If you would like assistance to further understand NAFLD, or could use some personalised support in your journey, you can click here to book an appointment with me. Not sure where to start on your gut health transformation?

Lots of support and no spam. Due to high demand, Dr Megan Rossi PhD, RD , award-winning gut health scientist at King's College London, is launching a new bloating masterclass that will include affordable, practical and science-backed solutions to help you master your bloating. Eat More, Live Well In her latest book, Dr Megan Rossi PhD, RD shares everything you need to know about boosting gut health and plant-based eating Learn more.

Eat Yourself Healthy Dr Megan Rossi explains how to feed your gut for a happier, healthier you using delicious, gut-boosting recipes Learn more. Bloating Masterclass now open! Book resources In Dr Megan Rossi's two books, you will find references to materials and assessments that can be downloaded here Learn more.

Tools My Gut Diary and Gut Health Assessments Booklet can help kickstart your gut health transformation Learn more. By The Gut Health Clinic team.

What is NAFLD? What are the symptoms? People with more advanced NAFLD may suffer from: A dull or aching pain in the top right of the tummy over the lower right side of the ribs Extreme tiredness Unexplained weight loss Weakness How is it diagnosed?

Potential interventions Probiotics and Prebiotics There is currently no standardized pharmacological treatment, and the only proven effective therapeutic strategy is lifestyle modification. Summary NAFLD is common and it may affect 1 in 5 people in the UK. Need extra support?

The Gut Health Clinic is here to help you wade through any complexities! The gut—liver axis and the intersection with the microbiome. Available from: doi Gut-Liver Axis, Gut Microbiota, and Its Modulation in the Management of Liver Diseases: A Review of the Literature.

International Journal of Molecular Sciences. Trust Your Gut: The Association of Gut Microbiota and Liver Disease. Role of Gut Dysbiosis in Liver Diseases: What Have We Learned So Far?. Function of Akkermansia Muciniphila in Obesity: Interactions with LipidMetabolism, Immune Response and Gut Systems.

Abo-Amer, Y. Relationship between Helicobacter Pylori Infection and Nonalcoholic Fatty Liver Disease NAFLD in a DevelopingCountry: A Cross-Sectional Study. Diabetes Metab. References Wijarnpreecha, K. Helicobacter Pyloriand Risk of Nonalcoholic Fatty Liver Disease: A Systematic Review and Meta-Analysis.

The fecal mycobiome in non-alcoholic fatty liver disease. J Hepatol. Nicoletti, A. The intestinal dysbiosis is accompanied by loss of gut barrier integrity and transfer of pathogen associated molecular patterns PAMPS to the portal circulation 29 Fig.

This leads to induction of pattern recognition receptors PRR like TOLL-like receptors and NOD-like receptors in liver cells, which results in activation of pro-inflammatory signaling cascades, which in turn bring about local inflammatory responses Toll-like receptors are one category of PRRs which are suppressed in healthy liver conditions 30 Fig.

This leads to an increase in the production of cytokines like Tumor Necrosis Factor α TNF α and Interleukin-1β, both of which are known to act on bacteria and viruses.

An elevated TLR signaling and expression of these cytokines due to prolonged stimulation can worsen hepatic injury in several liver diseases For example, NASH is known to affect the levels of TLR2 lipopolysaccharide , TLR4 peptidoglycan , TLR5 flagellin , and TLR9 bacterial DNA , all of which are activated by microbial antigens, thereby leading to inflammatory signaling cascades Systemic levels of LPS, a component of Gram-negative bacteria, are higher in cases of liver diseases like NAFLD and NASH.

Injecting LPS in mice model for NAFLD enhances liver injury as well as elevates the expression of pro-inflammatory cytokines 32 , Wild type mice fed with high fat diet develop steatohepatitis with an increased TLR4 expression and proinflammatory cytokines 32 , Further, TLR4 mutants are resistant to LPS induced release of pro-inflammatory cytokines, thus confirming role of TLR4 signaling in NAFLD and NASH Presence of bacterial DNA which is higher in NASH patients leads to elevated expression of TLR9 in NASH models Experiments with TLR9-deficient models fed with choline-deficient amino acid-defined CDAA diet show lesser inflammation, steatosis or fibrosis as compared to those in wild type model TLR9 signaling affects expression of inflammasome in macrophages, thereby resulting in formation of proinflammatory IL-1β and enhancement of the progression of hepatic injury in NASH TLR2 interacts with such Gram-positive bacterial cell wall components like lipoteichoic acids and peptidoglycan.

Based on the experimental observations on mice models, insulin resistance induced by high fat diet can be prevented by inhibition of TLR2 signaling Although, MCD diet may lead to features of steatohepatitis, it helps in increasing the insulin sensitivity and promotes weight reduction.

On the other hand, high fat and CDAA diets lead to weight gain and insulin resistance TLR5 binds to bacterial flagellin and plays a protective role for the intestine. TLR5-knockouts develop not only obesity and steatosis, but also display an imbalance in the gut microbiome Further, transfer of gut microbial communities from TLR5 knockout mice to WT germ-free mice gives rise to metabolic syndrome Thus, an interplay of gut microbiome and TLR5 probably contribute towards metabolic syndrome pathophysiology.

Several metabolites biosynthesised in the gut exert multiple effects in liver depicted in Fig. Choline, a dietary macronutrient, is involved in multiple physiological processes in liver, which include phospholipid biosynthesis phosphatidyl choline and other membrane lipids , cholesterol metabolism and enterohepatic circulation of bile and lipids 9.

Deficiency of choline in the diet leads to impairment in liver and brain function as well as metabolic processes and muscle movement. Free choline is absorbed by small intestine which then either gets integrated into the membrane or is transferred to liver where it is likely to get converted to betaine, lecithin, etc Lesser availability of choline leads to accumulation of triglycerides due to lower formation of phosphatidyl choline by the host in liver, a factor which has been associated with NASH and also in the manifestation of NAFLD While a choline-deficient diet induces steatohepatitis, excess choline in diet exceeding the absorptive capacity of host moves to the large intestine to get assimilated to Trimethylamine TMA by gut microbes Supplementary File 1 — 1.

Another route for biosynthesis of TMA involves degradation of carnitine obtained from dietary sources like red meat and dairy products Supplementary File 1 — 1.

The TMA thus formed is transferred to liver through portal circulation and gets converted to Trimethylamine Oxide TMAO , a component which has been implicated in multiple cardiometabolic disorders, hepatic diseases, etc Metabolites like short chain fatty acids SCFAs primarily include butyrate, propionate and acetate and are formed in the large intestine as a result of dietary assimilation of polysaccharides, resistant starch, fiber, etc The SCFAs work as nutrient and energy source for intestinal epithelium and act as precursors for lipogenesis and gluconeogenesis The butyrate level in the gut helps in maintaining the intestinal integrity as well as permeability A decrease in butyrate is observed in several liver ailments and alcohol influenced liver injuries SCFAs bind and activate G-protein coupled receptors GPCRs GPR41 and GPR43 This activation influences peptide-YY secretion as well as causes inhibition of gut motility, thereby increasing the nutrient utilization and yielding of energy.

The signaling across GPR41 and GPR43 leads to secretion of GLP1 which in turn reduces the food intake as well as emptying of gastric tract Further, GPCR signaling also affects regulation of fatty acid oxidation and insulin sensitivity by hepatocytes.

Apart from this, GPR43 activation also leads to inhibition of lipolysis and reduced plasma fatty acids In addition to GPCR-based signaling, SCFAs can reach the liver through the portal circulation and can have either beneficial or deleterious effects on the liver.

