Bacteria - derived short chain fatty acids restore sympathoadrenal responsiveness to hypoglycemia after antibiotic-induced gut microbiota depletion

Abstract

The microbiome co-evolved with their mammalian host over thousands of years. This commensal relationship serves a pivotal role in various metabolic, physiological, and immunological processes. Recently we discovered impaired adrenal catecholamine stress responses in germ-free mice suggesting developmental modification of the reflex arc or absence of an ongoing microbiome signal. To determine whether maturational arrest or an absent bacteria-derived metabolite was the cause, we tested whether depleting gut microbiome in young adult animals could also alter the peripheral stress responses to insulin-induced hypoglycemia. Groups of C57Bl6 male mice were given regular water (control) or a cocktail of non-absorbable broad-spectrum antibiotics (Abx) in the drinking water for two weeks before injection with insulin or saline. Abx mice displayed a profound decrease in microbial diversity and abundance of Bacteroidetes and Firmicutes, plus a markedly enlarged caecum and no detectable by-products of bacterial fermentation (sp. short chain fatty acids, SCFA). Tonic and stress-induced epinephrine levels were attenuated. Recolonization (Abx + R) restored bacterial diversity, but not the sympathoadrenal system responsiveness or caecal acetate, propionate and butyrate levels. In contrast, corticosterone (HPA) and glucagon (parasympathetic) resting values and responses to hypoglycemia remained similar across all conditions. Oral supplementation with SCFA improved epinephrine responses to hypoglycaemia. Whole genome shotgun sequence profiling of fecal samples from control, Abx and Abx + R cohorts identified nine microbes (SCFA producers) absent from both Abx and Abx + R groups. These results implicate gut microbiome depletion plus its attendant reduction in SCFA signalling in adversely affecting the release of epinephrine in response to hypoglycemia. We speculate that regardless of postnatal age, a mutable microbiome messaging system exists throughout life. Unravelling these mechanisms could lead to new therapeutic possibilities through controlled manipulation of the gut microbiota and its ability to alter systemic neurotransmitter responsiveness.

Resilience or susceptibility to traumatic stress: Potential influence of the microbiome

“…They can suppress the immune system, stimulate bacterial growth, enhance expression of genes required for virulence, increase the intestinal mucosa adherence to mammalian gut tissues and invasiveness of pathogens, and alter the secretion of gut microbial products ( Mittal et al, 2017 , Sandrini et al, 2015 ). Similarly, accumulating evidence is highlighting the ability of microbes residing in the gut to influence the function of sympatho-adrenal medullary system ( Giri et al, 2019 ; LaGamma et al, 2021 ). For instance, Nod1 ligands, released from commensal bacteria in the gut were shown to optimize catecholamines secretion, especially epinephrine, from adrenal chromaffin cells during immobilization stress ( Xiang et al, 2021 ).…”

“…The samples were acidified immediately by addition of an equal volume of 0.01 M HCl and stored at −80 °C for further analysis. Urine epinephrine and norepinephrine levels were quantified using commercially available competitive enzyme immunoassay kit (Rocky Mountain Diagnostics, Colorado Springs, CO) and normalized to urinary creatinine concentrations in the same samples (DetectX Urinary Creatinine Kit, Arbor Assays, Ann Arbor, MI), as described ( LaGamma et al, 2021 ).…”

The Role of Short Chain Fatty Acids in Irritable Bowel Syndrome

“… 83 In mouse models, gut microbiota dysbiosis and its reduction in SCFAs adversely affect epinephrine release, and oral SCFA supplementation improves the stress-induced epinephrine response. 84 Vagus nerve stimulation was a form of neuromodulation which provided a treatment for chronic pain and depression. 85 , 86 SCFAs such as butyrate can directly activate vagal afferent nerve terminals in the gut.…”

A study on the effect of symbiotic fermented milk products on human gastrointestinal health: Double‐blind randomized controlled clinical trial

“…Functionally, SCFAs may also support blood flow to the colon, mineral absorption, healthy intestinal pH, normal bile and cholesterol metabolism, and the motility of material passing through. By promoting healthy intestinal pH, SCFAs provide antimicrobial and probiotic benefits as pH can dictate what types of bacteria are able to grow (Pratiwi Dyah Kusumo, Maulahela, et al., 2019 , 2019 , 2019 , 2019 ; LaGamma et al., 2021 ; Nishida et al., 2021 ).…”

“…By promoting healthy intestinal pH, SCFAs provide antimicrobial and probiotic benefits as pH can dictate what types of bacteria are able to grow (Pratiwi Dyah Kusumo, Maulahela, et al, 2019a,b;LaGamma et al, 2021;Nishida et al, 2021).…”