect of IL-10 producing Th1 cells in regulation of colitis in vivo; and the differentiation of those cells through GPR43 induced by SCFAs; the effect of butyrate on activation of STAT3 and mTOR pathways that produce IL-10; and SCFA production of IL-10 in IBD patients, the authors clarified the mechanisms involved. Moreover…

“Interestingly, while butyrate promoted Foxp3+ Treg cells, which is consistent with previous reports in mice, it greatly inhibited production of IL-17 in T-cells from both healthy controls and IBD patients.”

IL-17 is a major promotor of autoimmune inflammation. They also found that mice fed butyrate had less severe experimental colitis induced by dextran sulfate sodium.

“We demonstrated in this report that SCFAs, produced by gut microbiota as fermentation products of dietary fiber, promoted Th1 cell production of IL-10, thereby inhibiting colitis induced by pathogenic Th1 cells…Therefore, secretion of the immunosuppressive cytokine IL-10 by Th1 effector cells is an essential mechanism of self-limitation during inflammation.”

Clinical note on dosage and route of butyrate enemas for IBD:

“…as short chain fatty acids are readily absorbed by the epithelial cells in the intestinal tract, an appropriate dose would be crucial. It has been reported that SCFA mixtures enemas and butyrate enemas had better beneficial effects in patients with UC42,43, an appropriate route should also be considered.”

Inflammation and neuropsychiatric disorders

Gut microbiota and neuroinflammationImmense evidence has been accumulating for the role of the gut-microbiota-brain axis on neuroinflammation and brain function. The authors of a paper published in Clinical Therapeutics review the relationship:

“Gut microbiota regulate intestinal function and health. However, mounting evidence indicates that they can also influence the immune and nervous systems and vice versa. Here we reviewed the bidirectional relationship between the gut microbiota and the brain, termed microbiota-gut-brain (MGB) axis, and we discuss how it contributes to the pathogenesis of certain disorders, that may involve brain inflammation.”

In their review they further confirmed this is a two-way street:

Various afferent or efferent pathways are involved in the MGB axis. Antibiotics, environmental and infectious agents, intestinal neurotransmitters/neuromodulators, sensory vagal fibers, cytokines, essential metabolites, all convey information about the intestinal state to the CNS. Conversely, the HPA axis, the CNS regulatory areas of satiety and neuropeptides released from sensory nerve fibers affect the gut microbiota composition directly or through nutrient availability. Such interactions appear to influence the pathogenesis of a number of disorders in which inflammation is implicated such as mood disorder, autism-spectrum disorders (ASDs), attention-deficit hypersensitivity disorder (ADHD), multiple sclerosis (MS) and obesity.”

Mast cells (MCs) response to gut microbes and neuroinflammation

Regarding mood disorders, they highlight the response of mast cells to gut pathogens:

MCs communicate with pathogens and have been invoked as key modulatory cells in innate immunity, as well as in inflammation and autoimmunity. A new finding concerning MCs is their ability to secrete mitochondrial components, including DNA, extracellularly. These components are then misconstrued by the body as “innate pathogens” and induce a strong auto-inflammatory response leading to inflammation and neuronal damage.”

Antibiotics

Metabolites of the gut microbiome, especially SCFAs (short-chain fatty acids) have more recently been shown to be crucially important for mucosal immune regulation. In this paper they mention the risk of antibiotics:

“The microbiota can also modulate the immune system through other mechanisms And the increased use of antibiotics results in depletion of microbiota-derived metabolites, impairs immune homeostasis and contributes to chronic inflammation.”

Mood disorders, ADHD and ASDs

Gut microbiome brain axisBrain-based disorders typically involve inflammation and mitochondrial dysfunction.