For example, increased acetate can be channeled to fatty acid biosynthesis pathway, thereby leading to triglyceride accumulation which has often been correlated to liver ailments 41 , Similarly, propionate which acts as a precursor for gluconeogenesis has also been associated to NAFLD 41 , On the other hand, butyrate may utilize multiple mechanisms to reduce the pathophysiology associated with liver diseases.

AMPK further suppresses lipogenic genes AMPK expression in liver regulated by butyrate reduces insulin resistance and obesity.

Administration of SCFAs has beneficial effects like reduction in hepatic steatosis and insulin resistance On the contrary, while enrichment of formate and acetate are found in adult subjects at advanced stages of NAFLD, butyrate and propionate are seen to be higher in mild NAFLD These differences in overall functioning of SCFAs in liver diseases may be affected by factors like diet and environment.

Ethanol is absorbed mostly in stomach and small intestine via diffusion by gastrointestinal mucosa Majority of ethanol in large intestine is obtained from systemic circulation. Some of the gut microbes can convert ethanol to acetaldehyde and to lesser extent acetate using alcohol metabolizing enzymes such as alcohol dehydrogenase Liver also expresses enzymes for ethanol metabolism in response to systemic ethanol content Interestingly, while certain small amounts of ethanol are observed in the bloodstream of subjects who do not consume alcohols, pediatric subjects with NASH are seen to possess higher serum ethanol levels as compared to obese children without NASH These levels of ethanol could be contributed by metabolism by the gut microbiome Consumption of ethanol is likely to add to the pathophysiology of liver diseases NASH, NAFLD, etc.

since it may cause not only an increase in intestinal permeability, but also may assist in production of inflammatory cytokines Endogenous ethanol can increase availability of acetate, a precursor of triglyceride formation through mechanisms involving inhibition of TCA cycle Ethanol oxidation by CYP2E1 can lead to production of free radicals which is likely to elevate inflammation Apart from this, ethanol can be metabolized to acetaldehyde which may either disrupt the tight junctions in the intestinal epithelium 55 or may have oxidant-dependent cytotoxic and metabolic effect on intestinal goblet like cells Oxidation of cholesterol to form primary bile acids, cholic acid, and chenodeoxycholic acid takes place in the hepatocytes through a multi-step process These bile acids are further conjugated to glycine or taurine which function as fat emulsifiers in the duodenum for solubilizing fats The released bile acids enter canaliculi through an export pump and move to the gallbladder where they get stored The bile acids are released into the duodenum upon consumption of food as a response to increase in production of cholecystokinin The intestinal microbiome converts these primary bile acids to secondary bile acids such as deoxycholic, lithocholic, and ursodeoxycholic acids Chenodeoxycholic acid CDCA activates FXR signaling, which in turn helps in not only regulating glucose levels and metabolism increase insulin sensitivity, glycogen synthesis and inhibit gluconeogenic genes , but also influences cholesterol transport, inhibits lipogenesis and enhances fatty acid oxidation Bile acids also lead to reduction in expression of lipogenic genes as well as help in reducing triglyceride levels by activating FXR and the pathway involving small heterodimer partner SHP and the sterol regulatory element-binding protein 1 SREBP-1 FXR also increases the proliferator-activated receptor alpha PPARalpha expression which in turn exerts anti-inflammatory effects and regulates lipid as well as glucose metabolism A small fraction of reabsorbed bile acids is likely to escape uptake into liver and reach the peripheral tissues through systemic circulation.

The changes observed in bile acids in liver disease have been detailed in Supplementary File 1 — 1. It affects the innate immunity in other organs and is responsible for secretion of inflammation mediators like serum IL-6 and the acute phase protein CRP 64 , 65 in.

Thus, it is important to understand the role of gut microbiome, the biosynthesized metabolites in liver and the overall effects on distal organs. Hepatic encephalopathy HE , linking brain function with liver diseases, involves a vast range of neurological and psychiatric abnormalities, ranging from subclinical alterations to coma HE has often been observed as one of the major complications in individuals with hepatic insufficiency which includes diseases like liver cirrhosis and fibrosis Having seen the link between the gut and liver, it is important to view this connection with respect to brain pathophysiology as observed in HE, i.

Gut—Liver—Brain axis. Gut microbial products like ammonia and oxindole, obtained after metabolism of amino acids, are deleterious for brain 12 Fig.

Oxindole functions as a sedative by acting as a ligand for voltage operated sodium channels in the brain. Ammonia functions by influencing neurotransmission, pH, membrane potential, astrocyte swelling, etc.

Liver diseases like cirrhosis are often associated with insufficiency in detoxification of ammonia and indole derivatives by the liver 10 , The reduction in clearance of ammonia from portal vein in cirrhotic patients is accompanied by higher ammonia uptake by brain astrocytes which has been associated to neurological symptoms Fig.

Ammonia is primarily formed in gastrointestinal tract by the action of glutaminase or urease enzymes as well as metabolism of other nitrogen-rich compounds This ammonia gets into portal circulation and reaches the liver where it is further detoxified by urea cycle. Individuals with portosystemic shunts or liver failure often have compromised liver detoxification abilities which lead to excessive accumulation of nitrogen wastes in systemic circulation Fig.

Excess ammonia is likely to cross blood brain barrier and be absorbed into astrocytes where it possibly gets converted to glutamine Glutamine thus formed may cause oxidative or osmotic stress and astrocyte swelling, further manifesting as cerebral edema and increased GABAergic activity Fig.

Impairment of liver urea cycle in liver disease condition leads to increase in uremic toxins and ammonia which reach the brain and affect neurotransmitter signaling and astrocyte swelling.

Systemic inflammation and sepsis have also been considered as factors which are involved in exacerbation of HE HE patients often show higher occurrence of inflammatory cytokines like IL-6, IL and TNFα The presence of systemic and local inflammation has been shown to augment the effect of hyperammonemia in HE.

Proinflammatory cytokines can be produced in brain, thereby giving rise to neuroinflammation Systemic inflammation can occur in case of liver cirrhosis due to multiple factors, one of them being increase in intestinal permeability which can lead to translocation of bacteria and their products into systemic circulation These bacteria along with their PAMPs help in activating the immune response with release of pro-inflammatory cytokines.

The loss in gut barrier integrity in case of liver failure can happen due to factors like reduction in formation of tight junction proteins, reduction in SCFA levels, dysbiosis in gut, endotoxemia, etc.

Systemic inflammation and hyperammonemia may lead to activation of resident macrophages in central nervous system called microglial cells This may result in formation of brain derived proinflammatory cytokines and result in neuronal death. Hepatic failure is often linked to kidney dysfunction or chronic kidney disease CKD A study in showed that Similarly, there is a correlation between loss of kidney function and dyslipidemia NAFLD leads to lipid accumulation, often involved in aggravating insulin resistance, inflammation, hypertension and obesity, which in turn may influence kidney dysfunction Increase in biosynthesis of pro-inflammatory, pro-thrombotic factors in NAFLD may contribute towards renal damage Further, changes in the expression of hepatic lipase lead to high triglyceride levels.

Levels of Apolipoprotein B containing lipoproteins biosynthesized in liver also show abnormalities in CKD patients Systemic inflammation during CKD can cause multiple effects and contribute to NAFLD. Dysbiosis in gut microbiome or high level of proteins in diet lead to high protein fermentation in the gut, thereby giving rise to formation of ammonia, indole, p-cresol, etc.

