Beyond Digestion: The Gastrointestinal Tract at the Centre of Metabolic Regulation

Why is it important

For better half of the twentieth century, the gastrointestinal (GI) tract was thought of as a conduit for digestion, absorption and excretion, while metabolism was governed by the pancreas, liver, and adipose tissue. This distinction is no longer accurate. The recent transition from nonalcoholic fatty liver disease (NAFLD) to metabolic dysfunction associated steatotic liver disease (MASLD) highlights the role of metabolic dysfunction in disease pathogenesis [1]. Gut hormone analogues are now used to treat type 2 diabetes and obesity [2]. Bariatric surgery has shown superior long-term glycemic control compared to intensive medical therapy in selected patients with type 2 diabetes [3]. As more therapies in metabolic medicine target the gut or act through it, the distinction between the two is becoming increasingly blurred. We propose a unified framework in which GI and metabolic health are viewed as interconnected components of a single physiological network, reshaping how physicians view and assess patients, deliver care, and direct future research.

The GI tract as a metabolic organ

The GI tract is a major endocrine organ. Enteroendocrine cells sense nutrients within the intestinal lumen and release hormones such as glucagon like peptide 1 (GLP-1), glucose dependent insulinotropic polypeptide (GIP), peptide YY (PYY) and cholecystokinin, that regulate intestinal function, insulin secretion, nutrient absorption, and appetite [4]. Similarly, bile acids also act as hormones and activate ileal farsenoid X receptor (FXR) which in turn induces fibroblast growth factor (FGF19), which regulates hepatic bile acid synthesis and metabolism, while takeda G protein-coupled receptor 5 (TGR5) signaling promotes GLP-1 release [5].

The gut microbes also influence metabolic function through the generation of bioactive metabolites. Fermentation of dietary fiber yields short-chain fatty acids that act through free fatty acid receptor 2 and 3 (FFAR2 and FFAR3( [6], whereas gut microbes metabolize dietary phosphatidylcholine and produce trimethylamine N-oxide, whose plasma levels predict major adverse cardiovascular events [7].  

A bidirectional relationship

Emerging evidence supports a bidirectional gut-metabolic axis. Obesity is known to be associated with reflux disease, cholelithiasis, and colorectal cancer [8]. Similarly, metabolic dysfunction is increasingly associated with intestinal barrier dysfunction and with host-microbial interaction alteration [9]. Conversely, the GI tract regulates metabolism through hormone signaling, microbial metabolites, and immune pathways. This bidirectional relationship is well depicted in MASLD: Microbial products that cross a compromised intestinal barrier are delivered directly to the liver through the portal circulation, while the steatotic liver alters bile acid metabolism and enterohepatic pathways, further influencing intestinal and metabolic function [9, 10].

From gut–liver axis to gut–metabolic network

The gut-liver axis has significantly advanced our understanding of metabolic disease, but it captures only one component of a broader physiologic network. In our proposal the intestine serves as the central integrator of metabolic signaling in the gut-metabolic network [Figure 1]. The liver is the primary recipient of portal nutrients, bile acids, and microbial metabolites, while the pancreas responds to intestinal hormone signals. Adipose tissue is influenced by microbial and inflammatory signals, and skeletal muscle by nutrient availability and systemic inflammation. The brain integrates neural and hormonal signals originating from the gut to regulate appetite and energy balance, while the immune system serves as a regulator of interactions through this network.

The value of this framework lies in its ability to predict multisystem effects. An intervention targeting one component of the network often produces benefits, and occasionally unintended consequences, across multiple organ systems. The pleiotropic effects of GLP-1 receptor agonists exemplify this principle, with demonstrated benefits extending beyond weight reduction to cardiovascular disease, chronic kidney disease, and MASH, while also highlighting trade-offs such as loss of lean body mass during weight loss. Together, these observations suggest that metabolic therapies should be understood not as acting on a single organ, but as modifying an interconnected physiological network [11,12,13,14].

