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Gut-derived systemic inflammation as a driver of depression in chronic liver disease

  • Victoria T. Kronsten
    Correspondence
    Corresponding author. Address: Institute of Liver Studies, 1st Floor James Black Centre, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King’s College London, 125 Coldharbour Lane, London, SE5 9NU, UK.
    Affiliations
    Institute of Liver Studies, 1st Floor James Black Centre, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King’s College London, 125 Coldharbour Lane, London, SE5 9NU, UK
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  • Thomas H. Tranah
    Affiliations
    Institute of Liver Studies, 1st Floor James Black Centre, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King’s College London, 125 Coldharbour Lane, London, SE5 9NU, UK
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  • Carmine Pariante
    Affiliations
    Institute of Psychiatry, Psychology and Neuroscience, King's College London, The Maurice Wohl Clinical Neuroscience Institute, Cutcombe Road, London, SE5 9RT, UK
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  • Debbie L. Shawcross
    Affiliations
    Institute of Liver Studies, 1st Floor James Black Centre, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King’s College London, 125 Coldharbour Lane, London, SE5 9NU, UK
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Published:November 16, 2021DOI:https://doi.org/10.1016/j.jhep.2021.11.008

      Summary

      Depression and chronic liver disease (CLD) are important causes of disability, morbidity and mortality worldwide and their prevalence continues to rise. The rate of depression in CLD is high compared to that of the general population and is comparable to the increased rates observed in other medical comorbidities and chronic inflammatory conditions. Notably, a comorbid diagnosis of depression has a detrimental effect on outcomes in cirrhosis. Systemic inflammation is pivotal in cirrhosis-associated immune dysfunction – a phenomenon present in advanced CLD (cirrhosis) and implicated in the development of complications, organ failure, disease progression, increased infection rates and poor outcome. The presence of systemic inflammation is also well-documented in a cohort of patients with depression; peripheral cytokine signals can result in neuroinflammation, behavioural change and depressive symptoms via neural mechanisms, cerebral endothelial cell and circumventricular organ signalling, and peripheral immune cell-to-brain signalling. Gut dysbiosis has been observed in both patients with cirrhosis and depression. It leads to intestinal barrier dysfunction resulting in increased bacterial translocation, in turn activating circulating immune cells, leading to cytokine production and systemic inflammation. A perturbed gut-liver-brain axis may therefore explain the high rates of depression in patients with cirrhosis. The underlying mechanisms explaining the critical relationship between depression and cirrhosis remain to be fully elucidated. Several other psychosocial and biological factors are likely to be involved, and therefore the cause is probably multifactorial. However, the role of the dysfunctional gut-liver-brain axis as a driver of gut-derived systemic inflammation requires further exploration and consideration as a target for the treatment of depression in patients with cirrhosis.

      Keywords

      Introduction

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      Prevalence of depression in chronic liver disease and its effect on outcome

      Depression and cirrhosis

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      Depression and non-alcoholic fatty liver disease

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      is well recognised, these studies importantly controlled for these confounders.
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      Depression is associated with non-alcoholic fatty liver disease among adults in the United States.
      Table 1Published studies analysing NAFLD and depression.
      Author (year)Study designPatientsNAFLD diagnosisPsychiatric assessmentFindings and significance
      Kim et al. (2019)
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      • Li A.A.
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      • Cholankeril G.
      • Harrison S.A.
      • et al.
      Depression is associated with non-alcoholic fatty liver disease among adults in the United States.
      Cross-sectional10,484 patients identified from a national databaseFLI, HSI, USFLIPHQ-9Prevalence of depression higher in patients with NAFLD.

      Patients with depression 1.6-2.2-fold more likely to have NAFLD.

      Depression was not associated with NAFLD-related advanced fibrosis.
      Labenz et al. (2020)
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      • Michel M.
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      • Kostev K.
      • et al.
      Nonalcoholic fatty liver disease increases the risk of anxiety and depression.
      Retrospective cohort19,871 patients with NAFLD, 19,871 matched controlsDatabase ICD-10 coding

      (NAFLD/NASH)
      Database ICD-10 code (depression)Within 10 years, 21.2% patients with NAFLD were diagnosed with depression, compared to 18.2% controls (p <0.001). HR for depression was 1.21 (p <0.001) and for first prescription of antidepressant medication (HR 1.21, p <0.001).
      Tomeno et al. (2015)
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      • Saito S.
      • Ogawa Y.
      • Honda Y.
      • et al.
      Non-alcoholic fatty liver disease comorbid with major depressive disorder: the pathological features and poor therapeutic efficacy.
      Prospective cohort258 patients with NAFLDHistologicalMDD diagnosis based on DSM-IV-TR. Stable/unstable based on being in full/partial remission as per DSM-IV-TR criteria12% comorbid with MDD. Patients with NAFLD and MDD had more severe histological steatosis, higher NAFLD score, high levels of AST, GGT and ferritin; they also had poorer response to standard of care for NAFLD, including weight loss.
      Weinstein et al. (2011)
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      • Stepanova M.
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      • Fang Y.
      • Moon J.
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      Depression in patients with nonalcoholic fatty liver disease and chronic viral hepatitis B and C.
      Cross-sectional878 patients with CLD (184 NAFLD, 190 HBV, 504 HCV)Pathology and/or radiologic testing (not specified)Self-reported depression (yes/no) and use of antidepressant medication23.6% of patients with CLD had a diagnosis of depression, 27.2% of NAFLD patients had a diagnosis of depression.
      Youssef et al. (2013)
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      • Binks M.
      • Guy C.D.
      • Omenetti A.
      • Smith A.D.
      • et al.
      Associations of depression, anxiety and antidepressants with histological severity of nonalcoholic fatty liver disease.
      Cross-sectional567 patients with NAFLDHistologicalHADSSubclinical and clinical depression observed in 53% and 14% of patients, respectively. Depression associated with more severe hepatocyte ballooning in dose-dependent manner.
      AST, aspartate aminotransferase; CLD, chronic liver disease; DSM-IV-TR, Diagnostic and Statistical Manual of Mental Disorders, fourth edition, Text Revision; FLI, Fatty Liver Index; GGT, gamma glutamyltransferase; HADS, Hospital Anxiety and Depression Scale; HR, hazard ratio; HSI, hepatic steatosis index; MDD, major depressive disorder; NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis; PHQ-9, Patient Health Questionnaire-9; USFLI, US Fatty Liver Index.

      Depression and other aetiologies of chronic liver disease

      Depression is also more common at the pre-cirrhotic level in other aetiologies of CLD. Depression is more common in patients with chronic HCV infection – independent of antiviral treatment use
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      Patients with cholestatic and autoimmune liver disease also exhibit higher rates of depression,
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      • et al.
      Health-related quality of life, depression, and anxiety in patients with autoimmune hepatitis.
      which may be related to their state of immune activation.
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      • Fontana A.
      Depression in autoimmune diseases.
      Fatigue is a common symptom of cholestatic liver disease and has profound effects on quality of life.
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      • Chrétien Y.
      • Chazouillères O.
      • Poupon R.
      • Chwalow J.
      Quality of life in patients with primary biliary cirrhosis.
      Fatigue is also a core symptom of depression. A study of 92 patients with primary biliary cholangitis (PBC) found that 42% of patients had depressive symptoms based on Beck Depression Inventory (BDI) criteria, but only 3.7% had depression based on DSM-IV criteria. This discrepancy is likely related to the fact that fatigue and other somatic symptoms are assessed in BDI scores but not DSM-IV, and therefore it is difficult to distinguish if fatigue in PBC is a manifestation of depression, or of the underlying liver disease.
      • Van Os E.
      • Van den Broek W.W.
      • Mulder P.G.
      • ter Borg P.C.
      • Bruijn J.A.
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      Depression in patients with primary biliary cirrhosis and primary sclerosing cholangitis.