While indole is formed by fermentation of tryptophan by intestinal bacteria, p-cresol is formed by decarboxylation of 4-hydroxyphenylacetic acid which is a product of tyrosine degradation by host enzyme 80 , These products are absorbed by intestinal mucosa and taken to the liver where they are further modified by host sulfotransferases or glucoronotransferases to give rise to indoxyl-sulfate, indoxyl glucuronate, p-cresyl-sulfate, and p-cresyl-glucuronate, all of which are uremic toxins These toxins move into systemic circulation and are cleared from the system by renal filtration.

Such toxins also affect the progression of renal ailments and are observed to be elevated in patients with CKD and end stage renal disease ESRD 82 Fig. The uremic toxins are expected to act as agonists of aryl hydrocarbon receptor AhR and influence release of pro-inflammatory cytokines as well as increase inflammation and oxidative stress The observed alterations in expression of genes like hepatic cytochrome P CYP and drug transporter function are expected since these genes have AhR sites on their promoters This leads to changes in drug metabolism in hepatocytes Fig.

In patients with CKD and advanced liver disease or cirrhosis, the activity of enzymes responsible for modification in liver sulfotransferases is lowered and could contribute towards reduction in the uremic toxin formation 82 Fig.

Thus, the amount of uremic toxins in the body in case of kidney damage is also influenced by the liver condition. Further, uremic toxins could have regulatory effects in liver Fig.

a Gut—Liver—kidney axis without liver damage: Oxindole and cresol produced by gut microbiome are converted to uremic toxins in liver. The uremic toxins reach kidneys through portal circulation.

b Gut—Liver—Kidney axis with liver damage: Oxindole and cresol produced in the gut are not converted to uremic toxins in liver. TMA produced by gut microbiome from choline metabolism is converted to TMAO in liver by flavin-like monooxygenases.

The TMAO is carried to kidneys by systemic circulation and cleared by glomerular filtration Further, a higher presence of TMAO is associated with liver ailments like NAFLD, NASH, liver cirrhosis, etc TMAO helps in suppression of bile acid mediated farnesoid X receptor signaling in liver, which in turn leads to aggravation in liver steatosis This indicates that change in TMAO levels during kidney dysfunction may also influence the physiology of liver.

An increase in innate immunity concomitant with an increase in inflammatory markers like C-reactive protein CRP has been associated with deterioration in lung function and exacerbation of diseases like Chronic Obstructive Pulmonary Disease COPD COPD refers to a lung disease that causes airflow blockage to the lungs and leads to breathing-related problems.

The prevalence of steatosis, NASH and fibrosis in COPD patients have been reported to be The higher innate immune response as well as pro-inflammatory markers like IL-6 have been correlated to pathophysiology of lung ailments The liver works as a site of immunomodulation with the mevalonate pathway playing a major role.

Statins which inhibits the mevalonate pathway in liver is observed to reduce the lung damage Lovastatin is seen to reduce deleterious effects of macrophage activation in mouse models.

In addition to mevalonate pathway, liver plays a crucial role in building up an innate immune response in terms of recruitment of macrophages and the neutrophils at the site of lung injury.

Studies on mouse model indicate its role in increasing release of IL-6 and acute phase proteins by alveolar macrophages These proteins are likely to generate chronic inflammation leading to activation of innate immunity in circulation as well as in lungs termed as innate immune hyper-responsiveness , especially in cases of injury as seen in diseases causing lung damage.

To assess possible link between diet and respiratory diseases, outcomes based on a study on ~, subjects indicate significant reduction in occurrence of COPD with intake of high-fiber diet comprising of whole food grains Evidences indicate the effect of dietary fibers on immunomodulation of innate immune response.

Epidemiological and clinical studies also suggest role of high-fiber diets in reducing systemic inflammation and leading to decrease markers of inflammation like CRP and IL-6 Some SCFAs get absorbed and enter portal circulation, thereby affecting organs like liver SCFAs function by modulating innate immune activation.

High-fiber diet is seen to reduce pulmonary inflammation in murine models. SCFAs influence the migration of neutrophils and macrophages via GPCR activation which helps in reducing pulmonary inflammatory response Furthermore, SCFAs inhibit the HMG-CoA reductase which catalyzes the rate limiting step of mevalonate pathway This inhibition enables reduction in inflammatory markers and lowering of the innate immune response.

This leads to a downstream inhibitory effect on the pro-inflammatory transcription factors NF-ĸB and signal transducer and activator of transcription Non-alcoholic fatty liver disease NAFLD is associated with a higher risk of cardiovascular disease CVD which includes coronary heart disease CHD , heart failure, stroke, and arrhythmia A follow up study on individuals with biopsy proven NAFLD and no incidence of CVD showed an occurrence of a cardiovascular event in 9.

Exposure to lipopolysaccharide and its binding to TLR4 lead to an inflammatory immune response with release of pro-inflammatory cytokines This process promotes LDL oxidation, formation of atherosclerotic plaques and thrombogenesis Dietary intake which are higher in choline, betaine or carnitine e.

red meat leads to formation of TMA by gut bacteria, which further gets converted to TMAO in liver 39 , 87 , The increase in TMAO levels is associated to liver as well as CV events Thus, TMAO can be considered as marker for a deteriorating liver condition or Cardiovascular health Higher TMAO levels and expression of pro-inflammatory cytokines TNF-α and IL-1β are observed to be accompanied with cardiac dysfunction in mouse models The inhibition of choline TMA lyase enzyme by chemicals like 3,3-dimethylbutanol DMB can prevent increase in TMA levels as well as other outcomes There exists a link between endothelial dysfunction and TMAO levels.

TMAO treatment carried out on human monocytic THP-1 cells and human umbilical vein endothelial cells HUVEC reveal an increase in monocyte adhesion which lead to increased expression of VCAM-1 Additionally, lipid metabolism is also regulated by TMAO which alters cholesterol and sterol metabolism Catabolism of cholesterol involves bile acid synthesizing enzyme Cyp7a1 catalyzing the rate limiting step.

TMAO lowers the expression of this enzyme which has been associated with atherosclerosis Supplementation of choline, carnitine or TMAO may decrease reverse cholesterol transport.

Further, TMAO influences the increase in expression of CD36 and SR-A1 scavenger receptors which leads to lipid accumulation and foam cell formation , These effects are induced by oxidative modification of LDL in presence of TMAO.

Some inconsistencies regarding link of plasma TMAO levels and CVDs still exist. For example, short- and long-term higher plasma TMAO levels are observed in people after bariatric surgery. The result is unexpected as high TMAO concentrations increase the CVD risk while the aim of bariatric surgery is to reduce CVD risk However, recording their diet and gut microbiome could have thrown some light on whether TMAO levels were found to be higher in subjects as a result of a surgery-induced change in gut microbiome or due to a greater ingestion of carnitine a TMA precursor which is often promoted as a weight loss inducing supplement.

There are also certain contrasting observations regarding role of TMAO in CVDs. Although, TMAO is shown to correlate with inflammatory markers and endothelial dysfunction, some studies indicate such associations only in case of HIV and type-II diabetes Few studies also indicate no significant correlation of TMAO levels with inflammatory marker CRP.

Protective role of TMAO in CVDs have also been reported. After carnitine supplementation, improvement is seen in some CVDs despite an increase in TMAO and TMA Food items like marine fish contain high levels of TMAO which are observed in circulation after dietary intake.

