Enterohormonal and Microbiota Pathophysiology Of Obesity


Introduction

Obesity has become a major public health crisis, with hundreds of millions of people classified as overweight in recent decades.[1][2][3] There is widespread research to find methods to mitigate this threat to human health. Obesity is defined as the excessive accumulation of fat in body tissues, most commonly measured by body mass index (BMI). However, the causes of obesity are numerous and very complex. 

Many biomedical, socioeconomic, cultural, and other factors contribute to the onset of obesity. Characteristic western lifestyle features, such as energy-intense diets, high meat consumption, and a sedentary lifestyle, contribute to this phenomenon.[4] The impact of other causes is less well understood, such as a family history of obesity and stress.[5] Therefore, practitioners must treat patients with obesity holistically and comprehensively.

One contributor to the pathophysiology of obesity that has garnered particular interest is the composition of gut microbiota, which may be simply defined as the microbes that live on us and within us.[6] The microbiota genome may be referred to as the microbiome. Research into the role of gut microbiota affecting host metabolism and homeostasis and their effect on disease processes began with Élie Metchnikoff in the early 1900s. Trillions of gut microbes occupy the gastrointestinal tract (GIT), mainly in the colon. These exist in a complex ecosystem that interacts in tandem with human metabolic activity and a highly diverse microbiome.[2][7] 

Recent literature has shown how diet influences the composition of gut microbiota and how diet can cause obesity. Nevertheless, there is much controversy regarding the precise mechanisms by which gut microbiota contribute to obesity. This chapter will focus on the interactions between gut microbiota and enteroendocrine hormone regulation and their relation to excessive adipose accumulation. Three particular mechanisms will be emphasized: the permeation of the intestinal barrier, the influence of the gut-brain axis on eating behavior, and non-alcoholic fatty liver disease.

Issues of Concern

"Obese Microbiome"

It has been suggested that specific microbiota patterns are associated with obesity, referred to as the "obese microbiome." While the exact mechanisms of how the "obese microbiome" contributes to the pathophysiology of obesity are not yet clear, it is reported that compared to lean individuals, patients with obesity are found to have less biodiversity of gut microbiota.[8][9][10] This may lead to the growth of pathogenic bacteria populations. Observational studies show that Lactobacillus reuteri and Lactobacillus sakei were found in higher numbers in patients with higher BMI in adult humans.[11] 

Intervention studies involving mice show the administration of A. mucinophila decreases adiposity in experimental models.[12][13] Other literature shows a pattern between obesity and lesser populations of butyrate-producing gut microbiota.[14] Current research into the contributions of specific taxa of gut microbiota to the onset of obesity is conflicting and only assigns correlations of specific microbiota populations with obesity, not causation. Thus, more research needs to be done involving human interventional studies to find which gut microbiota result in the phenotype of obesity.

Cellular

Effect of Gut Microbiota on Intestinal Permeability

Increased intestinal permeability and inflammation via lipopolysaccharides (LPS) appear to influence the pathogenesis of obesity.[15] The mucosa of the gastrointestinal tract (GIT) creates a protective barrier between the intestinal epithelial tissue and harmful substances such as toxins and pathogenic bacteria.[16] This barrier is maintained through various mechanisms involving short-chain fatty acid (SCFA) signaling, which improves the integrity of the intestinal wall.[12][17] 

Short-chain fatty acids are monocarboxylic acids that are byproducts of carbohydrate metabolism in microbes and are associated with lower body weight and adiposity.[15][18] Certain SCFAs modulate myofibroblast prostaglandin production, signaling enterocytes to express mucin-2 and maintaining the mucosa barrier's structural integrity.[19]

When a loss of gut microbiota diversity occurs in the patient with obesity, there is a concomitant loss in SCFAs. This loss is especially notable concerning Bifidobacterium.[20] Diminished intestinal barrier integrity can absorb harmful toxins, resulting in endotoxemia and low-grade inflammation that is consistently present with obesity.[12][21] 

Decreased gut barrier integrity that results from "obese microbiota" has been found to cause systemic inflammation. The signaling of peritoneal macrophages induces this by upregulating the production of tumor necrosis factor-alpha (TNF-alpha) and interleukin 1beta (IL-1beta).[22] 

