Hormones and the Microbiome

Hormones and the Microbiome

• Hormones directly affect microbiome richness and diversity in animals.
• The microbial community influences hormone production and functions.
• Microbes influence neurotransmitter and neuropeptide action in the central nervous system, which can lead to behavioral disruptions.
• Understanding the relationship between microbiota shifts and complex interactions is important.

Microbiota Basics

• The microbiota plays a significant role in supporting nutritional, metabolic, and immunologic homeostasis.
• The microbiota maintains gastrointestinal homeostasis.
• The microbiota has metabolic functions in nutrient digestion/absorption, detoxification, and vitamin production.
• The microbiota is important for the development of the lymphoid system.
• 70% of the immune system is located in the gut.

Microbial Endocrinology

• Studies the impact of microbes on health and well-being within multicellular hosts.
• Microbes impact metabolism, immunity, and behavior.
• The microbiota produces and secretes hormones.
• The microbiota responds to host hormones.
• The microbiota regulates host hormone expression levels.
• Specific changes in hormone levels correlate with the gut microbiota's presence.

Estrogen and the Microbiome

• Estrogen and estrogen receptors (ERs) impact organs and diseases of the gastrointestinal (GI) tract.
• Estrogen receptors serve an important role in the GI tract.
• Estrogen dysfunction contributes to GI diseases, including gastroesophageal reflux, esophageal cancer, peptic ulcers, gastric cancer, inflammatory bowel disease, irritable bowel syndrome, colon, and breast cancer.
• Longer estrogen exposure may decrease gastric cancer risk, so anti-estrogen drugs like tamoxifen might increase gastric adenocarcinoma risk.
• Estrogen receptor beta targets may prevent colorectal cancer.
• Estrogen relates closely to the mucosal barrier, GI function, and intestinal inflammation.
• Gut barrier integrity is crucial for metabolic health.
• Changes to intestinal permeability may play a role in food sensitivities, adipose inflammation, and autoimmune diseases.
• A healthy and diverse microbiome ensures gut barrier integrity.
• Estrogen assists in gut barrier function.
• Sufficient estrogen forms/maintains the epithelial layer of the gut, keeping it healthy and elastic.
• Animals treated with estrogen showed higher microbial diversity.

Estrogen-Gut Microbiome Axis

• The gut microbiota regulates estrogens through β-glucuronidase secretion, an enzyme that deconjugates estrogens into their active forms.
• Impairment in this process due by dysbiosis, decreases circulating estrogens.
• Altered estrogen levels can contribute to obesity, metabolic syndrome, cancer, endometrial hyperplasia, endometriosis, polycystic ovary syndrome, fertility, cardiovascular disease, and cognitive dysfunction.
• Modulating microbiome composition can impact the metabolic profile positively.
• Estrogens and steroid hormones and the gut microbiota may act synergistically to influence obesity and diabetes.
• The topic covered the latest advancements on the interactions between estrogens and the gut microbiome.
• The topic focused on innovative approaches to influence crosstalk between estrogen and the microbiome to improve metabolic outcomes.

Estrogen and Microbial Diversity

• Estrogen and estrogen-like compounds prevent the loss and promote the growth/proliferation of beneficial bacteria.

Estrogen as an Anti-Inflammatory

• Estrogen decreases pathogenic bacteria populations.
• Estrogen reduces lipopolysaccharide (LPS) induced inflammation.
• LPS is produced by gram-negative bacteria.
• LPScan impair the gut lining.
• LPS crosses into the rest of the body to produce an immune response.
• Estrogen working against enteric pathogens is another benefit.

Metabolic Endotoxemia

• Metabolic endotoxemia represents a situation in which bowel flora species dies and releases lipopolysaccharide (LPS); LPS is a component of their cell walls.
• LPS is released into the intestines, crosses the intestinal wall, and enters the bloodstream.
• Leptin Resistance, LPS causes inflammation in the enteric nervous system disrupting the gut-brain axis.
• Chronic Constipation, LPS enters the enteric nervous system and causes signal disruption for gastric emptying and bowel motility.
• Mood and Appetite Disorders, LPS disrupts ghrelin function, impacting appetite and mood.
• Depression, LPS migrates to the blood-brain barrier, causes inflammation, and inhibits dopamine receptors.
• Cognitive Decline, Inflammation in the blood-brain barrier leads to cognitive decline.
• Loss of Memory and Recall, LPS enters the amygdala and hippocampus disrupting memory function.
• Depression, LPS increases serotonin turnover in the synapse and CNS.
• Anorexia Nervosa, Reduced serotonin in the synapse and CNS may cause anorexia.
• Anxiety, LPS disrupts communication between the hypothalamic-adrenal-pituitary axis.
• Chronic Pain, Elevated LPS in sensory neurons of the dorsal root stimulates nociceptors.
• Parkinson's, Intracranial LPS induces microglial activation and neuronal loss.
• Hypogonadism (low testosterone), Increased LPS causes chronic immune activation, inhibiting testosterone production (GELDING theory).
• Autoimmunity, chronic activation affects self-tissues inadvertently targeted by the immune system.

Microbiome Regulation of Estrogen Levels

• It is the free estrogen fraction that has activity at the estrogen receptors (ER alpha and ER beta).
• Physiological effects include healthy weight maintenance, reduced abdominal fat, and glucose regulation.
• Disturbances in microbiota composition in dysbiosis impair estrogen deconjugation, which reduces circulating free estrogen.
• The study is characterized by diminished microbial diversity.
• Dysbiosis can lead to an inflammatory response and metabolic profile that is detrimental to overall health.