Despite that, studies on mice show that supplementation of fish oil along with a high fat diet alleviate damage caused by TMAO including increased glucose tolerance and inflammation of adipose tissue In summary, the Gut—Liver axis refers to bidirectional communication between gut, its microbiome and the liver.

The metabolites produced by gut microbiome are connected with liver through systemic circulation, portal circulation and the bile duct. While the metabolites produced in the gut influence immunity, metabolism and bile acid production, the bile acids produced in liver in turn regulate the gut microbial composition as well as gut epithelial barrier integrity.

Therefore, a dysbiosis in gut microbiome not only leads to a change in the bile acid pool within the host, but also often been observed in liver related pathophysiologies like NAFLD, NASH, ALD, etc.

Further, since some gut bacteria are capable of metabolizing bile acid, the bile acid pool determines and influences the composition of gut microbiome.

The shifting level of bile acids impacts the intestinal integrity and metabolism by affecting FXR signaling. Exposure of liver immune cells to metabolites like TMAO produced by gut bacteria can increase liver inflammation. Further, the liver regulates the innate immunity as well as metabolism of various toxins and metabolites in other organs.

In other words, a deterioration in liver condition can also impact the metabolism signaling and immunity in other important host organs. Hence, the Gut—Liver axis can be extended to distal organs like Gut—Liver—Brain, Gut—Liver—Kidney, Gut—Liver-Heart and Gut-Liver-Lung axes.

Findings from the Gut-Liver-X X being Brain or Kidney or Heart or Lung axes indicate potential of utilizing gut microbiome as diagnostic and therapeutic strategy for early detection and management of not only liver diseases, but also diseases effecting other organs e.

Identifying microbiome signatures which can be indicative of different health conditions is an active area of research.

An understanding of Gut—Liver axis and interactions with distal organs can further help in identifying probiotic and fecal transplant strategies as preventive therapeutic regimes for liver ailments. Although certain studies have indicated potential use of probiotics as a therapy for chronic liver diseases, long-term impacts as well as effects on host-microbiome balance have yet to be elucidated Supplementary Table 1.

Clinical trials with standardized dosage of probiotics and extended duration of administration along with regular follow-ups are necessary to confirm the efficacy of the probiotics in manipulating the Gut—Liver axis as well as understanding their impacts on other organs like brain, kidney, lung and heart.

Schmidt, T. The human gut microbiome: from association to modulation. Cell , — Article CAS PubMed Google Scholar.

Kho, Z. The human gut microbiome — a potential controller of wellness and disease. Anand, S. Diet, microbiota and gut-lung connection. Bajaj, J. Alcohol, liver disease and the gut microbiota.

Article PubMed Google Scholar. Kirpich, I. Gut-liver axis, nutrition, and non-alcoholic fatty liver disease. Article CAS PubMed PubMed Central Google Scholar. Milosevic, I. et al. Gut-liver axis, gut microbiota, and its modulation in the management of liver diseases: a review of the literature.

Toshikuni, N. Clinical differences between alcoholic liver disease and nonalcoholic fatty liver disease. World J. Article PubMed PubMed Central Google Scholar.

Gao, B. Inflammation in alcoholic and nonalcoholic fatty liver disease: friend or foe? Gastroenterology , — Tripathi, A. The gut-liver axis and the intersection with the microbiome. vom Dahl, S. Hepatic encephalopathy as a complication of liver disease. Ferenci, P. Hepatic encephalopathy.

Article Google Scholar. Mancini, A. Food Funct. Augustyn, M. Small intestinal bacterial overgrowth and nonalcoholic fatty liver disease. Fitriakusumah, Y.

The role of Small Intestinal Bacterial Overgrowth SIBO in Non-alcoholic Fatty Liver Disease NAFLD patients evaluated using Controlled Attenuation Parameter CAP Transient Elastography TE : a tertiary referral center experience.

They believe that this diet will stimulate a type of gut bacteria called Blautia producta, which produces a byproduct which causes liver injury. Li, Staveley-O'Carroll and fellow co-principal investigator R. Scott Rector, PhD , the Director of NextGen Precision Health Building and Interim Senior Associate Dean for Research — are part of NextGen Precision Health, an initiative to expand collaboration in personalized health care and the translation of interdisciplinary research for the benefit of society.

The Roy Blunt NextGen Precision Health building at MU anchors the overall initiative and expands collaboration between researchers, clinicians and industry partners in the state-of-the-art research facility.

Columbia, MO Contact. Copyright © — Curators of the University of Missouri. All rights reserved. DMCA and other copyright information. For website information, contact the Office of Communications.

Due to high demand, Dr Megan Rossi PhD, RD , award-winning gut health scientist at King's College London, is launching a new bloating masterclass that will include affordable, practical and science-backed solutions to help you master your bloating. Eat More, Live Well In her latest book, Dr Megan Rossi PhD, RD shares everything you need to know about boosting gut health and plant-based eating Learn more.

Eat Yourself Healthy Dr Megan Rossi explains how to feed your gut for a happier, healthier you using delicious, gut-boosting recipes Learn more. Bloating Masterclass now open! Book resources In Dr Megan Rossi's two books, you will find references to materials and assessments that can be downloaded here Learn more.

Tools My Gut Diary and Gut Health Assessments Booklet can help kickstart your gut health transformation Learn more. By The Gut Health Clinic team. What is NAFLD?

What are the symptoms? People with more advanced NAFLD may suffer from: A dull or aching pain in the top right of the tummy over the lower right side of the ribs Extreme tiredness Unexplained weight loss Weakness How is it diagnosed?

Potential interventions Probiotics and Prebiotics There is currently no standardized pharmacological treatment, and the only proven effective therapeutic strategy is lifestyle modification. Summary NAFLD is common and it may affect 1 in 5 people in the UK. Need extra support?

The Gut Health Clinic is here to help you wade through any complexities! The gut—liver axis and the intersection with the microbiome. Available from: doi Gut-Liver Axis, Gut Microbiota, and Its Modulation in the Management of Liver Diseases: A Review of the Literature. International Journal of Molecular Sciences.

Trust Your Gut: The Association of Gut Microbiota and Liver Disease. Role of Gut Dysbiosis in Liver Diseases: What Have We Learned So Far?. Function of Akkermansia Muciniphila in Obesity: Interactions with LipidMetabolism, Immune Response and Gut Systems. Abo-Amer, Y. Relationship between Helicobacter Pylori Infection and Nonalcoholic Fatty Liver Disease NAFLD in a DevelopingCountry: A Cross-Sectional Study.

Diabetes Metab. References Wijarnpreecha, K. Helicobacter Pyloriand Risk of Nonalcoholic Fatty Liver Disease: A Systematic Review and Meta-Analysis. The fecal mycobiome in non-alcoholic fatty liver disease.

J Hepatol. Nicoletti, A. IntestinalPermeability in the Pathogenesis of Liver Damage: From Non-Alcoholic Fatty Liver Disease to Liver Transplantation.

World J. Ma Y-Y. Effects of probiotics on nonalcoholic fatty liver disease: A meta-analysis. World Journal of Gastroenterology. Probiotic Therapy With VSL 3® in Patients With NAFLD: A Randomized Clinical Trial. Front Nutr.

doi: PMID: ; PMCID: PMC Nobili V, Alisi A, Musso G, Scorletti E, Calder PC, Byrne CD. Omega-3 fatty acids: Mechanisms of benefit and therapeutic effects in pediatric and adult NAFLD.

