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Microbes & Immunity Management of obesity

such as carbohydrate-responsive element-binding protein production and lymphoid function in the intestine. Studies
(CHREBP) and sterol regulatory binding protein 1 suggest that reduced tryptophan metabolism into AhR
(SREBP1), promoting lipogenesis and triglyceride storage. agonists is a hallmark of metabolic syndrome, contributing
They also inhibit fasting-induced adipocyte factor, leading to insulin resistance, liver steatosis, and increased
to triglyceride accumulation in adipocytes. In addition, intestinal permeability due to elevated LPS translocation.
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SCFAs bind to GPCRs, playing roles in lipid, glucose, and Therapeutic approaches include administration of AhR
cholesterol metabolism, regulation of gut inflammation, agonists or probiotic supplementation with Lactobacillus
and neurogenesis. Early studies show that SCFAs reuteri to improve intestinal barrier function and increase
modulate adiposity and glucose tolerance by stimulating GLP-1 secretion, thereby reversing metabolic disorders,
GLP-1 secretion through G protein-coupled receptor such as low-grade inflammation and intestinal barrier
(GPR) 41 and GPR43 receptors, with GPR43 capable of dysfunction. Indole administration has been found
dual signaling through different pathways. to prevent LPS-induced abnormalities in cholesterol
Butyric acid contributes to immune homeostasis by metabolism and liver inflammation. Research also shows
stimulating IL-18 secretion and suppressing inflammation that inhibiting indoleamine 2,3-dioxygenase (IDO) – a
through GPR109A activation and histone deacetylase key enzyme in the kynurenine pathway – can help mitigate
inhibition. Moreover, gut microbiota-derived propionate HFD-induced obesity and associated metabolic alterations.
and butyrate activate intestinal gluconeogenesis through IDO overactivation leads to increased concentrations
free fatty acid receptor 3 or a gut–brain neural circuit, of inflammatory metabolites, such as xanthurenic acid,
influencing glucose metabolism. While microbiota- kynurenic acid, and quinolinic acid, while reducing plasma
derived acetate serves as a pre-cursor for fatty acids and tryptophan levels, thereby contributing to metabolic
de novo lipogenesis in the liver, excessive acetate generation dysfunction. Serotonin, another tryptophan-derived
has been linked to obesity and NAFLD. Microbiota– metabolite, plays a role in obesity regulation by modulating
immune system interactions further regulate metabolic appetite and satiety. However, excessive serotonin levels
homeostasis. Studies indicate that fiber-derived SCFA suppress brown adipose tissue thermogenesis, resulting
binding to free fatty acid receptors suppresses high-fat diet in fat accumulation. Elevated levels of 5-hydroxyindole-3-
(HFD)-induced metabolic syndrome by restoring IL-22- acetic acid, the end-product of serotonin metabolism, have
mediated enterocyte function. In addition, Lactobacillus been observed in individuals with metabolic disorders
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johnsonii Q1–7 deficiency contributes to reduced food compared to healthy controls. This highlights the
intake and body mass through mammalian target of importance of gut microbiota-derived indole metabolites
rapamycin complex 1 signaling, affecting IgA production. in regulating inflammation, metabolic health, and obesity,
In clinical cases, Bacteroidetes abundance increases while suggesting potential therapeutic applications through
SCFA-producing Firmicutes decline in NAFLD patients, microbiota-based interventions.
further emphasizing the microbiota’s role in metabolic
disorders. Understanding these microbial interactions 5. Metabolite production by the host and
highlights their significance in metabolism, immune biochemical alteration by gut bacteria
regulation, and obesity, paving the way for microbiota- 5.1. Secondary bile acids
targeted therapies to enhance metabolic health. 14
Secondary bile acids, metabolized by gut microbiota, play
4.2. Indole derivatives a pivotal role in fat digestion, lipid metabolism, glucose
Indole and its derivatives produced by commensal bacteria, regulation, and inflammation. They shape the bile acid
such as Lactobacillus, Escherichia coli, and Bacteroides, pool and influence bile acid-activated receptors, including
play a significant role in bacterial communication and farnesoid X receptors (FXRs), pregnane X receptors, and
host interactions. These metabolites are generated from GPCRs, which regulate various metabolic processes.
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dietary tryptophan through the action of tryptophanase Dysregulation of these pathways can contribute to
and can reach high concentrations in the digestive tract metabolic disorders. Among the major secondary bile
and systemic circulation. 15,16 Indole is metabolized in acids, deoxycholic acid and lithocholic acid support energy
the liver by cytochrome P450 2E1 into 3-indoxyl sulfate homeostasis by activating Takeda G protein-coupled
(3-IS), with low urinary levels of 3-IS indicating gut receptor 5, thereby influencing metabolic functions.
dysbiosis. Indole derivatives – including indole-3-lactic Clinical studies suggest that bile acid composition is
acid, indole-3-aldehyde, indole-3-acetic acid, and indole- modulated by diet and medication. For instance, the
3-propionic acid – act as ligands for AhRs, which regulate anti-diabetic drug acarbose alters bile acid profiles, while
immune responses and inflammation by modulating IL-22 HFDs elevate overall bile acid levels and shift the balance

Volume 2 Issue 4 (2025) 43 doi: 10.36922/MI025160036