      Factors involved in the pathophysiology of depression in cirrhosis

      Psychological and psychosocial mechanisms

      It has been suggested that patients with depression and cirrhosis have similar health behaviours, including alcohol use, smoking, poor diet and increased treatment non-adherence,
      • DiMatteo M.R.
      • Lepper H.S.
      • Croghan T.W.
      Depression is a risk factor for noncompliance with medical treatment.
      and have more difficult social circumstances.
      • Mullish B.H.
      • Kabir M.S.
      • Thursz M.R.
      • Dhar A.
      Review article: depression and the use of antidepressants in patients with chronic liver disease or liver transplantation.
      Some aetiologies of cirrhosis, such as HCV infection and alcohol misuse, have shared underlying roots with depression.
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      • Fergusson D.M.
      Alcohol and depression.
      ,
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      • Kent Kwoh C.
      Co-morbid medical and psychiatric illness and substance abuse in HCV-infected and uninfected veterans.
      Nevertheless, studies have revealed no significant differences in the prevalence of the main lifestyle variables that are a factor in the development of depression (education level, marital status, employment, income and social support level) in patients with cirrhosis and depression compared to those with cirrhosis alone.
      • Singh N.
      • Gayowski T.
      • Wagener M.M.
      • Marino I.R.
      Depression in patients with cirrhosis. Impact on outcome.

      Hepatic encephalopathy

      Hepatic encephalopathy (HE) is a frequent debilitating complication of cirrhosis and is defined as ‘brain dysfunction caused by liver insufficiency and/or portosystemic shunting’ that presents with a wide array of clinical symptoms ranging from disturbance of sleep/wake cycle, non-specific cognitive impairment and personality changes through to acute confusion and coma.
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      • Mullen K.D.
      • et al.
      Hepatic encephalopathy in chronic liver disease: 2014 practice guideline by the European association for the study of the liver and the American association for the study of liver diseases.
      Overt HE affects 20-40% of patients with cirrhosis during their disease trajectory,
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      • Pettenò E.
      • Mapelli D.
      • Angeli P.
      • Iemmolo R.
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      Prevalence and prognostic value of quantified electroencephalogram (EEG) alterations in cirrhotic patients.
      and severely impacts on health-related quality of life and survival.
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      • Ott P.
      • Andersen P.K.
      • Sørensen H.T.
      • Vilstrup H.
      Clinical course of alcoholic liver cirrhosis: a Danish population-based cohort study.
      Minimal HE requires the use of neurophysiological or psychometric testing to diagnose, as it is clinically undetectable.
      • Vilstrup H.
      • Amodio P.
      • Bajaj J.
      • Cordoba J.
      • Ferenci P.
      • Mullen K.D.
      • et al.
      Hepatic encephalopathy in chronic liver disease: 2014 practice guideline by the European association for the study of the liver and the American association for the study of liver diseases.
      HE and depression share a number of similar clinical signs and symptoms, including cognitive impairment, fatigue and psychomotor retardation, creating a diagnostic challenge. It is often difficult to recognise symptoms as a separate manifestation of the same condition or, conversely, to co-diagnose both conditions. Furthermore, studies involving SPECT (single photon emission computed tomography) have shown an overlap in the neuropathological origin of depression and HE.
      • Mullish B.H.
      • Kabir M.S.
      • Thursz M.R.
      • Dhar A.
      Review article: depression and the use of antidepressants in patients with chronic liver disease or liver transplantation.
      The literature on the association between HE and depression is conflicting, with some studies suggesting a positive association,
      • Barboza K.C.
      • Salinas L.M.
      • Sahebjam F.
      • Jesudian A.B.
      • Weisberg I.L.
      • Sigal S.H.
      Impact of depressive symptoms and hepatic encephalopathy on health-related quality of life in cirrhotic hepatitis C patients.
      • Hilsabeck R.C.
      • Hassanein T.I.
      • Carlson M.D.
      • Ziegler E.A.
      • Perry W.
      Cognitive functioning and psychiatric symptomatology in patients with chronic hepatitis C.
      • Malaguarnera M.
      • Bella R.
      • Vacante M.
      • Giordano M.
      • Malaguarnera G.
      • Gargante M.P.
      • et al.
      Acetyl-l-carnitine reduces depression and improves quality of life in patients with minimal hepatic encephalopathy.
      • Malaguarnera G.
      • Pennisi M.
      • Bertino G.
      • Motta M.
      • Borzì A.M.
      • Vicari E.
      • et al.
      Resveratrol in patients with minimal hepatic encephalopathy.
      • Stewart C.A.
      • Enders F.T.B.
      • Mitchell M.M.
      • Felmlee-Devine D.
      • Smith G.E.
      The cognitive profile of depressed patients with cirrhosis.
      • Telles-Correia D.
      • João Freire M.
      • Mega I.
      • Barreiras D.
      • Cortez Pinto H.
      Anxiety and depression symptoms in hepatic encephalopathy: are they psychiatric or organic?.
      • Weissenborn K.
      • Ennen J.C.
      • Schomerus H.
      • Rückert N.
      • Hecker H.
      Neuropsychological characterization of hepatic encephalopathy.
      • Xiao G.
      • Ye Q.
      • Han T.
      • Yan J.
      • Sun L.
      • Wang F.
      Study of the sleep quality and psychological state of patients with hepatitis B liver cirrhosis.
      whilst others refute this (Table 2).
      • Nardelli S.
      • Pentassuglio I.
      • Pasquale C.
      • Ridola L.
      • Moscucci F.
      • Merli M.
      • et al.
      Depression, anxiety and alexithymia symptoms are major determinants of health related quality of life (HRQoL) in cirrhotic patients.
      ,
      • Hassan E.A.
      • Abd El-Rehim A.S.
      • Seifeldein G.S.
      • Shehata G.A.
      Minimal hepatic encephalopathy in patients with liver cirrhosis: magnetic resonance spectroscopic brain findings versus neuropsychological changes.
      Whilst cerebral accumulation of ammonia is central to the pathophysiology of HE, systemic inflammation, which further exacerbates the toxic effect of ammonia on astrocytes, is also fundamental to its development.
      • Keiding S.
      • Sørensen M.
      • Bender D.
      • Munk O.L.
      • Ott P.
      • Vilstrup H.
      Brain metabolism of 13N-ammonia during acute hepatic encephalopathy in cirrhosis measured by positron emission tomography.
      • Norenberg M.D.
      A light and electron microscopic study of experimental portal systemic (ammonia) encephalopathy. Progression and reversal of the disorder.
      • Shawcross D.L.
      • Davies N.A.
      • Williams R.
      • Jalan R.
      Systemic inflammatory response exacerbates the neuropsychological effects of induced hyperammonemia in cirrhosis.
      Thus, whilst they are clearly separate clinical entities, systemic inflammation may be the common link between HE and depression.
      Gut dysbiosis causes increased intestinal permeability and bacterial translocation.
      Table 2Published studies analysing depression and hepatic encephalopathy in cirrhosis.
      Author (year)Study designPatientsPsychiatric assessmentNeuro-psychological assessmentFindings and significance
      Barboza et al. (2016)
      • Barboza K.C.
      • Salinas L.M.
      • Sahebjam F.
      • Jesudian A.B.
      • Weisberg I.L.
      • Sigal S.H.
      Impact of depressive symptoms and hepatic encephalopathy on health-related quality of life in cirrhotic hepatitis C patients.
      Observational43, HCV cirrhosisBDI-IID-KEFS TMT

      NCT

      WAIS-III
      Positive association between depressive symptoms and HE severity.
      Hassan et al. (2014)
      • Hassan E.A.
      • Abd El-Rehim A.S.
      • Seifeldein G.S.
      • Shehata G.A.
      Minimal hepatic encephalopathy in patients with liver cirrhosis: magnetic resonance spectroscopic brain findings versus neuropsychological changes.
      Case - control35, HCV cirrhosisHAM-DCASINo association between depression and mHE.
      Hilsabeck et al. (2003)
      • Hilsabeck R.C.
      • Hassanein T.I.
      • Carlson M.D.
      • Ziegler E.A.
      • Perry W.
      Cognitive functioning and psychiatric symptomatology in patients with chronic hepatitis C.
      Observational21, chronic HCVBDI-IIBVMT-R

      SDMT

      TMT

      WAIS-III
      Trend towards higher BDI-II scores in patients with more cognitive complaints.
      Malaguarnera et al. (2011)
      • Malaguarnera M.
      • Bella R.
      • Vacante M.
      • Giordano M.
      • Malaguarnera G.
      • Gargante M.P.
      • et al.
      Acetyl-l-carnitine reduces depression and improves quality of life in patients with minimal hepatic encephalopathy.
      Randomised double-blind placebo-controlled33 + 34 (placebo), cirrhosis and mHEBDIPHES