“Genes involved in synapse formation between neurons in the brain and neurons in the GI tract are quite similar, and any mutations could possibly lead to both brain and GI abnormalities. Recent studies analyzing the human genome in brains from diseased individuals with psychiatric disorders reported only two clusters of affected genes with: (a) increased inflammation and (b) decreased mitochondrial function. Depression is associated with increased inflammatory biomarkers, such as interleukin (IL)-6, tumor necrosis factor (TNF)-α, and C reactive protein (CRP). Schizophrenia has been linked to intestinal inflammation and gastrojejunal ulcers.”

Regards ADHD:

“Increasing evidence from clinical and epidemiological studies suggests that children and adults with food allergies, eczema or asthma are associated with behavioral problems and neuropsychiatric disorders, including ADHD. The gut microbiota are known to participate in susceptibility to allergies, especially food allergens.”

Factors linking gut microbiota and ASDs (autistic spectrum disorders) include”

“Many children with ASDs present with GI symptoms and altered GI flora. Increasing evidence indicates that ASD pathogenesis may involve brain inflammation especially activation of microglia. Moreover, about 30% of children with ASDs have auto-antibodies against brain proteins and the presence of such antibodies strongly correlated with allergic symptoms.”

Microbiota effects on the intestinal barrier and food tolerance also come into play:

“Increased intestinal permeability would permit bacterial products, cytokines and chemokines to enter the circulation and cross the BBB influencing brain and behavior. For example, children with ASDs had higher levels of immunoglobulins (IgA, IgG, IgM) against cow’s milk-derived allergens, and milk intake by these patients significantly worsened some of their behavioral symptoms. Elimination of caseinomorphin, gliadomorphin, colorings, sweeteners and preservatives led to significant benefit. The gut microbiota composition appears to differ between healthy children and those with ASDs.”

The authors summarize their findings:

“Various afferent or efferent pathways are involved in the MGB axis. Antibiotics, environmental and infectious agents, intestinal neurotransmitters/neuromodulators, sensory vagal fibers, cytokines, essential metabolites, all convey information about the intestinal state to the CNS. Conversely, the HPA axis, the CNS regulatory areas of satiety and neuropeptides released from sensory nerve fibers affect the gut microbiota composition directly or through nutrient availability. Such interactions appear to influence the pathogenesis of a number of disorders in which inflammation is implicated such as mood disorder, autism-spectrum disorders (ASDs), attention-deficit hypersensitivity disorder (ADHD), multiple sclerosis (MS) and obesity.

Ketogenic diet reduces seizures by modulating the gut microbiome

Ketogenic diet and seizuresA fascinating study just published in the journal Cell offers evidence that the well-known benefit of the ketogenic diet for seizure disorders is due, at least in part, through modulation of the gut microbiome. The authors state:

“The ketogenic diet (KD) is used to treat refractory epilepsy, but the mechanisms underlying its neuroprotective effects remain unclear. Here, we show that the gut microbiota is altered by the KD and required for protection against acute electrically induced seizures and spontaneous tonic-clonic seizures in two mouse models. Mice treated with antibiotics or reared germ free are resistant to KD-mediated seizure protection. Enrichment of, and gnotobiotic co-colonization with,KDassociated Akkermansia and Parabacteroides restores seizure protection. Moreover, transplantation of the KD gut microbiota and treatment with Akkermansia and Parabacteroides each confer seizure protection to mice fed a control diet. Alterations in colonic lumenal, serum, and hippocampal metabolomic profiles correlate with seizure protectionOverall, this study reveals that the gut microbiota modulates host metabolism and seizure susceptibility in mice.

Ketogenic diet gut microbiome seizuresThey highlight their findings:

  • Changes in the gut microbiota are required for the anti-seizure effects of the KD
  • Specific KD-associated bacteria mediate and confer the anti-seizure effects of the KD
  • KD microbiota regulate amino acid γ-glutamylation and hippocampal GABA/glutamate

 

Bottom Line

SCFA (short-chain fatty acid) production by the gut microbiome has a large effect on autoimmunity, brain inflammation, neuropsychiatric disorders and seizures by Immune system modulation; and this positive effect can be damaged by antibiotics.

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