Crit Rev Clin Lab Sci. Vranešić Bender D, Nutrizio M, Jošić M, Ljubas Kelečić D, Karas I, Premužić M, Domislović V, Rotim C, Krznarić Ž. Nutritional status and nutrition quality in patients with non-alcoholic fatty liver disease. Acta Clin Croat ; 56 4 : Sofi, F.

Mediterranean diet and non-alcoholic fatty liver disease: New therapeutic option around the corner? World J Gastroenterol. View all articles. First Name.

An understanding of connections between gut microbiome and liver has provided important insights into the pathophysiology of liver diseases.

Since gut microbial dysbiosis increases gut permeability, the metabolites biosynthesized by them can reach the liver through portal circulation and affect hepatic immunity and inflammation.

The immune cells activated by these metabolites can also reach liver through lymphatic circulation. Liver influences immunity and metabolism in multiple organs in the body, including gut. It releases bile acids and other metabolites into biliary tract from where they enter the systemic circulation.

In this review, the bidirectional communication between the gut and the liver and the molecular cross talk between the host and the microbiome has been discussed. This review also provides details into the intricate level of communication and the role of microbiome in Gut-Liver-Brain, Gut-Liver-Kidney, Gut-Liver-Lung, and Gut-Liver-Heart axes.

These observations indicate a complex network of interactions between host organs influenced by gut microbiome. The role of gut microbial community microbiome in maintaining host health has gained a lot of attention in the recent past 1.

Scientific studies indicate links between dysbiosis or disturbance in microbiome and diseases that not only affect the gut, but also organs like brain, liver, lung, kidneys, etc.

The pathophysiology of diseases effecting distal organs has often been associated with gastrointestinal discomfort or disorders. The crosstalk between the gut microbiome and distal organs is being increasingly recognized and host-microbiome interactions are being delineated piece by piece 2 , 3.

The increasing socio-economic burden of various diseases associated with changes in gut microbiome suggest the importance of understanding the molecular events facilitating such interactions. Diseases affecting distal organ like liver e. Increase in fat cells in liver leads to a state known as fatty liver disease.

In both cases the observed pathological spectra may range from simple hepatic steatosis, steatohepatitis to liver cirrhosis 7. In cases where an accumulation of fat leads to inflammation and damage, an advanced form of non-alcoholic fatty liver disease NAFLD called as Non-alcoholic steatohepatitis NASH is observed.

Similarly, alcoholic steatohepatitis is the inflammatory state of Alcoholic liver disease ALD 8. Since, these liver associated diseases are linked with dysbiosis in gut microbiome, it is important to understand the mechanisms involved in the cross-talk between gut and liver.

Certain mechanisms govern the tight bidirectional communication between the gut and liver Fig. For example, metabolic machinery of the host and resident gut microbiome metabolize several exogenous dietary and environmental components as well as endogenous substrates like amino acids and bile acid.

The products generated during this process are carried to liver by portal vein, thereby influencing hepatic physiology 9. Similarly, the immune cells activated by several dietary compounds as well as metabolites from gut microbiome can enter lymphatic system and modulate immune responses in distal organ like the liver 9.

On the other hand, the liver communicates with the gut through the release of bile acids and other metabolites into biliary tract of the systemic circulation 9.

The release of bile salts by liver also helps to control unrestricted gut microbial growth 9. Translocation of metabolites and pathogen associated molecular patterns PAMPs biosynthesized by microbes in the gut through the portal circulation to liver where they exert multiple effects on liver health condition.

Liver dysfunction influences immunity and metabolism of not only the gut, but also other organs. For example, brain malfunction due to Hepatic encephalopathy HE as well as kidney disorders are often observed in people with liver ailments Hepatic encephalopathy HE leads to an impaired brain function often observed in patients with advanced liver diseases.

The factors like decreased metabolism of ammonia associated with liver failure have often been associated with occurrence of HE Similarly, cardiovascular diseases effecting heart and blood vessels CVD are seen to be associated with fatty liver and other liver disorders Thus, it is important to understand the mechanisms involved in the interaction of Gut—Liver axis with distal organs.

The beneficial effects of certain probiotics and Fecal Microbial Transfer FMT in liver diseases as well as ailments like HE and CVDs which are linked to Gut-Liver interaction with other organs further highlight the importance of the close-knit interaction of gut microbiome with host physiology.

The non- progressive form of these diseases e. NAFLD often involves fat accumulation in liver or steatosis, while the progressive form e. NASH is diagnosed by liver injury and inflammation steatohepatitis 9. Analysis of stool samples of 57 patients showed lower levels of Prevotella and higher Bacteroides as well as Ruminococcus are seen in the gut of patients with NASH at stage 2 fibrosis or higher as compared to those in control subjects with fibrosis stage 1 This indicates that gut microbiome changes are associated with severity of disease fibrosis stage 1 vs.

stage 2 in this case. Whole genome sequencing of gut microbial community obtained using stool samples indicates higher abundances of Escherichia coli and Bacteroides vulgatus in the gut of NAFLD patients in early 72 patients as well as advanced stages of fibrosis 14 patients Similarly, pediatric subjects suffering with NASH are seen to have higher occurrence of genus Escherichia as compared to obese non-NASH subjects 9.

Multiple studies on gut samples stool as well as biopsy of human as well as animal systems have indicated that while patients with ALD have an increased number of bacteria belonging to the family Enterobacteriaceae in their gut, they have lower abundances of genera Lactobacillus and Bacteroidetes 17 , Alterations in gut microbial community have also been observed in cirrhosis patients.

Interestingly, analysis of stool samples of 95 liver cirrhosis patients and 47 healthy controls indicated an invasion of oral microbes like Streptococcus and Veillonella into the small intestine is observed in cirrhosis patients 19 , Bacterial genera like Veillonella, Megasphaera, Dialister, Atopobium , and Prevotella are also found in higher abundances in biopsies of distal duodenum from 30 cirrhosis patients as compared to 28 healthy controls used in the study In addition to ascertaining the role of gut microbiome in liver diseases certain studies have indicated potential use of probiotics as a therapy for chronic liver diseases.

The outcomes of these therapeutic strategies differ in terms of their efficacy and long-term impacts as well as effects on host-microbiome balance have yet to be elucidated. some of these studies have been mentioned in Supplementary Table 1.

While most of these studies indicate a decrease in pro-inflammatory markers like cytokines, Lipopolysaccharides LPS etc. as well as improvement in liver lesions, few studies also indicate that no significant change is observed with the intake of probiotics in liver disease Supplementary Table 1.

The efficacy of a synbiotic combination of a prebiotic fructo-oligosaccharides and a probiotic Bifidobacterium animalis subsp.

lactis BB administered for 10—14 months on the gut microbiome, liver fat and fibrosis was studied as a part of a placebo controlled study called Insyte.

The study recruited 55 NAFLD patients with symbiotic administration while 49 were administered a placebo. The results indicated that although a gut microbiome change was observed, no significant changes in liver pathophysiology could be observed The intestinal barrier, comprising of tightly bound cells, ensures selective transfer of nutrients and restricts the movement of pathogenic organisms from the gut lumen into the host system The gut microbiome influences gut barrier integrity by either maintaining immune signaling mechanisms or by producing metabolites like short chain fatty acids SCFAs Thus, disturbances in any of these factors can lead to an increase in gut permeability.

For example, dysbiosis in gut microbiome in cases of inflammatory diseases or due to intake of high fat diet, alcohol and antibiotics can bring about loss of gut barrier integrity 24 , A compromised gut barrier integrity is likely to lead to translocation of microorganisms and microbes- derived molecules into the portal system Under such condition, these microbes as well as their biosynthesized metabolites can translocate to the liver from where they can be carried through the portal system to distal organs, thereby causing their inflammation and injury Fig.