      TMT
      BDI score pre intervention indicative of moderate depression.
      Malaguarnera et al. (2018)
      • Malaguarnera G.
      • Pennisi M.
      • Bertino G.
      • Motta M.
      • Borzì A.M.
      • Vicari E.
      • et al.
      Resveratrol in patients with minimal hepatic encephalopathy.
      Randomised placebo-controlled, observational35 + 35 (placebo), cirrhosis and mHEBDIPHESBDI score pre intervention indicative of moderate depression.
      Nardelli et al. (2013)
      • Nardelli S.
      • Pentassuglio I.
      • Pasquale C.
      • Ridola L.
      • Moscucci F.
      • Merli M.
      • et al.
      Depression, anxiety and alexithymia symptoms are major determinants of health related quality of life (HRQoL) in cirrhotic patients.
      Observational60, cirrhosisZung-STHPHESNo differences in psychological test score between patients with or without minimal HE.
      Stewart et al. (2011)
      • Stewart C.A.
      • Enders F.T.B.
      • Mitchell M.M.
      • Felmlee-Devine D.
      • Smith G.E.
      The cognitive profile of depressed patients with cirrhosis.
      Observational75, cirrhosisBDI-IICVLT

      TMT

      WAIS-III
      Higher BDI-II scores in patients with decrease in cognitive function in domains of working memory.
      Telles-Correia et al. (2015)
      • Telles-Correia D.
      • João Freire M.
      • Mega I.
      • Barreiras D.
      • Cortez Pinto H.
      Anxiety and depression symptoms in hepatic encephalopathy: are they psychiatric or organic?.
      Observational60, cirrhosisHADSPHESNo correlation between HADS and PHES, but correlation between anhedonia, loss of energy and some parts of PHES.
      Xiao et al. (2018)
      • Xiao G.
      • Ye Q.
      • Han T.
      • Yan J.
      • Sun L.
      • Wang F.
      Study of the sleep quality and psychological state of patients with hepatitis B liver cirrhosis.
      Cross-sectional341, HBV cirrhosisHADSNCT-AHADS-D subscore higher in NCT-A positive patients.
      BDI, Beck Depression Inventory; BDI-II, Beck Depression Inventory second edition; BVMT-R, Brief Visuospatial Memory Test – Revised; CASI, Cognitive Abilities Screening Instrument; CVLT, California Verbal Learning Test; D-KEFS TMT, Delis-Kaplan Executive Function System Trail Making Test; HADS, Hospital Anxiety and Depression Scale; HAM-D, Hamilton Depression Rating Scale; HE, hepatic encephalopathy; mHE, minimal hepatic encephalopathy; NCT-A, Number Connection Test – A; NCT, Number Connection Test; PHES, Psychometric Hepatic Encephalopathy Score; SDMT, Symbol Digital Modalities Test; TMT, Trail Making Test; WAIS-III, Wechsler Adult Intelligence Scale third revision; Zung-STH, Zung Self Rating Depression Scale.

      Medications prescribed in cirrhosis

      Another postulation is that commonly prescribed medications in cirrhosis may be contributory to the high rates of depression observed. Notably, the antiviral agent interferon (IFN)-α, previously used to treat HCV, has a well-documented causal role in the development of depression.

      Sockalingam S, Abbey SE. Managing Depression During Hepatitis C Treatment n.d.

      However, major depression in chronic HCV has been demonstrated to be independent of antiviral treatment use.
      • Carta M.G.
      • Hardoy M.C.
      • Garofalo A.
      • Pisano E.
      • Nonnoi V.
      • Intilla G.
      • et al.
      Association of chronic hepatitis C with major depressive disorders: irrespective of interferon-alpha therapy.
      Though data regarding the association of beta-blockers, prescribed for primary or secondary prophylaxis for variceal bleeding, are conflicting, a recent systematic review of randomised controlled trials (RCTs) of beta-blockers vs. placebo revealed that patients on beta-blockers had lower rates of depression.
      • Barron A.J.
      • Zaman N.
      • Cole G.D.
      • Wensel R.
      • Okonko D.O.
      • Francis D.P.
      Systematic review of genuine versus spurious side-effects of beta-blockers in heart failure using placebo control: recommendations for patient information.
      Significant pharmacokinetic and pharmacodynamic changes occur in cirrhosis,
      • Lewis J.H.
      • Stine J.G.
      Review article: prescribing medications in patients with cirrhosis - a practical guide.
      and therefore there is significant concern amongst clinicians when considering antidepressants for patients with cirrhosis, owing to the potential risk of drug-induced liver injury and adverse events.
      • Mullish B.H.
      • Kabir M.S.
      • Thursz M.R.
      • Dhar A.
      Review article: depression and the use of antidepressants in patients with chronic liver disease or liver transplantation.
      Selective serotonin reuptake inhibitors (SSRIs) and selective noradrenergic reuptake inhibitors, particularly SSRIs, are safe and effective pharmacotherapeutic options to treat depression in cirrhosis, though the maintenance dose of some SSRIs should be halved due to prolonged half-life and reduced drug clearance.
      • Lewis J.H.
      • Stine J.G.
      Review article: prescribing medications in patients with cirrhosis - a practical guide.

      Unifying biological theories

      The increased prevalence of depression in liver disease, and its detrimental effect on patient outcome, cannot solely be explained by psychological and social factors, severity of liver disease and presence of HE.
      Increased rates of depression have been noted in most aetiologies of CLD, including NAFLD,
      • Kim D.
      • Yoo E.R.
      • Li A.A.
      • Tighe S.P.
      • Cholankeril G.
      • Harrison S.A.
      • et al.
      Depression is associated with non-alcoholic fatty liver disease among adults in the United States.
      ,
      • Labenz C.
      • Huber Y.
      • Michel M.
      • Nagel M.
      • Galle P.R.
      • Kostev K.
      • et al.
      Nonalcoholic fatty liver disease increases the risk of anxiety and depression.
      alcohol-related cirrhosis,
      • Ewusi-Mensah I.
      • Saunders J.B.
      • Wodak A.D.
      • Murray R.M.
      • Williams R.
      Psychiatric morbidity in patients with alcoholic liver disease.
      viral hepatitis
      • Carta M.G.
      • Hardoy M.C.
      • Garofalo A.
      • Pisano E.
      • Nonnoi V.
      • Intilla G.
      • et al.
      Association of chronic hepatitis C with major depressive disorders: irrespective of interferon-alpha therapy.
      ,
      • Barboza K.C.
      • Salinas L.M.
      • Sahebjam F.
      • Jesudian A.B.
      • Weisberg I.L.
      • Sigal S.H.
      Impact of depressive symptoms and hepatic encephalopathy on health-related quality of life in cirrhotic hepatitis C patients.
      and cholestatic and autoimmune liver disease.
      • Biagini M.R.
      • Tozzi A.
      • Milani S.
      • Grippo A.
      • Amantini A.
      • Capanni M.
      • et al.
      Fatigue in primary biliary cirrhosis: a possible role of comorbidities.
      ,
      • Schramm C.
      • Wahl I.
      • Weiler-Normann C.
      • Voigt K.
      • Wiegard C.
      • Glaubke C.
      • et al.
      Health-related quality of life, depression, and anxiety in patients with autoimmune hepatitis.
      These diseases vary considerably in their pathogenesis, and therefore the increased rates of depression observed in all suggest a unifying biological mechanism.
      • Mullish B.H.
      • Kabir M.S.
      • Thursz M.R.
      • Dhar A.
      Review article: depression and the use of antidepressants in patients with chronic liver disease or liver transplantation.
      Biological theories have centred on the dysregulated immune system and pro-inflammatory state observed in both depression
      • Miller A.H.
      • Maletic V.
      • Raison C.L.
      Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression.
      ,
      • Enache D.
      • Pariante C.M.
      • Mondelli V.
      Markers of central inflammation in major depressive disorder: a systematic review and meta-analysis of studies examining cerebrospinal fluid, positron emission tomography and post-mortem brain tissue.
      and cirrhosis.
      • Albillos A.
      • Lario M.
      • Álvarez-Mon M.
      Cirrhosis-associated immune dysfunction: distinctive features and clinical relevance.
      Indeed, it has been shown that an imbalance in the gut microbiome, and increased bacterial translocation, contribute to the similar inflammatory pathophysiology of both depression and cirrhosis.