Gut microbiota can also influence intestinal permeability by modifying alkaline phosphatase activity, interfering with tight junctions, and changing gene expression of cannabinoid receptor 1 in the colon, which has downstream effects on permeability.[23]

Development

Newborns develop microbial colonization during the first month of life.[4] It is noted that infants delivered by the Cesarian section have lower gut bacterial counts than a natural birth, suggesting that the birth canal contributes to a healthy microbiota.[24] Breast milk contains oligosaccharides and bacteria such as Bifidobacterium and Lactobacillus, which may also be critical to developing the immune system.[25][26] 

A progression of bacterial microflora occurs as the diet becomes more diverse and includes solid food, which is likely very important for immune system development and the prevention of autoimmune conditions such as some forms of asthma and eczema.[26][27] The geographic region where a child resides also impacts the microbiota during development.  For example, microbial diversity is greater in children from Africa than children in the European Union.[28]

Organ Systems Involved

In addition to the gastrointestinal tract in which gut microbiota reside, they interact with the liver and pancreas via complex signaling pathways.[29] Gut microbiota and enteroendocrine cells also interact with the central nervous system by affecting eating behavior, appetite, and satiety.

Function

Gut microbiota plays an essential role in maintaining overall health. Commensal bacteria in the gut communicate with the host via signaling pathways involving enteroendocrine cells.[30][31] Normal gut flora exists symbiotically with the host and aid in digestion, metabolism, and energy regulation, to name several benefits they serve.

Mechanism

The microbiome impacts health through other mechanisms than gut permeability. Gut microbiota have also been shown to contribute to the pathogenesis of obesity through interaction with the central nervous system, inducing changes in appetite and satiety. One such mechanism is the development of leptin resistance. Leptin is a signaling protein that is made by adipose cells. As adipose tissue increases, more leptin is produced and released. Leptin acts on the central nervous system to reduce food intake. Neuropeptide Y is released from the central and peripheral nervous system, causing increased energy expenditure.[1] 

Leptin resistance in the central nervous system occurs as plasma levels increase, causing increased food intake and body weight.[32] Specific microbial taxa are associated with increased plasma leptin levels, such as Bilophila wadsworthia, suggesting that this species may worsen leptin resistance. On the other hand, Bifidobacterium and other species are also associated with increased leptin sensitivity.[2] Increased LPS levels caused indirectly by microbial dysbiosis have also been shown to result in leptin resistance.[33]

Related Testing

Testing fecal samples for gut microbiota is currently most useful clinically for suspected or known infection with Clostridium difficile, but research often involves identifying and quantifying a much broader spectrum of bacterial flora.[34] Determining the diversity of gut bacteria is generally executed using DNA and RNA gene sequencing since the use of cultures has been problematic. In the future, gut diversity and specific makeup may translate to a greater variety of clinical applications.[35]

Pathophysiology

Interaction Between Gut Microbiota and the Gut-Brain Axis

The SCFAs produced by gut microbiota also interact with gut hormone signaling to affect eating behavior. These SCFAs interact with the host metabolism by binding to specific G-protein coupled receptors (GPR), including GPR41 and GPR43, causing the release of the peptide tyrosine-tyrosine (PYY), which enters circulation and interacts with the hypothalamus to reduce overall food intake.[36] 

One specific SCFA, butyrate, is believed to reduce energy expenditure by increasing plasma glucagon-like peptide 1 (GLP-1), glucose-dependent insulinotropic peptide (GIP), and PYY.[1] In a randomized clinical trial, propionate, another SCFA, also was found to cause the release of PYY and GLP-1. Still, it also upregulates genes involved in intestinal gluconeogenesis by binding to GPR41, thereby reducing adiposity.[37] 

Literature also shows that gut microbiota may be directly involved in stimulating the vagal nerve, at least partially through the release of GLP-1, PYY, and cholecystokinin (CCK) by enteroendocrine cells which transmits information from the gut to the hypothalamus to regulate appetite and energy homeostasis.[30][31][38][39] 

Gut microbiota also influences the release of serotonin and gamma-aminobutyric acid (GABA), which control host appetite and energy regulation.[40]