Certain metabolites formed in the intestine may also directly interact with host factors in order to bring about exacerbation of liver disease 27 , The intestinal dysbiosis is accompanied by loss of gut barrier integrity and transfer of pathogen associated molecular patterns PAMPS to the portal circulation 29 Fig.

This leads to induction of pattern recognition receptors PRR like TOLL-like receptors and NOD-like receptors in liver cells, which results in activation of pro-inflammatory signaling cascades, which in turn bring about local inflammatory responses Toll-like receptors are one category of PRRs which are suppressed in healthy liver conditions 30 Fig.

This leads to an increase in the production of cytokines like Tumor Necrosis Factor α TNF α and Interleukin-1β, both of which are known to act on bacteria and viruses. An elevated TLR signaling and expression of these cytokines due to prolonged stimulation can worsen hepatic injury in several liver diseases For example, NASH is known to affect the levels of TLR2 lipopolysaccharide , TLR4 peptidoglycan , TLR5 flagellin , and TLR9 bacterial DNA , all of which are activated by microbial antigens, thereby leading to inflammatory signaling cascades Systemic levels of LPS, a component of Gram-negative bacteria, are higher in cases of liver diseases like NAFLD and NASH.

Injecting LPS in mice model for NAFLD enhances liver injury as well as elevates the expression of pro-inflammatory cytokines 32 , Wild type mice fed with high fat diet develop steatohepatitis with an increased TLR4 expression and proinflammatory cytokines 32 , Further, TLR4 mutants are resistant to LPS induced release of pro-inflammatory cytokines, thus confirming role of TLR4 signaling in NAFLD and NASH Presence of bacterial DNA which is higher in NASH patients leads to elevated expression of TLR9 in NASH models Experiments with TLR9-deficient models fed with choline-deficient amino acid-defined CDAA diet show lesser inflammation, steatosis or fibrosis as compared to those in wild type model TLR9 signaling affects expression of inflammasome in macrophages, thereby resulting in formation of proinflammatory IL-1β and enhancement of the progression of hepatic injury in NASH TLR2 interacts with such Gram-positive bacterial cell wall components like lipoteichoic acids and peptidoglycan.

Based on the experimental observations on mice models, insulin resistance induced by high fat diet can be prevented by inhibition of TLR2 signaling Although, MCD diet may lead to features of steatohepatitis, it helps in increasing the insulin sensitivity and promotes weight reduction.

On the other hand, high fat and CDAA diets lead to weight gain and insulin resistance TLR5 binds to bacterial flagellin and plays a protective role for the intestine.

TLR5-knockouts develop not only obesity and steatosis, but also display an imbalance in the gut microbiome Further, transfer of gut microbial communities from TLR5 knockout mice to WT germ-free mice gives rise to metabolic syndrome Thus, an interplay of gut microbiome and TLR5 probably contribute towards metabolic syndrome pathophysiology.

Several metabolites biosynthesised in the gut exert multiple effects in liver depicted in Fig. Choline, a dietary macronutrient, is involved in multiple physiological processes in liver, which include phospholipid biosynthesis phosphatidyl choline and other membrane lipids , cholesterol metabolism and enterohepatic circulation of bile and lipids 9.

Deficiency of choline in the diet leads to impairment in liver and brain function as well as metabolic processes and muscle movement.

Free choline is absorbed by small intestine which then either gets integrated into the membrane or is transferred to liver where it is likely to get converted to betaine, lecithin, etc Lesser availability of choline leads to accumulation of triglycerides due to lower formation of phosphatidyl choline by the host in liver, a factor which has been associated with NASH and also in the manifestation of NAFLD While a choline-deficient diet induces steatohepatitis, excess choline in diet exceeding the absorptive capacity of host moves to the large intestine to get assimilated to Trimethylamine TMA by gut microbes Supplementary File 1 — 1.

Another route for biosynthesis of TMA involves degradation of carnitine obtained from dietary sources like red meat and dairy products Supplementary File 1 — 1. The TMA thus formed is transferred to liver through portal circulation and gets converted to Trimethylamine Oxide TMAO , a component which has been implicated in multiple cardiometabolic disorders, hepatic diseases, etc Metabolites like short chain fatty acids SCFAs primarily include butyrate, propionate and acetate and are formed in the large intestine as a result of dietary assimilation of polysaccharides, resistant starch, fiber, etc The SCFAs work as nutrient and energy source for intestinal epithelium and act as precursors for lipogenesis and gluconeogenesis The butyrate level in the gut helps in maintaining the intestinal integrity as well as permeability A decrease in butyrate is observed in several liver ailments and alcohol influenced liver injuries SCFAs bind and activate G-protein coupled receptors GPCRs GPR41 and GPR43 This activation influences peptide-YY secretion as well as causes inhibition of gut motility, thereby increasing the nutrient utilization and yielding of energy.

The signaling across GPR41 and GPR43 leads to secretion of GLP1 which in turn reduces the food intake as well as emptying of gastric tract Further, GPCR signaling also affects regulation of fatty acid oxidation and insulin sensitivity by hepatocytes.

Apart from this, GPR43 activation also leads to inhibition of lipolysis and reduced plasma fatty acids In addition to GPCR-based signaling, SCFAs can reach the liver through the portal circulation and can have either beneficial or deleterious effects on the liver.

For example, increased acetate can be channeled to fatty acid biosynthesis pathway, thereby leading to triglyceride accumulation which has often been correlated to liver ailments 41 , Similarly, propionate which acts as a precursor for gluconeogenesis has also been associated to NAFLD 41 , On the other hand, butyrate may utilize multiple mechanisms to reduce the pathophysiology associated with liver diseases.

AMPK further suppresses lipogenic genes AMPK expression in liver regulated by butyrate reduces insulin resistance and obesity. Administration of SCFAs has beneficial effects like reduction in hepatic steatosis and insulin resistance On the contrary, while enrichment of formate and acetate are found in adult subjects at advanced stages of NAFLD, butyrate and propionate are seen to be higher in mild NAFLD These differences in overall functioning of SCFAs in liver diseases may be affected by factors like diet and environment.

Ethanol is absorbed mostly in stomach and small intestine via diffusion by gastrointestinal mucosa Majority of ethanol in large intestine is obtained from systemic circulation. Some of the gut microbes can convert ethanol to acetaldehyde and to lesser extent acetate using alcohol metabolizing enzymes such as alcohol dehydrogenase Liver also expresses enzymes for ethanol metabolism in response to systemic ethanol content Interestingly, while certain small amounts of ethanol are observed in the bloodstream of subjects who do not consume alcohols, pediatric subjects with NASH are seen to possess higher serum ethanol levels as compared to obese children without NASH These levels of ethanol could be contributed by metabolism by the gut microbiome Consumption of ethanol is likely to add to the pathophysiology of liver diseases NASH, NAFLD, etc.