      Role of the immune system and inflammation

      Cirrhosis-associated immune dysfunction

      Cirrhosis-associated immune dysfunction (CAID) describes key abnormalities observed in the immune system of patients with cirrhosis; firstly, acquired immunodeficiency with impaired response to pathogens, and secondly, overt systemic inflammation. Whilst innate immune dysfunction has mainly been described, adaptive immune defects have also been established.
      • Lebossé F.
      • Gudd C.
      • Tunc E.
      • Singanayagam A.
      • Nathwani R.
      • Triantafyllou E.
      • et al.
      CD8+ T cells from patients with cirrhosis display a phenotype that may contribute to cirrhosis-associated immune dysfunction.
      CAID describes a dynamic pattern; over time the immune response shifts from a pro-inflammatory to an anti-inflammatory compensatory response. CAID contributes to disease progression in cirrhosis, increases the propensity to develop infection and is associated with the progression to acute decompensation (AD) and acute-on-chronic liver failure (ACLF). Furthermore, CAID occurs across the spectrum of all aetiologies of cirrhosis.
      • Albillos A.
      • Lario M.
      • Álvarez-Mon M.
      Cirrhosis-associated immune dysfunction: distinctive features and clinical relevance.
      Systemic inflammation, in the absence of infection, is the hallmark of CAID and is likely instigated by bacterial translocation from the gut to the systemic circulation.
      • Woodhouse C.A.
      • Patel V.C.
      • Singanayagam A.
      • Shawcross D.L.
      Review article: the gut microbiome as a therapeutic target in the pathogenesis and treatment of chronic liver disease.
      Increased bacteria and resultant pathogen-associated molecular patterns (PAMPs), from enteric microbes, stimulate pattern recognition receptors (PRRs) on innate immune cells. Increased generation of damage-associated molecular patterns from necrotic liver cells also stimulates immune cells. Once stimulated, PRRs activate a transcriptional response inducing gene expression and the synthesis of pro-inflammatory cytokines, chemokines and cell adhesion molecules involved in the adaptive immune response.
      • Chen G.Y.
      • Nuñez G.
      Sterile inflammation: sensing and reacting to damage.
      Further activated PRR responses include: vascular endothelial injury,
      • Buck M.
      • Garcia-Tsao G.
      • Groszmann R.J.
      • Stalling C.
      • Grace N.D.
      • Burroughs A.K.
      • et al.
      Novel inflammatory biomarkers of portal pressure in compensated cirrhosis patients.
      acute phase protein synthesis in the liver,
      • Buck M.
      • Garcia-Tsao G.
      • Groszmann R.J.
      • Stalling C.
      • Grace N.D.
      • Burroughs A.K.
      • et al.
      Novel inflammatory biomarkers of portal pressure in compensated cirrhosis patients.
      leucocyte recruitment to sites of inflammation
      • Albillos A.
      • Lario M.
      • Álvarez-Mon M.
      Cirrhosis-associated immune dysfunction: distinctive features and clinical relevance.
      and augmented phagocytic activity. Such pathways lead to systemic inflammation, without overt sepsis, which carries a poor prognosis. There is a wealth of research data demonstrating evidence of systemic inflammation in cirrhosis including, but not limited to: increased serum levels of acute phase reactants (e.g. CRP) [72], increased serum levels of markers of endothelial activation (vascular endothelial growth factor, intercellular adhesion molecule-1, vascular cell adhesion molecule 1, nitrates/nitrites)
      • Albillos A.
      • Lario M.
      • Álvarez-Mon M.
      Cirrhosis-associated immune dysfunction: distinctive features and clinical relevance.
      ,
      • Buck M.
      • Garcia-Tsao G.
      • Groszmann R.J.
      • Stalling C.
      • Grace N.D.
      • Burroughs A.K.
      • et al.
      Novel inflammatory biomarkers of portal pressure in compensated cirrhosis patients.
      ,
      • Girón-González J.A.
      • Martínez-Sierra C.
      • Rodriguez-Ramos C.
      • Rendón P.
      • Macías M.A.
      • Fernández-Gutiérrez C.
      • et al.
      Adhesion molecules as a prognostic marker of liver cirrhosis.
      increased pro-inflammatory cytokine production (TNF-α, IL-17, IFN-γ) by circulating immune cells
      • Albillos A.
      • Lario M.
      • Álvarez-Mon M.
      Cirrhosis-associated immune dysfunction: distinctive features and clinical relevance.
      ,
      • Lemmers A.
      • Moreno C.
      • Gustot T.
      • Maréchal R.
      • Degré D.
      • Demetter P.
      • et al.
      The interleukin-17 pathway is involved in human alcoholic liver disease.
      and increased serum levels of pro-inflammatory cytokines (TNF-α, IFN-γ, IL-1β, IL-6, IL-17, IL-18).
      • Albillos A.
      • Lario M.
      • Álvarez-Mon M.
      Cirrhosis-associated immune dysfunction: distinctive features and clinical relevance.
      ,
      • Buck M.
      • Garcia-Tsao G.
      • Groszmann R.J.
      • Stalling C.
      • Grace N.D.
      • Burroughs A.K.
      • et al.
      Novel inflammatory biomarkers of portal pressure in compensated cirrhosis patients.
      • Girón-González J.A.
      • Martínez-Sierra C.
      • Rodriguez-Ramos C.
      • Rendón P.
      • Macías M.A.
      • Fernández-Gutiérrez C.
      • et al.
      Adhesion molecules as a prognostic marker of liver cirrhosis.
      • Lemmers A.
      • Moreno C.
      • Gustot T.
      • Maréchal R.
      • Degré D.
      • Demetter P.
      • et al.
      The interleukin-17 pathway is involved in human alcoholic liver disease.
      • Albillos A.
      • De La Hera A.
      • Reyes E.
      • Monserrat J.
      • Muñoz L.
      • Nieto M.
      • et al.
      Tumour necrosis factor-alpha expression by activated monocytes and altered T-cell homeostasis in ascitic alcoholic cirrhosis: amelioration with norfloxacin.
      • Lee F.Y.
      • Lu R.H.
      • Tsai Y.T.
      • Lin H.C.
      • Hou M.C.
      • Li C.P.
      • et al.
      Plasma interleukin-6 levels in patients with cirrhosis: relationship to endotoxemia, tumor necrosis factor-α, and hyperdynamic circulation.