Symptoms of Dysbiosis

• Nausea
• Belching, bloating
• Heartburn
• Abdominal pain
• Cramping and abdominal distention
• Depression and anxiety
• Altered bowel function (constipation and/or diarrhea)
• Cramps and spasms
• Hypersecretion of colonic mucus
• Flatulence
• Halitosis
• Arthralgias
• Anxiety
• Brain fog
• Cognitive and memory deficit
• Depression
• Fatigue
• Fever of unknown origin
• Frequent urination
• Malaise
• Myalgias
• Palpitations
• Phlebitis
• Pruritis
• Skin rashes
• Seizures
• Vasculitis

Causes of Dysbiosis

• Injurious agents
• Antacids
• Poor nutrition/SAD
• Free radical production
• Stress
• Alcohol
• Drugs (NSAIDs, antibiotics)
• Viruses
• Diminished HCL
• Decreased enzymes
• Diminished bile
• Food allergies
• Travel (food, water, bacteria)
• Hypoxia/exposure to extreme altitude
• Yeast infections
• Lectins

Estrogen Metabolism and The GI Tract

• Estrogens are produced in the ovaries, adrenal glands, and adipose tissue.
• Estrogens circulate in free or protein-bound form.
• They are metabolized in the liver.
• Their metabolites are conjugated through glucuronidation and sulfonation.
• Allows biliary excretion.
• Conjugated estrogens are eliminated via metabolic conversion to water-soluble molecules through bile into feces or urine.
• 10-15% of estradiol, estrone, and estriol are found in conjugated form in feces.
• Conjugated estrogens can be deconjugated by gut bacteria via beta-glucuronidase activity, which leads to reabsorption.
• Gut bacteria with hydrolytic enzymes are involved in the deconjugation of estrogens.
• Microorganism strains in the 'estrobolome' are constituents of the collection of microbial reactions involving estrogens.
• The Estrobolome Modulates Enterohepatic Circulation to affect the circulation of Estrogens and their Excretion Level.
• Disturbances in microbiota composition impairs the process of deconjugating estrogen in dysbiosis, reducing circulating free estrogen levels.
• Sixty bacterial genera colonize the human intestinal tract that encodes beta-glucuronidase.
• Beta-glucuronidase activity can be modulated by diet and by bacterial context.
• Diets high in fat or protein can increase the levels of beta-glucuronidase
• High Fiber Consumption Decreases Beta-glucuronidase Acitivity
• Lactobacillus acidophilus consumption reduces fecal enzyme activity, including beta-glucuronidase.

Estrogen: The Microbiome and Breast Cancer

• The bacterial estrobolome may be affected by host factors like age and ethnicity.

• Bacteria may be impacted by lifetime environmental influences, including diet, alcohol, and antibiotic use.

• Some of these microbiome factors are related to breast cancer risk.

• Certain factors are independent and additive modifiable risks.

• Human microbiome regulates steorid hormone metabolism, since endogenous estrogens are the most important risk factor in breast cancer development, especially in postmenopausal women.

• Intestinal microbes encode enzymes that deconjugate estrogen to reenter the circulation in a biologically active form.

• Gut microbes break down dietary polyphenols into varied estrogen-like compounds.

  Potential Role to consider regarding risks related to breat cancer:

• Potential GI hormone development with mediation metabolism hormone synthesis

Progesterone and GI Motility

• Estrogen and progesterone can impact contractility and myoelectric activity in the gastrointestinal smooth muscle.
• Estradiol and a mixture of estradiol/progesterone inhibit, whereas progesterone enhances gastric emptying — testosterone did not play a role in GI motility.
• Elevated serum estradiol and reduced progesterone, compared to luteal phases.
• Inversely elevated progesterone vs estradiol: prolonged GI transit.
• GI motility is more prolonged during periods when progesterone levels are increased versus when progesterone levels are low.
• Low dose progesterone increases GI motility, while high doses decrease it.

Testosterone/PCOS and the Gut Microbiome

• PCOS is the most common endocrine disorder in women of reproductive age globally.
• PCOS accounts for 85% of women with androgen excess and hirsutism.
• Women with PCOS had lower alpha diversity of gut microbiota compared with healthy women.
• Regression analyses show negative correlations between hyperandrogenism, total testosterone, hirsutism, and alpha diversity.
• Hyperandrogenism may critically alter the gut microbiome in women with PCOS.
• Gut microbiota dysbiosis may play a role in hormonal imbalances that cause diseases including polycystic ovary syndrome with hormone level modulations
• A poor diet leads to increasing gut inflammation and serum insulin levels.
• Increased Insulin leads to androgen overproduction and interferes with normal follicle development.
• A review revealed specific bacteria are associated with PCOS microbiome.
• A search yielded nine studies that compared a-diversity. Six showed the alpha diversity was reduced in PCOS patients.
• Seven reported having difference to healthy controlled group and PCOS patients.
• Common alts included: Bacteroidaceae, Coprococcus, Bacteroides, Prevotella, Lactobacillus, Parabacteroides, Escherichia/Shigella, and Faecalibacterium.
• A trial showed lower stool diversity and change phylogenetic composition of PCOS patients.
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