Gut Microbiota and Fatty Liver Disease

Gut microbiota dysbiosis has also been linked with fatty liver disease (FLD) associated with obesity.[41] Patients with non-alcoholic FLD usually experience gut bacteria overgrowth and decreased intestinal barrier integrity. Research shows that worsening of non-alcoholic FLD is associated with increased Bacteroides populations, and hepatic fibrosis correlates with increased Ruminococcus.[42] 

Gut microbiota are also indirectly involved with triglyceride deposition in the liver via interactions with fasting-induced adiposity factor (FIAF). FIAF is a lipoprotein lipase inhibitor released by enterocytes whose expression is inhibited by gut microbiota.[43] FIAF also activates carbohydrate-responsive element-binding protein and sterol regulatory element-binding protein 1, which ultimately upregulates triglyceride production and accumulation in the liver.

Clinical Significance

Gut microbial populations can be modified through various therapeutic and surgical approaches, and this presents several methods of treating obesity. One such avenue is using probiotic supplements to provide live bacteria to restore the gut microbiota biodiversity lost in patients with obesity.[44] Bifidobacterium is a common microbial species in probiotics that appears to reduce intestinal permeability, which can be expected to protect against harmful bacteria and other toxins entering the circulation, causing inflammation.[15] 

Recently, more research is exploring the potential use of certain strains of Lactobacillus to treat obesity.[45] Specific prebiotics and other dietary supplements that stimulate the growth of potentially therapeutic bacteria have also been suggested to treat obesity. One such example is fish oil which may alter populations of Bifidobacterium and other species to improve intestinal barrier integrity.[46]

Surgical interventions that alter gut microbiota composition may also serve to treat obesity. Gastric bypass surgery decreases food intake and body weight. This surgical procedure also increases the population of A. muciniphila and other species. These same therapeutic effects have been shown when these bacteria species are transferred to germ-free mice. This suggests that gut microbiota changes may at least partially explain the impact of gastric bypass on reducing obesity.[2] 

Fecal microbiota transplantation (FMT) is a method whereby microbiota populations within fecal material from lean individuals are transferred to patients with obesity. This is being explored as a potential method of treating obesity by mitigating dysbiosis. Still, more research is needed to refine its limitations and confirm its safety and efficacy in treating obesity.[2][47]

Lifestyle and diet may play an essential role in maintaining gut microbiota homeostasis. Dietary changes can influence the microbial population in early life, which can have a long-term impact on the individual. Non-dietary factors can also impact GIT microbiota. For example, smoking has been associated with increased Bacteroides-Prevotella and may contribute to Crohn disease.[4] Smoking may also affect the microbiota in such a way as to increase the risk of colorectal cancer.[48] 

More research is needed into the use of dietary changes, prebiotics, and probiotics to modify GIT microbiota positively. Lifestyle modification should usually be introduced along with any pharmacologic interventions which are planned. These changes include diet modification and smoking cessation.


Article Details

Article Author

Blake I. Hardin

Article Editor:

Daniel Keyes

Updated:

2/20/2022 5:30:42 PM

References

[1]

Cunningham AL,Stephens JW,Harris DA, A review on gut microbiota: a central factor in the pathophysiology of obesity. Lipids in health and disease. 2021 Jul 7;     [PubMed PMID: 34233682]

[2]

Mulders RJ,de Git KCG,Schéle E,Dickson SL,Sanz Y,Adan RAH, Microbiota in obesity: interactions with enteroendocrine, immune and central nervous systems. Obesity reviews : an official journal of the International Association for the Study of Obesity. 2018 Apr;     [PubMed PMID: 29363272]

[3]

Panuganti KK,Nguyen M,Kshirsagar RK, Obesity StatPearls. 2022 Jan     [PubMed PMID: 29083734]

[4]

Conlon MA,Bird AR, The impact of diet and lifestyle on gut microbiota and human health. Nutrients. 2014 Dec 24;     [PubMed PMID: 25545101]

[5]

Pereira MA,Kartashov AI,Ebbeling CB,Van Horn L,Slattery ML,Jacobs DR Jr,Ludwig DS, Fast-food habits, weight gain, and insulin resistance (the CARDIA study): 15-year prospective analysis. Lancet (London, England). 2005 Jan 1-7;     [PubMed PMID: 15639678]