      Non-alcoholic fatty liver disease and inflammation

      Whilst the detrimental role of systemic inflammation in cirrhosis of all aetiologies has been discussed, special mention is required in relation to NAFLD.
      NAFLD covers a spectrum of disease ranging from excessive fat accumulation/steatosis without necroinflammatory injury through significant hepatocellular injury and inflammation (non-alcoholic steatohepatitis [NASH]) to cirrhosis, and is closely related with obesity, insulin resistance (IR) and the components of the metabolic syndrome: hypertension, type 2 diabetes mellitus and dyslipidaemia.
      • Byrne C.D.
      • Targher G.
      NAFLD: a multisystem disease.
      Gut dysbiosis and systemic inflammation are present in cirrhosis and depression.
      Whilst the pathophysiology of NAFLD and the metabolic syndrome is outside the scope of this review, oxidative stress and inflammation appear key to their development. Chronic low-level inflammation in visceral adipose tissue, adipocyte dysfunction and IR impair lipid and glucose homeostasis in insulin-sensitive tissues,
      • Zafar U.
      • Khaliq S.
      • Ahmad H.U.
      • Manzoor S.
      • Lone K.P.
      Metabolic syndrome: an update on diagnostic criteria, pathogenesis, and genetic links.
      and the gene expression of adipose-derived inflammatory cytokines (such as TNF-α and IL-6) is increased in obese patients.
      • Mohammadi M.
      • Gozashti M.H.
      • Aghadavood M.
      • Mehdizadeh M.R.
      • Hayatbakhsh M.M.
      Clinical significance of serum IL-6 and TNF-α levels in patients with metabolic syndrome.
      Ectopic fat accumulates in NAFLD, and this is linked to increased hepatokine secretion, augmented gluconeogenesis, reduced glycogen synthesis and inhibition of insulin signalling.
      • Samuel V.T.
      • Liu Z.-X.
      • Qu X.
      • Elder B.D.
      • Bilz S.
      • Befroy D.
      • et al.
      Mechanism of hepatic insulin resistance in non-alcoholic fatty liver disease∗ downloaded from.
      Hepatokines, proteins that are secreted by hepatocytes, can manipulate metabolic processes through autocrine, paracrine and endocrine signalling.
      • Meex R.C.R.
      • Watt M.J.
      Hepatokines: linking nonalcoholic fatty liver disease and insulin resistance.
      Hepatic steatosis provokes changes in hepatokine secretion which result in metabolic dysfunction, promoting IR, and drive systemic inflammation by activating pro-inflammatory pathways.
      • Meex R.C.
      • Hoy A.J.
      • Morris A.
      • Brown R.D.
      • Lo J.C.
      • Burke M.
      • et al.
      Fetuin B is a secreted hepatocyte factor linking steatosis to impaired glucose metabolism.
      Levels of fetuin A, a glycoprotein present in the plasma, are increased in NAFLD and increase the risk of IR.
      • Meex R.C.R.
      • Watt M.J.
      Hepatokines: linking nonalcoholic fatty liver disease and insulin resistance.
      Fetuin A also stimulates the production of pro-inflammatory cytokines from adipocytes and macrophages.
      • Mukhopadhyay S.
      • Bhattacharya S.
      Plasma fetuin-A triggers inflammatory changes in macrophages and adipocytes by acting as an adaptor protein between NEFA and TLR-4.
      Excess hepatic lipid also adds to IR, and leads to oxidative stress, chronic inflammation and lipotoxicity, increasing the risk of fibrosis and cirrhosis development.
      • Shao M.
      • Ye Z.
      • Qin Y.
      • Wu T.
      Abnormal metabolic processes involved in the pathogenesis of non-alcoholic fatty liver disease (Review).
      Alongside hepatic lipid metabolism, adipose tissue dysfunction and inflammation, as in the metabolic syndrome, appear to be central to the development of NAFLD.
      • Byrne C.D.
      • Targher G.
      NAFLD: a multisystem disease.
      Many studies have demonstrated the increased levels of pro-inflammatory cytokines, including TNF-α and IL-6, in the development of NASH.
      • Bocsan I.C.
      • Milaciu M.V.
      • Pop R.M.
      • Vesa S.C.
      • Ciumarnean L.
      • Matei D.M.
      • et al.
      Cytokines genotype-phenotype correlation in nonalcoholic steatohepatitis.
      ,
      • Zahran W.E.
      • Salah El-Dien K.A.
      • Kamel P.G.
      • El-Sawaby A.S.
      Efficacy of tumor necrosis factor and interleukin-10 analysis in the follow-up of nonalcoholic fatty liver disease progression.
      Hepatocytes and immune cells produce TNF-α, which stimulates liver steatosis and activates Kupffer cells that promote liver fibrosis.
      • Shao M.
      • Ye Z.
      • Qin Y.
      • Wu T.
      Abnormal metabolic processes involved in the pathogenesis of non-alcoholic fatty liver disease (Review).
      IL-6, which is mainly secreted by adipose tissue, is involved in fatty acid metabolism and, whilst it protects against liver steatosis development, it may paradoxically stimulate hepatic inflammation.
      • Vida M.
      • Gavito A.L.
      • Pavoń F.J.
      • Bautista D.
      • Serrano A.
      • Suarez J.
      • et al.
      Chronic administration of recombinant IL-6 upregulates lipogenic enzyme expression and aggravates high-fat-diet-induced steatosis in IL-6-deficient mice.
      Hence, the systemic inflammation observed in NAFLD and NASH may be separate from that seen in CAID, and may therefore explain the increased rates of depression seen in NAFLD as well as NASH cirrhosis.

      Role of systemic inflammation in depression in cirrhosis

      Whilst the theory that the dysregulated immune system and overt systemic inflammation are key to the increased prevalence of depression in cirrhosis, there are few studies examining this (summarised in Table 3).
      Table 3Published studies examining the relationship between systemic inflammation, depression and liver disease.
      Author (year)Study designPatientsPsychiatric assessmentFindings and significance
      D’Mello et al. (2009)
      • D’Mello C.
      • Le T.
      • Swain M.G.
      Cerebral microglia recruit monocytes into the brain in response to tumor necrosis factora signaling during peripheral organ inflammation.
      Animal studyMouse model of inflammatory liver injury (BDL)Sickness behaviourIn the presence of hepatic inflammation, TNF-α signalling stimulated cerebral microglia to produce MCP-1/CCL2 to recruit monocytes into the brain. Inhibition of monocyte recruitment led to improvement in sickness behaviour of the mice.
      D’Mello et al. (2013)
      • D’Mello C.
      • Riazi K.
      • Le T.
      • Stevens K.M.
      • Wang A.
      • McKay D.M.
      • et al.
      P-selectin-mediated monocyte-cerebral endothelium adhesive interactions link peripheral organ inflammation to sickness behaviors.
      Animal studyMouse model of inflammatory liver injury (BDL)Sickness behaviourIncreased monocyte-specific rolling and adhesion along CECs was observed in mice with hepatic inflammation. Peripheral TNF-TNFR1 signalling and P-selectin were found to be central to monocyte-CEC adhesion, which led to microglial activation and development of sickness behaviour.
      Ko et al. (2013)
      • Ko F.Y.
      • Yang A.C.
      • Tsai S.J.
      • Zhou Y.
      • Xu L.M.
      Physiologic and laboratory correlates of depression, anxiety, and poor sleep in liver cirrhosis.
      Cross-sectional125 patients with cirrhosis (varying aetiologies)HAM-DHAM-D was correlated with AST, but not Child-Pugh score.
      Ko et al. (2013)
      • Ko F.-Y.
      • Tsai S.-J.
      • Yang A.C.
      • Zhou Y.
      • Xu L.-M.
      Association of CD8 T cells with depression and anxiety in patients with liver cirrhosis.
      Cross-sectional59 patients with cirrhosis (varying aetiologies)HAM-DThe percentage of CD8 T cells, but not CD3 nor CD4 cells, positively correlated with depression, after controlling for age and Child-Pugh score.
      AST, aspartate aminotransferase; BDL, bile duct ligated; CECs; cerebrovascular endothelial cells; HAM-D, Hamilton Depression Rating Scale; MCP-1/CCL2, monocyte chemoattractant protein-1; TNF-α, tumour necrosis factor alpha; TNFR1, tumour necrosis factor receptor 1.
      Hepatic and systemic inflammation have been shown to trigger neuroinflammation and depressive symptoms in two studies employing mouse models (Table 3),
      • D’Mello C.
      • Riazi K.
      • Le T.
      • Stevens K.M.
      • Wang A.
      • McKay D.M.
      • et al.
      P-selectin-mediated monocyte-cerebral endothelium adhesive interactions link peripheral organ inflammation to sickness behaviors.
      ,
      • D’Mello C.
      • Le T.
      • Swain M.G.
      Cerebral microglia recruit monocytes into the brain in response to tumor necrosis factora signaling during peripheral organ inflammation.
      however, human studies are lacking. Ko et al. (2013) demonstrated that depression scores correlate with serum levels of aspartate aminotransferase (AST) in patients with cirrhosis.
      • Ko F.Y.
      • Yang A.C.
      • Tsai S.J.
      • Zhou Y.
      • Xu L.M.
      Physiologic and laboratory correlates of depression, anxiety, and poor sleep in liver cirrhosis.
      AST is a cytoplasmic enzyme, its extracellular presence signals cell necrosis and, whilst not specific to the liver, suggests hepatic inflammation and damage. In a separate study, Ko et al. (2013) demonstrated that the percentage of CD8 T cells, but not CD3 or CD4 T cells, positively correlated with depression in patients with cirrhosis (Table 3).
      • Ko F.-Y.
      • Tsai S.-J.
      • Yang A.C.
      • Zhou Y.
      • Xu L.-M.
      Association of CD8 T cells with depression and anxiety in patients with liver cirrhosis.
      The functional state of T-lymphocytes often depends on T-lymphocyte subset percentage distribution, and they are involved in cell-mediated immunity. An imbalance in T-lymphocyte subsets may therefore facilitate depression in cirrhosis, potentially through increased pro-inflammatory cytokine release (such as TNF-α) or increased permeability of the BBB.
      • Huseby E.S.
      • Liggitt D.
      • Brabb T.
      • Schnabel B.
      • Öhlén C.
      • Goverman J.
      A pathogenic role for myelin-specific CD8+ T cells in a model for multiple sclerosis.
      Of note, studies have indicated that phenotypic and functional changes in CD8 T cells may contribute to CAID in patients with cirrhosis.
      • Lebossé F.
      • Gudd C.
      • Tunc E.
      • Singanayagam A.
      • Nathwani R.
      • Triantafyllou E.
      • et al.
      CD8+ T cells from patients with cirrhosis display a phenotype that may contribute to cirrhosis-associated immune dysfunction.
      Thus, the innate and adaptive immune system are activated in cirrhosis, resulting in a pro-inflammatory state, similar to that seen in depression.
      • Miller A.H.
      • Raison C.L.
      The role of inflammation in depression: from evolutionary imperative to modern treatment target.
      Whilst no published studies have compared the levels of pro-inflammatory cytokines in patients with cirrhosis, with and without depression, the main pro-inflammatory cytokines implicated in the development of depression (TNF-α, IL-1β and IL-6)
      • Enache D.
      • Pariante C.M.
      • Mondelli V.
      Markers of central inflammation in major depressive disorder: a systematic review and meta-analysis of studies examining cerebrospinal fluid, positron emission tomography and post-mortem brain tissue.
      ,
      • Maes M.
      • Meltzer H.Y.
      • Bosmans E.
      • Bergmans R.
      • Vandoolaeghe E.
      • Ranjan R.
      • et al.
      Increased plasma concentrations of interleukin-6, soluble interleukin-6, soluble interleukin-2 and transferrin receptor in major depression.
      • Penninx B.W.J.H.
      • Kritchevsky S.B.
      • Yaffe K.
      • Newman A.B.
      • Simonsick E.M.
      • Rubin S.
      • et al.
      Inflammatory markers and depressed mood in older persons: results from the health, aging and body composition study.
      • Thomas A.J.
      • Davis S.
      • Morris C.
      • Jackson E.
      • Harrison R.
      • O’Brien J.T.
      Increase in interleukin-1β in late-life depression.
      are notably raised in patients with cirrhosis.
      • Lee F.Y.
      • Lu R.H.
      • Tsai Y.T.
      • Lin H.C.
      • Hou M.C.
      • Li C.P.
      • et al.
      Plasma interleukin-6 levels in patients with cirrhosis: relationship to endotoxemia, tumor necrosis factor-α, and hyperdynamic circulation.
      ,
      • Solé C.
      • Solà E.
      • Morales-Ruiz M.
      • Fernàndez G.
      • Huelin P.
      • Graupera I.
      • et al.
      Characterization of inflammatory response in acute-on-chronic liver failure and relationship with prognosis.