Therapeutic convergence

Therapeutic advances are increasingly blurring the traditional boundaries between gastroenterology and metabolic medicine. In the ESSENCE trial, semaglutide achieved resolution of steatohepatitis without worsening fibrosis in 62.9% of patients versus 34.3% with placebo, and improved fibrosis in 36.8% versus 22.4% [13]; These findings resulted in its accelerated approval in the United States for noncirrhotic MASH with moderate-to-advanced fibrosis in 2025 [15]. Other agents have demonstrated similar cross-disciplinary promise. Tirzepatide and survodutide showed histological benefit in phase 2 MASH trials [16,17], and the thyroid hormone receptor-β agonist resmetirom was effective in a phase 3 study [18]. Beyond liver disease, newer incretin-based therapies continue to reshape obesity management; in topline phase 3 data not yet peer reviewed, retatrutide produced mean weight loss of 28.3% at 80 weeks [19], and oral orforglipron became the first nonpeptide GLP-1 receptor agonist approved for weight management in 2026 [20]. Procedural interventions also show the same principle, with bariatric surgery associated with lower risks of major adverse liver outcomes in biopsy-proven steatohepatitis [21] and endoscopic sleeve gastroplasty producing greater weight loss than lifestyle modification alone [22].

Despite these advances, some important limitations remain. Weight reduction with GLP-1 receptor agonists is accompanied by loss of both fat and lean muscle mass [14]. Delayed gastric emptying has raised concerns regarding retained gastric contents and aspiration risk during sedated endoscopy [23]. Discontinuation of semaglutide resulted in substantial weight regain, with participants recovering approximately two-thirds of lost weight within one year [24]. Likewise, microbiome-directed therapies have produced variable and often transient benefits; in one study, lean-donor faecal microbiota transplantation improved insulin sensitivity at 6 weeks but not 18 weeks, with response influenced by the recipient's baseline microbial composition [25]. Long-term liver outcomes and durability data for many emerging therapies remain unavailable.

What is missing from clinical practice

Clinical practice has yet to fully capture the convergence of gastrointestinal and metabolic disease. Gastroenterologists routinely manage patients with obesity, diabetes, and MASLD, yet metabolic phenotyping remains inconsistent. Measures such as waist circumference, glycemic status, lipid profiles, body composition, and muscle function are not systematically incorporated into routine care, and fibrosis risk stratification often remains confined to hepatology settings. Referral for obesity pharmacotherapy or surgery is inconsistent. Sarcopenia assessment is largely limited to cirrhosis, and nutritional assessment is often omitted. At the same time, the gastrointestinal consequences of incretin-based therapies are increasingly encountered in clinics and endoscopy units, often without integrated care pathways. A practical first step would be the adoption of a minimum GI-metabolic dataset that can be collected routinely across outpatient practice.

Future directions

Key gaps remain in our understanding of the GI–metabolic interface. First, integrated phenotyping approaches that combine metabolic, hepatic, microbial, nutritional, and body-composition assessments may improve disease characterization and treatment selection. Second, future trials should incorporate hard clinical endpoints, including liver-related, cardiovascular, and functional outcomes, while evaluating strategies to preserve muscle mass during weight loss.  Finally, training programs should evolve to incorporate obesity medicine, clinical nutrition, and body-composition assessment into routine clinical education. Implementation research and real-world data platforms will be equally important in determining whether integrated GI–metabolic care models improve treatment delivery, patient outcomes, and healthcare utilization. 

Conclusion

The gut is not merely a target of metabolic disease; it is a central regulator of metabolic health. Viewing gastrointestinal and metabolic disease as components of an interconnected network represents more than a change in terminology. It reframes the questions gastroenterologists ask, the measurements they collect, and the therapies they consider. The emergence of incretin-based therapies has brought this interdependence into sharper clinical focus; the next challenge is to align clinical practice, research, and training with that reality.

References

1.            Rinella ME, Lazarus JV, Ratziu V, et al. A multisociety Delphi consensus statement on new fatty liver disease nomenclature. Hepatology. 2023;78:1966–1986.

2.            Drucker DJ, Holst JJ. The expanding incretin universe: from basic biology to clinical translation. Diabetologia. 2023;66:1765–1779.

3.            Schauer PR, Bhatt DL, Kirwan JP, et al. Bariatric surgery versus intensive medical therapy for diabetes—5-year outcomes. N Engl J Med. 2017;376:641–651.

4.            Gribble FM, Reimann F. Function and mechanisms of enteroendocrine cells and gut hormones in metabolism. Nat Rev Endocrinol. 2019;15:226–237.