[6]

Turnbaugh PJ,Ley RE,Hamady M,Fraser-Liggett CM,Knight R,Gordon JI, The human microbiome project. Nature. 2007 Oct 18     [PubMed PMID: 17943116]

[7]

Shen J,Obin MS,Zhao L, The gut microbiota, obesity and insulin resistance. Molecular aspects of medicine. 2013 Feb;     [PubMed PMID: 23159341]

[8]

Turnbaugh PJ,Hamady M,Yatsunenko T,Cantarel BL,Duncan A,Ley RE,Sogin ML,Jones WJ,Roe BA,Affourtit JP,Egholm M,Henrissat B,Heath AC,Knight R,Gordon JI, A core gut microbiome in obese and lean twins. Nature. 2009 Jan 22;     [PubMed PMID: 19043404]

[9]

Bruce-Keller AJ,Salbaum JM,Luo M,Blanchard E 4th,Taylor CM,Welsh DA,Berthoud HR, Obese-type gut microbiota induce neurobehavioral changes in the absence of obesity. Biological psychiatry. 2015 Apr 1;     [PubMed PMID: 25173628]

[10]

Ley RE,Turnbaugh PJ,Klein S,Gordon JI, Microbial ecology: human gut microbes associated with obesity. Nature. 2006 Dec 21;     [PubMed PMID: 17183309]

[11]

Million M,Thuny F,Angelakis E,Casalta JP,Giorgi R,Habib G,Raoult D, Lactobacillus reuteri and Escherichia coli in the human gut microbiota may predict weight gain associated with vancomycin treatment. Nutrition     [PubMed PMID: 24018615]

[12]

Everard A,Lazarevic V,Gaïa N,Johansson M,Ståhlman M,Backhed F,Delzenne NM,Schrenzel J,François P,Cani PD, Microbiome of prebiotic-treated mice reveals novel targets involved in host response during obesity. The ISME journal. 2014 Oct;     [PubMed PMID: 24694712]

[13]

Shin NR,Lee JC,Lee HY,Kim MS,Whon TW,Lee MS,Bae JW, An increase in the Akkermansia spp. population induced by metformin treatment improves glucose homeostasis in diet-induced obese mice. Gut. 2014 May;     [PubMed PMID: 23804561]

[14]

Vallianou N,Stratigou T,Christodoulatos GS,Dalamaga M, Understanding the Role of the Gut Microbiome and Microbial Metabolites in Obesity and Obesity-Associated Metabolic Disorders: Current Evidence and Perspectives. Current obesity reports. 2019 Sep;     [PubMed PMID: 31175629]

[15]

Cani PD,Possemiers S,Van de Wiele T,Guiot Y,Everard A,Rottier O,Geurts L,Naslain D,Neyrinck A,Lambert DM,Muccioli GG,Delzenne NM, Changes in gut microbiota control inflammation in obese mice through a mechanism involving GLP-2-driven improvement of gut permeability. Gut. 2009 Aug;     [PubMed PMID: 19240062]

[16]

Hartmann P,Chen P,Wang HJ,Wang L,McCole DF,Brandl K,Stärkel P,Belzer C,Hellerbrand C,Tsukamoto H,Ho SB,Schnabl B, Deficiency of intestinal mucin-2 ameliorates experimental alcoholic liver disease in mice. Hepatology (Baltimore, Md.). 2013 Jul;     [PubMed PMID: 23408358]

[17]

Wang J,Tang H,Zhang C,Zhao Y,Derrien M,Rocher E,van-Hylckama Vlieg JE,Strissel K,Zhao L,Obin M,Shen J, Modulation of gut microbiota during probiotic-mediated attenuation of metabolic syndrome in high fat diet-fed mice. The ISME journal. 2015 Jan;     [PubMed PMID: 24936764]

[18]

Roy CC,Kien CL,Bouthillier L,Levy E, Short-chain fatty acids: ready for prime time? Nutrition in clinical practice : official publication of the American Society for Parenteral and Enteral Nutrition. 2006 Aug;     [PubMed PMID: 16870803]

[19]