      Pathway between peripheral and central inflammation

      The pathway between peripheral inflammation, neuroinflammation and clinical symptoms of depression remains to be fully elucidated.
      Systemic inflammation and oxidative stress increase BBB permeability driving neuroinflammation.
      • Dröge W.
      Free radicals in the physiological control of cell function.
      Animal models have identified three main cytokines, TNF-α, IL-1β and IL-6 (all of which are increased in cirrhosis)
      • Albillos A.
      • Lario M.
      • Álvarez-Mon M.
      Cirrhosis-associated immune dysfunction: distinctive features and clinical relevance.
      that enable peripheral to central communication in systemic inflammation. There are four well-documented pathways by which peripheral cytokines communicate with the brain; neural routes via peripheral afferent nerve fibre cytokine receptors (such as the vagus nerve),
      • Watkins L.R.
      • Maier S.F.
      • Goehler L.E.
      Cytokine-to-brain communication: a review & analysis of alternative mechanisms.
      permeable areas of the BBB such as circumventricular organs, peripheral immune cell-to-brain signalling and cerebrovascular endothelial cells (CECs).
      • D’Mello C.
      • Swain M.G.
      Immune-to-brain communication pathways in inflammation-associated sickness and depression.
      CECs at the BBB become activated by circulating peripheral inflammatory chemokines, resulting in pro-inflammatory mediator release into the brain. CECs have TNF-α and IL-1β receptors. Their activation generates intracerebral synthesis of nitric oxide and prostanoids
      • Schiltz J.C.
      • Sawchenko P.E.
      Signaling the brain in systemic inflammation: the role of perivascular cells.
      which, in turn, stimulate microglial cells and astrocytes.
      • Coltart I.
      • Tranah T.H.
      • Shawcross D.L.
      Inflammation and hepatic encephalopathy.
      In brief, these peripheral cytokine signals can then affect practically all central nervous system (CNS) fields involved in depression, including: neuroendocrine function (by activating the hypothalamic-pituitary-adrenal axis), neurotransmitter metabolism (serotonin, dopamine, noradrenaline, glutamate and kynurenine pathways), and neural plasticity.
      • Miller A.H.
      • Raison C.L.
      The role of inflammation in depression: from evolutionary imperative to modern treatment target.
      Furthermore, they can act directly on microglia and astrocytes, the CNS glial cells chiefly implicated in the neuroinflammation of depression.
      • Miller A.H.
      • Maletic V.
      • Raison C.L.
      Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression.
      Microglia are resident cerebral immune cells, essential for mounting a neuroinflammatory response and comprise 5-10% of total brain cells.
      • Kim S.U.
      • de Vellis J.
      Microglia in health and disease.
      When activated, microglia produce their own pro-inflammatory cytokines which, in health, are vital modulators of various CNS functions.
      • Beurel E.
      • Toups M.
      • Nemeroff C.B.
      The bidirectional relationship of depression and inflammation: double trouble.
      However, excessive pro-inflammatory cytokine activity in the brain disturbs many neuronal functions, including neurotransmitter signalling,
      • Deverman B.E.
      • Patterson P.H.
      Cytokines and CNS development.
      ,
      • Stephan A.H.
      • Barres B.A.
      • Stevens B.
      The complement system: an unexpected role in synaptic pruning during development and disease.
      ultimately affecting the neurocircuits involved in cognition and mood.
      • Dantzer R.
      • O’Connor J.C.
      • Freund G.G.
      • Johnson J.W.
      • Kelley K.W.
      From inflammation to sickness and depression: when the immune system subjugates the brain.

      Role of the gut microbiome

      There is growing evidence that the gut microbiome plays a central role in the development of the pro-inflammatory state observed in cirrhosis
      • Woodhouse C.A.
      • Patel V.C.
      • Singanayagam A.
      • Shawcross D.L.
      Review article: the gut microbiome as a therapeutic target in the pathogenesis and treatment of chronic liver disease.
      ,
      • Tranah T.H.
      • Edwards L.A.
      • Schnabl B.
      • Shawcross D.L.
      Targeting the gut-liver-immune axis to treat cirrhosis.
      and the microbiota-gut-brain axis is also proving increasingly important in the pathophysiology of depression.
      • Cryan J.F.
      • O’Riordan K.J.
      • Cowan C.S.M.
      • Sandhu K.V.
      • Bastiaanssen T.F.S.
      • Boehme M.
      • et al.
      The microbiota-gut-brain Axis.