5.            Perino A, Demagny H, Velazquez-Villegas L, Schoonjans K. Molecular physiology of bile acid signaling in health, disease, and aging. Physiol Rev. 2021;101:683–731.

6.            Koh A, De Vadder F, Kovatcheva-Datchary P, Bäckhed F. From dietary fiber to host physiology: short-chain fatty acids as key bacterial metabolites. Cell. 2016;165:1332–1345.

7.            Tang WHW, Wang Z, Levison BS, et al. Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk. N Engl J Med. 2013;368:1575–1584.

8.            Camilleri M, Malhi H, Acosta A. Gastrointestinal complications of obesity. Gastroenterology. 2017;152:1656–1670.

9.            Portincasa P, Bonfrate L, Khalil M, De Angelis M, Calabrese FM, D'Amato M, et al. Intestinal barrier and permeability in health, obesity and NAFLD. Biomedicines. 2022;10(1):83.

10.         Lau HCH, Zhang X, Yu J. Gut microbiome in metabolic dysfunction-associated steatotic liver disease and associated hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol. 2025;22(9):619-638.

11.         Lincoff AM, Brown-Frandsen K, Colhoun HM, et al. Semaglutide and cardiovascular outcomes in obesity without diabetes. N Engl J Med. 2023;389:2221–2232.

12.         Perkovic V, Tuttle KR, Rossing P, et al. Effects of semaglutide on chronic kidney disease in patients with type 2 diabetes. N Engl J Med. 2024;391:109–121.

13.         Sanyal AJ, Newsome PN, Kliers I, et al. Phase 3 trial of semaglutide in metabolic dysfunction–associated steatohepatitis. N Engl J Med. 2025;392:2089–2099.

14.         Rubino D, Abrahamsson N, Davies M, et al. Effect of continued weekly subcutaneous semaglutide vs placebo on weight loss maintenance in adults with overweight or obesity: The STEP 4 randomized clinical trial. JAMA. 2021;325:1414-1425

15.         Novo Nordisk A/S. Wegovy® approved in the US for the treatment of MASH [company announcement]. August 15, 2025.

16.         Loomba R, Hartman ML, Lawitz EJ, et al. Tirzepatide for metabolic dysfunction–associated steatohepatitis with liver fibrosis. N Engl J Med. 2024;391:299–310.

17.         Sanyal AJ, Bedossa P, Fraessdorf M, et al. A phase 2 randomized trial of survodutide in MASH and fibrosis. N Engl J Med. 2024;391:311–319.

18.         Harrison SA, Bedossa P, Guy CD, et al. A phase 3, randomized, controlled trial of resmetirom in NASH with liver fibrosis. N Engl J Med. 2024;390:497–509.

19.         Eli Lilly and Company. Lilly’s triple agonist, retatrutide, delivered powerful weight loss in pivotal Phase 3 obesity trial [news release]. May 21, 2026.

20.         US Food and Drug Administration. FDA approves first new molecular entity under National Priority Voucher program [press release]. April 1, 2026.

21.         Aminian A, Al-Kurd A, Wilson R, et al. Association of bariatric surgery with major adverse liver and cardiovascular outcomes in patients with biopsy-proven nonalcoholic steatohepatitis. JAMA. 2021;326:2031–2042.

22.         Abu Dayyeh BK, Bazerbachi F, Vargas EJ, et al. Endoscopic sleeve gastroplasty for treatment of class 1 and 2 obesity (MERIT): a prospective, multicentre, randomised trial. Lancet. 2022;400:441–451.

23.         Hashash JG, Thompson CC, Wang AY. AGA rapid clinical practice update on the management of patients taking GLP-1 receptor agonists prior to endoscopy: communication. Clin Gastroenterol Hepatol. 2024;22:705–707.

24.         Wilding JPH, Batterham RL, Davies M, et al. Weight regain and cardiometabolic effects after withdrawal of semaglutide: the STEP 1 trial extension. Diabetes Obes Metab. 2022;24:1553–1564.

25.          Kootte RS, Levin E, Salojärvi J, et al. Improvement of insulin sensitivity after lean donor feces in metabolic syndrome is driven by baseline intestinal microbiota composition. Cell Metab. 2017;26:611–619.e6.