Willemsen LE,Koetsier MA,van Deventer SJ,van Tol EA, Short chain fatty acids stimulate epithelial mucin 2 expression through differential effects on prostaglandin E(1) and E(2) production by intestinal myofibroblasts. Gut. 2003 Oct;     [PubMed PMID: 12970137]

[20]

Singh RK,Chang HW,Yan D,Lee KM,Ucmak D,Wong K,Abrouk M,Farahnik B,Nakamura M,Zhu TH,Bhutani T,Liao W, Influence of diet on the gut microbiome and implications for human health. Journal of translational medicine. 2017 Apr 8;     [PubMed PMID: 28388917]

[21]

Sohail MU,Althani A,Anwar H,Rizzi R,Marei HE, Role of the Gastrointestinal Tract Microbiome in the Pathophysiology of Diabetes Mellitus. Journal of diabetes research. 2017;     [PubMed PMID: 29082264]

[22]

Sanz Y,Moya-Pérez A, Microbiota, inflammation and obesity. Advances in experimental medicine and biology. 2014;     [PubMed PMID: 24997040]

[23]

Muccioli GG,Naslain D,Bäckhed F,Reigstad CS,Lambert DM,Delzenne NM,Cani PD, The endocannabinoid system links gut microbiota to adipogenesis. Molecular systems biology. 2010 Jul;     [PubMed PMID: 20664638]

[24]

Kelly D,King T,Aminov R, Importance of microbial colonization of the gut in early life to the development of immunity. Mutation research. 2007 Sep 1     [PubMed PMID: 17612575]

[25]

Harmsen HJ,Wildeboer-Veloo AC,Raangs GC,Wagendorp AA,Klijn N,Bindels JG,Welling GW, Analysis of intestinal flora development in breast-fed and formula-fed infants by using molecular identification and detection methods. Journal of pediatric gastroenterology and nutrition. 2000 Jan;     [PubMed PMID: 10630441]

[26]

Coppa GV,Zampini L,Galeazzi T,Gabrielli O, Prebiotics in human milk: a review. Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver. 2006 Dec;     [PubMed PMID: 17259094]

[27]

Arslanoglu S,Moro GE,Schmitt J,Tandoi L,Rizzardi S,Boehm G, Early dietary intervention with a mixture of prebiotic oligosaccharides reduces the incidence of allergic manifestations and infections during the first two years of life. The Journal of nutrition. 2008 Jun     [PubMed PMID: 18492839]

[28]

Delzenne NM,Cani PD, Interaction between obesity and the gut microbiota: relevance in nutrition. Annual review of nutrition. 2011 Aug 21     [PubMed PMID: 21568707]

[29]

Schroeder BO,Bäckhed F, Signals from the gut microbiota to distant organs in physiology and disease. Nature medicine. 2016 Oct     [PubMed PMID: 27711063]

[30]

Balakumar M,Prabhu D,Sathishkumar C,Prabu P,Rokana N,Kumar R,Raghavan S,Soundarajan A,Grover S,Batish VK,Mohan V,Balasubramanyam M, Improvement in glucose tolerance and insulin sensitivity by probiotic strains of Indian gut origin in high-fat diet-fed C57BL/6J mice. European journal of nutrition. 2018 Feb;     [PubMed PMID: 27757592]

[31]

Torres-Fuentes C,Schellekens H,Dinan TG,Cryan JF, The microbiota-gut-brain axis in obesity. The lancet. Gastroenterology     [PubMed PMID: 28844808]

[32]

Morris DL,Rui L, Recent advances in understanding leptin signaling and leptin resistance. American journal of physiology. Endocrinology and metabolism. 2009 Dec;     [PubMed PMID: 19724019]

[33]

de Lartigue G,Barbier de la Serre C,Espero E,Lee J,Raybould HE, Diet-induced obesity leads to the development of leptin resistance in vagal afferent neurons. American journal of physiology. Endocrinology and metabolism. 2011 Jul;     [PubMed PMID: 21521717]

[34]

Woodworth MH,Neish EM,Miller NS,Dhere T,Burd EM,Carpentieri C,Sitchenko KL,Kraft CS, Laboratory Testing of Donors and Stool Samples for Fecal Microbiota Transplantation for Recurrent Clostridium difficile Infection. Journal of clinical microbiology. 2017 Apr;     [PubMed PMID: 28077694]