      Gut-liver-immune axis and inflammation in chronic liver disease and cirrhosis

      Patients with cirrhosis have an imbalance between healthy and pathogenic bacteria that affects the structure and function of the microbiome, termed enteric dysbiosis, which is associated with impaired intestinal barrier function and dysregulated immune homeostasis.
      • Woodhouse C.A.
      • Patel V.C.
      • Singanayagam A.
      • Shawcross D.L.
      Review article: the gut microbiome as a therapeutic target in the pathogenesis and treatment of chronic liver disease.
      The gut microbiome has been implicated in the development of NAFLD; animal and human studies have revealed an association between intestinal dysbiosis and NAFLD and its severity.
      • Mouzaki M.
      • Comelli E.M.
      • Arendt B.M.
      • Bonengel J.
      • Fung S.K.
      • Fischer S.E.
      • et al.
      Intestinal microbiota in patients with nonalcoholic fatty liver disease.
      ,
      • Wigg A.J.
      • Roberts-Thomson I.C.
      • Grose R.H.
      • Cummins A.G.
      • Dymock R.B.
      • McCarthy P.J.
      The role of small intestinal bacterial overgrowth, intestinal permeability, endotoxaemia, and tumour necrosis factor α in the pathogenesis of non-alcoholic steatohepatitis.
      Patients with NAFLD have reduced microbial diversity, increased Firmicutes and reduced Bacteriodetes.
      • Mouzaki M.
      • Comelli E.M.
      • Arendt B.M.
      • Bonengel J.
      • Fung S.K.
      • Fischer S.E.
      • et al.
      Intestinal microbiota in patients with nonalcoholic fatty liver disease.
      Furthermore, the differential abundance of Firmicutes, Bacteriodetes and Proteobacteria phyla has been shown to predict advanced fibrosis in patients with NAFLD.
      • Loomba R.
      • Seguritan V.
      • Li W.
      • Long T.
      • Klitgord N.
      • Bhatt A.
      • et al.
      Gut microbiome-based metagenomic signature for non-invasive detection of advanced fibrosis in human nonalcoholic fatty liver disease.
      Gut-derived TNF-α, IL-1β and IL-6 can influence the brain resulting in depression.
      Gut microbiome modifications have been observed in patients with alcohol misuse, alcohol-related liver disease and alcohol-related cirrhosis.
      • Wang S.C.
      • Chen Y.C.
      • Chen S.J.
      • Lee C.H.
      • Cheng C.M.
      Alcohol addiction, gut microbiota, and alcoholism treatment: a review.
      Higher proportions of Enterobacteriaceae and lower proportions of Lachnospiraceae, Ruminococcaceae and Clostridiales XIV are observed in patients with alcohol-related cirrhosis.
      • Bajaj J.S.
      • Heuman D.M.
      • Hylemon P.B.
      • Sanyal A.J.
      • White M.B.
      • Monteith P.
      • et al.
      Altered profile of human gut microbiome is associated with cirrhosis and its complications.
      Chronic alcohol abuse can modulate faecal pH which encourages pathogen overgrowth and is also associated with alterations in metabolite secretions that affect gut microbiota function.
      • Wang S.C.
      • Chen Y.C.
      • Chen S.J.
      • Lee C.H.
      • Cheng C.M.
      Alcohol addiction, gut microbiota, and alcoholism treatment: a review.
      Alcohol use also impairs the function of the intestinal barrier. Alcohol and acetaldehyde, the toxic metabolite of alcohol, increase intestinal permeability by altering the expression of tight-junction proteins.
      • Ying W.
      • Jing T.
      • Bing C.
      • Baifang W.
      • Dai Z.
      • Bingyuan W.
      Effects of alcohol on intestinal epithelial barrier permeability and expression of tight junction-associated proteins.
      Patients with chronic alcohol use display higher levels of pro-inflammatory cytokines
      • Leclercq S.
      • De Saeger C.
      • Delzenne N.
      • De Timary P.
      • Stärkel P.
      Role of inflammatory pathways, blood mononuclear cells, and gut-derived bacterial products in alcohol dependenc.
      and are at greater risk of depression. The modified gut microbiome following alcohol use may result in increased bacterial translocation, an activated innate immune system, subsequent systemic inflammation and an increase in pro-inflammatory cytokines
      • Leclercq S.
      • De Saeger C.
      • Delzenne N.
      • De Timary P.
      • Stärkel P.
      Role of inflammatory pathways, blood mononuclear cells, and gut-derived bacterial products in alcohol dependenc.
      which signal to the brain and induce depressive symptoms.
      • D’Mello C.
      • Swain M.G.
      Immune-to-brain communication pathways in inflammation-associated sickness and depression.
      Patients with cirrhosis exhibit gut dysbiosis, encompassing a significantly reduced bacterial diversity, overexpression of pathogens such as Fusobacteria, Proteobacteria and Streptococaccae and reduction in species central to healthy microbiome function such as Bacteriodetes, Lachnospiracae and Firmicutes.
      • Chen Y.
      • Yang F.
      • Lu H.
      • Wang B.
      • Chen Y.
      • Lei D.
      • et al.
      Characterization of fecal microbial communities in patients with liver cirrhosis.
      ,
      • Qin N.
      • Yang F.
      • Li A.
      • Prifti E.
      • Chen Y.Y.
      • Shao L.
      • et al.
      Alterations of the human gut microbiome in liver cirrhosis.
      This dysbiosis worsens with more advanced disease.
      • Bajaj J.S.
      • Heuman D.M.
      • Hylemon P.B.
      • Sanyal A.J.
      • White M.B.
      • Monteith P.
      • et al.
      Altered profile of human gut microbiome is associated with cirrhosis and its complications.
      Patients with cirrhosis also exhibit small bowel bacterial overgrowth. Quantitative metagenomics have revealed that 75,245 microbial genes differ between patients with cirrhosis and healthy individuals.
      • Qin N.
      • Yang F.
      • Li A.
      • Prifti E.
      • Chen Y.Y.
      • Shao L.
      • et al.
      Alterations of the human gut microbiome in liver cirrhosis.
      Dysbiosis is greater in patients with cirrhosis who develop complications and correlates with plasma endotoxin levels and 30-day mortality.
      • Bajaj J.S.
      • Heuman D.M.
      • Hylemon P.B.
      • Sanyal A.J.
      • White M.B.
      • Monteith P.
      • et al.
      Altered profile of human gut microbiome is associated with cirrhosis and its complications.
      Cirrhotic dysbiosis encourages intestinal barrier dysfunction in cirrhosis, which allows pathogens to adhere to the mucosa and enables bacteria, their products (such as lipopolysaccharide, flagellin, peptidoglycan and bacterial DNA) and PAMPs to translocate into the portal circulation. The portal hypertension and endothelial dysfunction that develop in cirrhosis further increase this intestinal permeability.
      • Wiest R.
      • Garcia-Tsao G.
      Bacterial translocation (BT) in cirrhosis.
      Portal hypertension, in both patients with and without cirrhosis, results in venous congestion and splanchnic neoangiogenesis, which lead to impaired microcirculation and gut barrier dysfunction.
      • Reiberger T.
      • Ferlitsch A.
      • Payer B.A.
      • Mandorfer M.
      • Heinisch B.B.
      • Hayden H.
      • et al.
      Non-selective betablocker therapy decreases intestinal permeability and serum levels of LBP and IL-6 in patients with cirrhosis.
      Bacterial translocation leads to endotoxemia, and delivers gut-derived pathogens and their products directly to the liver, via the portal vein, activating the innate immune response.
      • Woodhouse C.A.
      • Patel V.C.
      • Singanayagam A.
      • Shawcross D.L.
      Review article: the gut microbiome as a therapeutic target in the pathogenesis and treatment of chronic liver disease.
      Portosystemic shunting in cirrhosis further enables direct delivery of immune-activating bacterial degradation products to the systemic circulation.
      • Cirera I.
      • Martin Bauer T.
      • Miguel N.
      • Vila J.
      • Grande L.
      • Taurá P.
      • et al.
      Bacterial translocation of enteric organisms in patients with cirrhosis.
      Endotoxins activate hepatic macrophages via toll-like receptors and stimulate the production of pro-inflammatory cytokines, including TNF-α and IL-8, which recruit monocytes and neutrophils to the liver.
      • Singh R.
      • Bullard J.
      • Kalra M.
      • Assefa S.
      • Kaul A.K.
      • Vonfeldt K.
      • et al.
      Status of bacterial colonization, Toll-like receptor expression and nuclear factor-kappa B activation in normal and diseased human livers.
      Ultimately this drives hepatic injury, systemic inflammation and CAID, promoting the development of infection, decompensation and disease progression.
      • Bajaj J.S.
      • Heuman D.M.
      • Hylemon P.B.
      • Sanyal A.J.
      • White M.B.
      • Monteith P.
      • et al.
      Altered profile of human gut microbiome is associated with cirrhosis and its complications.
      Research is now focused on restoring gut eubiosis, for example via faecal microbial transplantation (FMT), and repairing intestinal barrier function to prevent complications, infection and decompensation in patients with cirrhosis.
      • Tranah T.H.
      • Edwards L.A.
      • Schnabl B.
      • Shawcross D.L.
      Targeting the gut-liver-immune axis to treat cirrhosis.