since it may cause not only an increase in intestinal permeability, but also may assist in production of inflammatory cytokines Endogenous ethanol can increase availability of acetate, a precursor of triglyceride formation through mechanisms involving inhibition of TCA cycle Ethanol oxidation by CYP2E1 can lead to production of free radicals which is likely to elevate inflammation Apart from this, ethanol can be metabolized to acetaldehyde which may either disrupt the tight junctions in the intestinal epithelium 55 or may have oxidant-dependent cytotoxic and metabolic effect on intestinal goblet like cells Oxidation of cholesterol to form primary bile acids, cholic acid, and chenodeoxycholic acid takes place in the hepatocytes through a multi-step process These bile acids are further conjugated to glycine or taurine which function as fat emulsifiers in the duodenum for solubilizing fats The released bile acids enter canaliculi through an export pump and move to the gallbladder where they get stored The bile acids are released into the duodenum upon consumption of food as a response to increase in production of cholecystokinin The intestinal microbiome converts these primary bile acids to secondary bile acids such as deoxycholic, lithocholic, and ursodeoxycholic acids Chenodeoxycholic acid CDCA activates FXR signaling, which in turn helps in not only regulating glucose levels and metabolism increase insulin sensitivity, glycogen synthesis and inhibit gluconeogenic genes , but also influences cholesterol transport, inhibits lipogenesis and enhances fatty acid oxidation Bile acids also lead to reduction in expression of lipogenic genes as well as help in reducing triglyceride levels by activating FXR and the pathway involving small heterodimer partner SHP and the sterol regulatory element-binding protein 1 SREBP-1 FXR also increases the proliferator-activated receptor alpha PPARalpha expression which in turn exerts anti-inflammatory effects and regulates lipid as well as glucose metabolism A small fraction of reabsorbed bile acids is likely to escape uptake into liver and reach the peripheral tissues through systemic circulation.

The changes observed in bile acids in liver disease have been detailed in Supplementary File 1 — 1. It affects the innate immunity in other organs and is responsible for secretion of inflammation mediators like serum IL-6 and the acute phase protein CRP 64 , 65 in.

Thus, it is important to understand the role of gut microbiome, the biosynthesized metabolites in liver and the overall effects on distal organs.

Hepatic encephalopathy HE , linking brain function with liver diseases, involves a vast range of neurological and psychiatric abnormalities, ranging from subclinical alterations to coma HE has often been observed as one of the major complications in individuals with hepatic insufficiency which includes diseases like liver cirrhosis and fibrosis Having seen the link between the gut and liver, it is important to view this connection with respect to brain pathophysiology as observed in HE, i.

Gut—Liver—Brain axis. Gut microbial products like ammonia and oxindole, obtained after metabolism of amino acids, are deleterious for brain 12 Fig. Oxindole functions as a sedative by acting as a ligand for voltage operated sodium channels in the brain.

Ammonia functions by influencing neurotransmission, pH, membrane potential, astrocyte swelling, etc. Liver diseases like cirrhosis are often associated with insufficiency in detoxification of ammonia and indole derivatives by the liver 10 , The reduction in clearance of ammonia from portal vein in cirrhotic patients is accompanied by higher ammonia uptake by brain astrocytes which has been associated to neurological symptoms Fig.

Ammonia is primarily formed in gastrointestinal tract by the action of glutaminase or urease enzymes as well as metabolism of other nitrogen-rich compounds This ammonia gets into portal circulation and reaches the liver where it is further detoxified by urea cycle.

Individuals with portosystemic shunts or liver failure often have compromised liver detoxification abilities which lead to excessive accumulation of nitrogen wastes in systemic circulation Fig.

Excess ammonia is likely to cross blood brain barrier and be absorbed into astrocytes where it possibly gets converted to glutamine Glutamine thus formed may cause oxidative or osmotic stress and astrocyte swelling, further manifesting as cerebral edema and increased GABAergic activity Fig.

Impairment of liver urea cycle in liver disease condition leads to increase in uremic toxins and ammonia which reach the brain and affect neurotransmitter signaling and astrocyte swelling. Systemic inflammation and sepsis have also been considered as factors which are involved in exacerbation of HE HE patients often show higher occurrence of inflammatory cytokines like IL-6, IL and TNFα The presence of systemic and local inflammation has been shown to augment the effect of hyperammonemia in HE.

Proinflammatory cytokines can be produced in brain, thereby giving rise to neuroinflammation Systemic inflammation can occur in case of liver cirrhosis due to multiple factors, one of them being increase in intestinal permeability which can lead to translocation of bacteria and their products into systemic circulation These bacteria along with their PAMPs help in activating the immune response with release of pro-inflammatory cytokines.

The loss in gut barrier integrity in case of liver failure can happen due to factors like reduction in formation of tight junction proteins, reduction in SCFA levels, dysbiosis in gut, endotoxemia, etc.

Systemic inflammation and hyperammonemia may lead to activation of resident macrophages in central nervous system called microglial cells This may result in formation of brain derived proinflammatory cytokines and result in neuronal death.

Hepatic failure is often linked to kidney dysfunction or chronic kidney disease CKD A study in showed that Similarly, there is a correlation between loss of kidney function and dyslipidemia NAFLD leads to lipid accumulation, often involved in aggravating insulin resistance, inflammation, hypertension and obesity, which in turn may influence kidney dysfunction Increase in biosynthesis of pro-inflammatory, pro-thrombotic factors in NAFLD may contribute towards renal damage Further, changes in the expression of hepatic lipase lead to high triglyceride levels.

Levels of Apolipoprotein B containing lipoproteins biosynthesized in liver also show abnormalities in CKD patients Systemic inflammation during CKD can cause multiple effects and contribute to NAFLD. Dysbiosis in gut microbiome or high level of proteins in diet lead to high protein fermentation in the gut, thereby giving rise to formation of ammonia, indole, p-cresol, etc.

While indole is formed by fermentation of tryptophan by intestinal bacteria, p-cresol is formed by decarboxylation of 4-hydroxyphenylacetic acid which is a product of tyrosine degradation by host enzyme 80 , These products are absorbed by intestinal mucosa and taken to the liver where they are further modified by host sulfotransferases or glucoronotransferases to give rise to indoxyl-sulfate, indoxyl glucuronate, p-cresyl-sulfate, and p-cresyl-glucuronate, all of which are uremic toxins These toxins move into systemic circulation and are cleared from the system by renal filtration.

Such toxins also affect the progression of renal ailments and are observed to be elevated in patients with CKD and end stage renal disease ESRD 82 Fig. The uremic toxins are expected to act as agonists of aryl hydrocarbon receptor AhR and influence release of pro-inflammatory cytokines as well as increase inflammation and oxidative stress The observed alterations in expression of genes like hepatic cytochrome P CYP and drug transporter function are expected since these genes have AhR sites on their promoters This leads to changes in drug metabolism in hepatocytes Fig.

In patients with CKD and advanced liver disease or cirrhosis, the activity of enzymes responsible for modification in liver sulfotransferases is lowered and could contribute towards reduction in the uremic toxin formation 82 Fig.

Thus, the amount of uremic toxins in the body in case of kidney damage is also influenced by the liver condition. Further, uremic toxins could have regulatory effects in liver Fig. a Gut—Liver—kidney axis without liver damage: Oxindole and cresol produced by gut microbiome are converted to uremic toxins in liver.

The uremic toxins reach kidneys through portal circulation. b Gut—Liver—Kidney axis with liver damage: Oxindole and cresol produced in the gut are not converted to uremic toxins in liver. TMA produced by gut microbiome from choline metabolism is converted to TMAO in liver by flavin-like monooxygenases.

The TMAO is carried to kidneys by systemic circulation and cleared by glomerular filtration Further, a higher presence of TMAO is associated with liver ailments like NAFLD, NASH, liver cirrhosis, etc TMAO helps in suppression of bile acid mediated farnesoid X receptor signaling in liver, which in turn leads to aggravation in liver steatosis This indicates that change in TMAO levels during kidney dysfunction may also influence the physiology of liver.

