Intestinal-related substances in obesity regulation: A comprehensive review

Table 1 The Role of gut origined indole-3-propionic acid in the weight loss

Affiliation	Method	Result	Conclusion	Ref.
Stanford University, United States	Gene editing using pMTL007C-E2 plasmid with Ll.LtrB group II intron	Identified tryptophan-derived metabolite IPA	Enhances intestinal function: (1) Restores gut barrier integrity; and (2) Attenuates inflammatory responses	[6]
Zhejiang University, China	In vitro pull-down with site mutation to find STAT3 binding site	Trp623 in SH2 domain is key site for IPA binding; IPA enhances leptin sensitivity to combat obesity	Metabolic modulation: (1) Suppresses appetite; and (2) Enhances glucose metabolism	[8]
Shanghai Jiao Tong University, China	Obesity model by high-fat diet; 16S sequencing and LC-MS/MS used for serum IPA quantification	IPA ameliorates hepatic steatosis	Hepatic protection: (1) Suppresses hepatic lipid accumulation; and (2) Promotes intrahepatic lipolysis	[7]
All India Institute of Medical Sciences	Liver histology + LC-MS quantification	Circulating IPA level negatively correlated with liver fibrosis severity	Hepatoprotective effects of IPA. Inhibits liver injury to maintain normal lipid metabolism	[13]
China Agricultural University	High-fat diet mouse model; FMT and microbiome sequencing	IPA + SB + VA combination modulates gut-liver-brain axis and shows anti-obesity potential	Anti-obesity mechanisms: (1) Preserves gut microbiota homeostasis; and (2) Activates hepatic leptin signaling	[14]
King’s College London, United Kingdom	16S rRNA gene sequencing (V3–V4 region)	Gut microbiota composition (esp. butyrate-producers) significantly affects circulating IPA levels	Metabolic function prediction: (1) IPA levels correlate with clinical parameters of metabolic syndrome; and (2) Predicts type 2 diabetes onset	[23]
Southern Medical University, China	IPA administered externally in HFD-induced model	IPA activates tuft cell–IL-25 axis, restores colonic barrier, and prevents obesity/metabolic disorders	Multifunctional effects of IPA: (1) Ameliorates glucose/Lipid metabolic disorders; (2) Attenuates adipose and intestinal inflammation; and (3) Suppresses adipocyte hypertrophy	[24]

16S: 16S ribosomal RNA; 16S-seq: 16S rRNA gene sequencing; FMT: Fecal microbiota transplantation; HFD: High-fat diet; IL-25: Interleukin-25; IPA: Indole-3-propionic acid; LC-MS/MS: Liquid chromatography–tandem mass spectrometry; LC-MS: Liquid chromatography–mass spectrometry; SB: Sodium butyrate; SH2: Src homology 2 domain; VA: Valeric acid.

Table 2 The role of short-chain fatty acid in the gut

Affiliation	Method	Result	Conclusion	Ref.
Institute of Microecology, Germany	Controlled human study comparing SCFA levels across BMI groups	SCFA levels were significantly higher in obese and overweight groups vs healthy individuals	The acetate/propionate/butyrate ratio modulates obesity development	[24]
Imperial College London, United Kingdom	Nanoparticle-based acetate intervention in HFD-induced obese mice	Acetate improved liver mitochondrial function and reduced lipid accumulation	Anti-obesity effects of acetate: (1) Reduces hepatic lipid accumulation; and (2) Enhances systemic thermogenesis	[17]

SCFA: Short-chain fatty acid; BMI: Body mass index; HFD: High-fat diet.

Table 3 The role of peptides in the gut

Affiliation	Method	Result	Conclusion	Ref.
Eli Lilly and Company, United States	Administer once weekly. Phase 1 included SAD, MAD, and POC with dulaglutide as control.	LY3298176 activated GIP/GLP-1 receptors, improving glucose tolerance and reducing weight/food intake in mice	This drug achieves the goal of weight loss by reducing food intake and lowering blood sugar	[31]
National University Health System, Singapore	Evaluate GLP-1 RAs on weight, BMI, and waist circumference in overweight/obese adults. 47 RCTs included	GLP-1 RAs reduced weight, BMI, and waist	GLP-1 RAs demonstrated significant weight, BMI, and waist circumference reduction benefits	[29]
McGill University Health Centre, Canada	Narrative review using keywords on GLP-1-based therapies, obesity, and energy regulation	GLP-1 RAs act centrally and peripherally to reduce appetite, improve glucose control, and enhance metabolic health	GLP-1 RAs regulate obesity via central/peripheral mechanisms, suppressing appetite and improving metabolism	[28]
King Saud University, Saudi Arabia	Review of gut hormones' role in obesity, SCFAs, and protein-based interventions. Covered GLP-1, PYY, ghrelin, individual/combined therapies, and SCFAs' influence on hormone secretion	GLP-1 RAs and PYY reduce intake/weight, while SCFAs stimulate GLP-1/PYY for satiety/weight control	PYY and GLP-1 receptor mechanisms drive weight loss by regulating appetite and energy balance through gut hormone modulation	[4]
University of Texas Southwestern Medical Center, United States	Explored ghrelin’s effect on insulin, glucagon, and CNS, and glucose’s feedback on ghrelin secretion	Ghrelin increases blood glucose, reduces insulin effects, and worsens glucose tolerance. May contribute to hyperglycemia in obesity/diabetes	Ghrelin elevates blood glucose via insulin resistance and appetite stimulation, promoting obesity; blocking its action aids weight loss	[45]

GLP-1 RA: Glucagon-like peptide-1 receptor agonist; GIP: Glucose-dependent insulinotropic polypeptide; PYY: Peptide YY; CCK: Cholecystokinin; HFD: High-fat diet; RCT: Randomized controlled trial; SAD: Single ascending dose; MAD: Multiple ascending dose; POC: Proof-of-concept.

Table 4 Changes in gut hormones under obesity conditions

Hormone	Alteration in obesity	Response to weight loss	Ref.
GLP-1	Blunted postprandial response, reduced levels	Diet reduces fasting levels, exercise may increase postprandial levels	[55]
Peptide YY	Attenuated postprandial response, lower levels	Diet decreases fasting levels, exercise may increase in some cases	[55]
Pancreatic polypeptide	Conflicting results, often lower fasting levels	Diet increases postprandial levels, sustained for 1 year	[55]
Cholecystokinin	Reduced postprandial levels post-weight loss	Diet reduces levels, exercise has minimal effect	[55]
Leptin	Higher baseline levels in obese individuals	Decreases significantly with diet (35% with 15% weight loss), sustained reduction	[55]
Ghrelin	Lower fasting/postprandial levels, less suppression post-meal	Increases with diet (17% with 4.5% weight loss), exercise enhances post-loss levels	[55]