[35]

Lau JT,Whelan FJ,Herath I,Lee CH,Collins SM,Bercik P,Surette MG, Capturing the diversity of the human gut microbiota through culture-enriched molecular profiling. Genome medicine. 2016 Jul 1;     [PubMed PMID: 27363992]

[36]

Tolhurst G,Heffron H,Lam YS,Parker HE,Habib AM,Diakogiannaki E,Cameron J,Grosse J,Reimann F,Gribble FM, Short-chain fatty acids stimulate glucagon-like peptide-1 secretion via the G-protein-coupled receptor FFAR2. Diabetes. 2012 Feb;     [PubMed PMID: 22190648]

[37]

Chambers ES,Viardot A,Psichas A,Morrison DJ,Murphy KG,Zac-Varghese SE,MacDougall K,Preston T,Tedford C,Finlayson GS,Blundell JE,Bell JD,Thomas EL,Mt-Isa S,Ashby D,Gibson GR,Kolida S,Dhillo WS,Bloom SR,Morley W,Clegg S,Frost G, Effects of targeted delivery of propionate to the human colon on appetite regulation, body weight maintenance and adiposity in overweight adults. Gut. 2015 Nov;     [PubMed PMID: 25500202]

[38]

McLaughlin MB,Jialal I, Biochemistry, Hormones StatPearls. 2022 Jan     [PubMed PMID: 31082156]

[39]

Parikh A,Thevenin C, Physiology, Gastrointestinal Hormonal Control StatPearls. 2022 Jan     [PubMed PMID: 30725969]

[40]

Sun L,Ma L,Ma Y,Zhang F,Zhao C,Nie Y, Insights into the role of gut microbiota in obesity: pathogenesis, mechanisms, and therapeutic perspectives. Protein     [PubMed PMID: 29725936]

[41]

Kudaravalli P,John S, Nonalcoholic Fatty Liver StatPearls. 2022 Jan     [PubMed PMID: 31082077]

[42]

Boursier J,Mueller O,Barret M,Machado M,Fizanne L,Araujo-Perez F,Guy CD,Seed PC,Rawls JF,David LA,Hunault G,Oberti F,Calès P,Diehl AM, The severity of nonalcoholic fatty liver disease is associated with gut dysbiosis and shift in the metabolic function of the gut microbiota. Hepatology (Baltimore, Md.). 2016 Mar;     [PubMed PMID: 26600078]

[43]

Bäckhed F,Ding H,Wang T,Hooper LV,Koh GY,Nagy A,Semenkovich CF,Gordon JI, The gut microbiota as an environmental factor that regulates fat storage. Proceedings of the National Academy of Sciences of the United States of America. 2004 Nov 2;     [PubMed PMID: 15505215]

[44]

Nova E,Pérez de Heredia F,Gómez-Martínez S,Marcos A, The Role of Probiotics on the Microbiota: Effect on Obesity. Nutrition in clinical practice : official publication of the American Society for Parenteral and Enteral Nutrition. 2016 Jun;     [PubMed PMID: 26869611]

[45]

Drissi F,Raoult D,Merhej V, Metabolic role of lactobacilli in weight modification in humans and animals. Microbial pathogenesis. 2017 May;     [PubMed PMID: 27033001]

[46]

Lam YY,Ha CW,Hoffmann JM,Oscarsson J,Dinudom A,Mather TJ,Cook DI,Hunt NH,Caterson ID,Holmes AJ,Storlien LH, Effects of dietary fat profile on gut permeability and microbiota and their relationships with metabolic changes in mice. Obesity (Silver Spring, Md.). 2015 Jul;     [PubMed PMID: 26053244]

[47]

Lee P,Yacyshyn BR,Yacyshyn MB, Gut microbiota and obesity: An opportunity to alter obesity through faecal microbiota transplant (FMT). Diabetes, obesity     [PubMed PMID: 30328245]

[48]

Huxley RR,Ansary-Moghaddam A,Clifton P,Czernichow S,Parr CL,Woodward M, The impact of dietary and lifestyle risk factors on risk of colorectal cancer: a quantitative overview of the epidemiological evidence. International journal of cancer. 2009 Jul 1;     [PubMed PMID: 19350627]