An increase in innate immunity concomitant with an increase in inflammatory markers like C-reactive protein CRP has been associated with deterioration in lung function and exacerbation of diseases like Chronic Obstructive Pulmonary Disease COPD COPD refers to a lung disease that causes airflow blockage to the lungs and leads to breathing-related problems.

The prevalence of steatosis, NASH and fibrosis in COPD patients have been reported to be The higher innate immune response as well as pro-inflammatory markers like IL-6 have been correlated to pathophysiology of lung ailments The liver works as a site of immunomodulation with the mevalonate pathway playing a major role.

Statins which inhibits the mevalonate pathway in liver is observed to reduce the lung damage Lovastatin is seen to reduce deleterious effects of macrophage activation in mouse models. In addition to mevalonate pathway, liver plays a crucial role in building up an innate immune response in terms of recruitment of macrophages and the neutrophils at the site of lung injury.

Studies on mouse model indicate its role in increasing release of IL-6 and acute phase proteins by alveolar macrophages These proteins are likely to generate chronic inflammation leading to activation of innate immunity in circulation as well as in lungs termed as innate immune hyper-responsiveness , especially in cases of injury as seen in diseases causing lung damage.

To assess possible link between diet and respiratory diseases, outcomes based on a study on ~, subjects indicate significant reduction in occurrence of COPD with intake of high-fiber diet comprising of whole food grains Evidences indicate the effect of dietary fibers on immunomodulation of innate immune response.

Epidemiological and clinical studies also suggest role of high-fiber diets in reducing systemic inflammation and leading to decrease markers of inflammation like CRP and IL-6 Some SCFAs get absorbed and enter portal circulation, thereby affecting organs like liver SCFAs function by modulating innate immune activation.

High-fiber diet is seen to reduce pulmonary inflammation in murine models. SCFAs influence the migration of neutrophils and macrophages via GPCR activation which helps in reducing pulmonary inflammatory response Furthermore, SCFAs inhibit the HMG-CoA reductase which catalyzes the rate limiting step of mevalonate pathway This inhibition enables reduction in inflammatory markers and lowering of the innate immune response.

This leads to a downstream inhibitory effect on the pro-inflammatory transcription factors NF-ĸB and signal transducer and activator of transcription Non-alcoholic fatty liver disease NAFLD is associated with a higher risk of cardiovascular disease CVD which includes coronary heart disease CHD , heart failure, stroke, and arrhythmia A follow up study on individuals with biopsy proven NAFLD and no incidence of CVD showed an occurrence of a cardiovascular event in 9.

Exposure to lipopolysaccharide and its binding to TLR4 lead to an inflammatory immune response with release of pro-inflammatory cytokines This process promotes LDL oxidation, formation of atherosclerotic plaques and thrombogenesis Dietary intake which are higher in choline, betaine or carnitine e.

red meat leads to formation of TMA by gut bacteria, which further gets converted to TMAO in liver 39 , 87 , The increase in TMAO levels is associated to liver as well as CV events Thus, TMAO can be considered as marker for a deteriorating liver condition or Cardiovascular health Higher TMAO levels and expression of pro-inflammatory cytokines TNF-α and IL-1β are observed to be accompanied with cardiac dysfunction in mouse models The inhibition of choline TMA lyase enzyme by chemicals like 3,3-dimethylbutanol DMB can prevent increase in TMA levels as well as other outcomes There exists a link between endothelial dysfunction and TMAO levels.

TMAO treatment carried out on human monocytic THP-1 cells and human umbilical vein endothelial cells HUVEC reveal an increase in monocyte adhesion which lead to increased expression of VCAM-1 Additionally, lipid metabolism is also regulated by TMAO which alters cholesterol and sterol metabolism Catabolism of cholesterol involves bile acid synthesizing enzyme Cyp7a1 catalyzing the rate limiting step.

TMAO lowers the expression of this enzyme which has been associated with atherosclerosis Supplementation of choline, carnitine or TMAO may decrease reverse cholesterol transport.

Further, TMAO influences the increase in expression of CD36 and SR-A1 scavenger receptors which leads to lipid accumulation and foam cell formation , These effects are induced by oxidative modification of LDL in presence of TMAO. Some inconsistencies regarding link of plasma TMAO levels and CVDs still exist.

For example, short- and long-term higher plasma TMAO levels are observed in people after bariatric surgery. The result is unexpected as high TMAO concentrations increase the CVD risk while the aim of bariatric surgery is to reduce CVD risk However, recording their diet and gut microbiome could have thrown some light on whether TMAO levels were found to be higher in subjects as a result of a surgery-induced change in gut microbiome or due to a greater ingestion of carnitine a TMA precursor which is often promoted as a weight loss inducing supplement.

There are also certain contrasting observations regarding role of TMAO in CVDs. Although, TMAO is shown to correlate with inflammatory markers and endothelial dysfunction, some studies indicate such associations only in case of HIV and type-II diabetes Few studies also indicate no significant correlation of TMAO levels with inflammatory marker CRP.

Protective role of TMAO in CVDs have also been reported. After carnitine supplementation, improvement is seen in some CVDs despite an increase in TMAO and TMA Food items like marine fish contain high levels of TMAO which are observed in circulation after dietary intake. Despite that, studies on mice show that supplementation of fish oil along with a high fat diet alleviate damage caused by TMAO including increased glucose tolerance and inflammation of adipose tissue In summary, the Gut—Liver axis refers to bidirectional communication between gut, its microbiome and the liver.

The metabolites produced by gut microbiome are connected with liver through systemic circulation, portal circulation and the bile duct. While the metabolites produced in the gut influence immunity, metabolism and bile acid production, the bile acids produced in liver in turn regulate the gut microbial composition as well as gut epithelial barrier integrity.

Therefore, a dysbiosis in gut microbiome not only leads to a change in the bile acid pool within the host, but also often been observed in liver related pathophysiologies like NAFLD, NASH, ALD, etc.

Further, since some gut bacteria are capable of metabolizing bile acid, the bile acid pool determines and influences the composition of gut microbiome.

The shifting level of bile acids impacts the intestinal integrity and metabolism by affecting FXR signaling. Exposure of liver immune cells to metabolites like TMAO produced by gut bacteria can increase liver inflammation.

Further, the liver regulates the innate immunity as well as metabolism of various toxins and metabolites in other organs. In other words, a deterioration in liver condition can also impact the metabolism signaling and immunity in other important host organs. Hence, the Gut—Liver axis can be extended to distal organs like Gut—Liver—Brain, Gut—Liver—Kidney, Gut—Liver-Heart and Gut-Liver-Lung axes.

Findings from the Gut-Liver-X X being Brain or Kidney or Heart or Lung axes indicate potential of utilizing gut microbiome as diagnostic and therapeutic strategy for early detection and management of not only liver diseases, but also diseases effecting other organs e.

Identifying microbiome signatures which can be indicative of different health conditions is an active area of research. An understanding of Gut—Liver axis and interactions with distal organs can further help in identifying probiotic and fecal transplant strategies as preventive therapeutic regimes for liver ailments.

Although certain studies have indicated potential use of probiotics as a therapy for chronic liver diseases, long-term impacts as well as effects on host-microbiome balance have yet to be elucidated Supplementary Table 1.

Clinical trials with standardized dosage of probiotics and extended duration of administration along with regular follow-ups are necessary to confirm the efficacy of the probiotics in manipulating the Gut—Liver axis as well as understanding their impacts on other organs like brain, kidney, lung and heart.

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