      Microbiota-gut-brain axis and inflammation in depression

      The microbiota-gut-brain axis influences behaviour, and is also implicated in the development of depression. Most evidence has come from pre-clinical models
      • Dinan T.G.
      • Cryan J.F.
      Gut-brain axis in 2016: brain-gut-microbiota axis-mood, metabolism and behaviour.
      ; the absence of a gut microbiome induces depression-like behaviour in mice and germ-free mice transplanted with stool from patients with depression resulted in depression-like behaviours not seen with FMT of ‘healthy microbiota’ from controls.
      • Zheng P.
      • Zeng B.
      • Zhou C.
      • Liu M.
      • Fang Z.
      • Xu X.
      • et al.
      Gut microbiome remodeling induces depressive-like behaviors through a pathway mediated by the host’s metabolism.
      Human studies have also found significant differences in the gut microbiome in patients with depression compared to healthy individuals.
      • Cryan J.F.
      • O’Riordan K.J.
      • Cowan C.S.M.
      • Sandhu K.V.
      • Bastiaanssen T.F.S.
      • Boehme M.
      • et al.
      The microbiota-gut-brain Axis.
      ,
      • Aizawa E.
      • Tsuji H.
      • Asahara T.
      • Takahashi T.
      • Teraishi T.
      • Yoshida S.
      • et al.
      Possible association of Bifidobacterium and Lactobacillus in the gut microbiota of patients with major depressive disorder.
      • Jiang H.
      • Ling Z.
      • Zhang Y.
      • Mao H.
      • Ma Z.
      • Yin Y.
      • et al.
      Altered fecal microbiota composition in patients with major depressive disorder.
      • Naseribafrouei A.
      • Hestad K.
      • Avershina E.
      • Sekelja M.
      • Linløkken A.
      • Wilson R.
      • et al.
      Correlation between the human fecal microbiota and depression.
      However, there is disparity in their findings with one study noting that Bifidobacterium and Lactobacillus were reduced in patients with depression;
      • Aizawa E.
      • Tsuji H.
      • Asahara T.
      • Takahashi T.
      • Teraishi T.
      • Yoshida S.
      • et al.
      Possible association of Bifidobacterium and Lactobacillus in the gut microbiota of patients with major depressive disorder.
      another noting that Bacteroidetes, Proteobacteria, and Actinobacteria were increased, and Firmicutes were decreased in individuals with depression;
      • Jiang H.
      • Ling Z.
      • Zhang Y.
      • Mao H.
      • Ma Z.
      • Yin Y.
      • et al.
      Altered fecal microbiota composition in patients with major depressive disorder.
      and another noting that the family Lachnospiraceae was significantly decreased in patients with depression vs. healthy controls.
      • Naseribafrouei A.
      • Hestad K.
      • Avershina E.
      • Sekelja M.
      • Linløkken A.
      • Wilson R.
      • et al.
      Correlation between the human fecal microbiota and depression.
      Further studies have reported reduced microbial richness in patients with depression.
      • Cryan J.F.
      • O’Riordan K.J.
      • Cowan C.S.M.
      • Sandhu K.V.
      • Bastiaanssen T.F.S.
      • Boehme M.
      • et al.
      The microbiota-gut-brain Axis.
      Interestingly some of these changes, such as decreased Lachnospiraceae (involved in short-chain fatty acid [SCFA] production) and decreased microbial richness are similar to those observed in patients with cirrhosis.
      • Woodhouse C.A.
      • Patel V.C.
      • Singanayagam A.
      • Shawcross D.L.
      Review article: the gut microbiome as a therapeutic target in the pathogenesis and treatment of chronic liver disease.
      A recent observational study determined that patients with depression deemed non-responders to conventional treatment had a lower alpha diversity in the Phylogenetic diversity whole tree index during treatment, as well as increased microbiome glutamate synthesis, compared to responders.
      • Kurokawa S.
      • Tomizawa Y.
      • Miyaho K.
      • Ishii D.
      • Takamiya A.
      • Ishii C.
      • et al.
      Fecal microbial and metabolomic change during treatment course for depression: an observational study.
      The exact communication pathways between the gut microbiome and brain require further clarification, but the activated immune system is likely a significant pathway leading to depressive symptoms.
      • Cryan J.F.
      • O’Riordan K.J.
      • Cowan C.S.M.
      • Sandhu K.V.
      • Bastiaanssen T.F.S.
      • Boehme M.
      • et al.
      The microbiota-gut-brain Axis.
      Dysbiosis results in gut immune cell activation, cytokine production and increased permeability of intestinal mucosa, leading to increased translocation of bacteria.
      • Woodhouse C.A.
      • Patel V.C.
      • Singanayagam A.
      • Shawcross D.L.
      Review article: the gut microbiome as a therapeutic target in the pathogenesis and treatment of chronic liver disease.
      This triggers cytokine production by circulating immune cells, an exaggerated immune response and resultant neuroinflammation.
      Favourably modifying the gut microbiome may decrease inflammation and depression in cirrhosis.
      Together with the activation of the innate immune system, gut microbiota can produce a variety of metabolites, including neurotransmitters, secondary bile acids, choline, SCFAs, bacteriocins and branched-chain amino acids
      • Cryan J.F.
      • O’Riordan K.J.
      • Cowan C.S.M.
      • Sandhu K.V.
      • Bastiaanssen T.F.S.
      • Boehme M.
      • et al.
      The microbiota-gut-brain Axis.
      which are immunomodulatory. Mounting evidence suggests that microbiota-host interactions at the gut level result in cytokine, chemokine, neuropeptide, neurotransmitter, endocrine and by-product release that can travel via the systemic circulation and lymphatics, or communicate with the brain via the autonomic nervous system and influence behaviour.
      • Cryan J.F.
      • O’Riordan K.J.
      • Cowan C.S.M.
      • Sandhu K.V.
      • Bastiaanssen T.F.S.
      • Boehme M.
      • et al.
      The microbiota-gut-brain Axis.
      The effect of the gut microbiome on microglial homeostasis appears to be key to the microbiota-gut-brain axis and behavioural changes.
      • Erny D.
      • De Angelis A.L.H.
      • Jaitin D.
      • Wieghofer P.
      • Staszewski O.
      • David E.
      • et al.
      Host microbiota constantly control maturation and function of microglia in the CNS.
      The gut is the main source of serotonin in the body.
      • Erspamer V.
      Occurrence of indolealkylamines in nature.
      The gut microbiota may also be crucial in the regulation of tryptophan metabolism, affecting serotonin synthesis and downstream kynurenine pathway metabolism in both the periphery and the CNS, and consequently affecting behaviour and inducing depressive symptoms.
      • Kennedy P.J.
      • Cryan J.F.
      • Dinan T.G.
      • Clarke G.
      Kynurenine pathway metabolism and the microbiota-gut-brain axis.
      The vagus nerve, the principal component of the parasympathetic nervous system, is one of the vital modes of communication between the gut and the brain.
      • Long-Smith C.
      • O’Riordan K.J.
      • Clarke G.
      • Stanton C.
      • Dinan T.G.
      • Cryan J.F.
      Microbiota-gut-brain Axis: new therapeutic opportunities.
      Vagal afferent fibres are located in the gastrointestinal tract wall but do not cross the epithelium; thus, they are not in direct contact with gut microbiota.
      • Wang F.B.
      • Powley T.L.
      Vagal innervation of intestines: afferent pathways mapped with new en bloc horseradish peroxidase adaptation.
      Instead, metabolites can travel across the epithelial cell layer and act directly on vagus nerve afferent fibres to signal to the brain.
      • Fülling C.
      • Dinan T.G.
      • Cryan J.F.
      Gut microbe to brain signaling: what happens in vagus….
      The luminal wall is also richly innervated by the enteric nervous system, which is predominantly responsible for gut motility, and can be targeted by SCFAs and neurotransmitters.
      • Long-Smith C.
      • O’Riordan K.J.
      • Clarke G.
      • Stanton C.
      • Dinan T.G.
      • Cryan J.F.
      Microbiota-gut-brain Axis: new therapeutic opportunities.
      The implication of the gut microbiome in the pathophysiology of depression has led to the notion of psychobiotics – microbiota-targeted interventions, mainly focussing on prebiotics and probiotics, affecting the microbiota-gut-brain axis, used for the treatment of mental health and neurological disorders. Several bacterial strains or combinations, mainly containing Lactobacillus and Bifidobacterium species, have proved efficacious in multiple studies at treating psychiatric disorders, and have been shown to reduce depression scores and enhance cognition.
      • Cryan J.F.
      • O’Riordan K.J.
      • Cowan C.S.M.
      • Sandhu K.V.
      • Bastiaanssen T.F.S.
      • Boehme M.
      • et al.
      The microbiota-gut-brain Axis.
      ,
      • Akkasheh G.
      • Kashani-Poor Z.
      • Tajabadi-Ebrahimi M.
      • Jafari P.
      • Akbari H.
      • Taghizadeh M.
      • et al.
      Clinical and metabolic response to probiotic administration in patients with major depressive disorder: a randomized, double-blind, placebo-controlled trial.
      ,
      • Kazemi A.
      • Noorbala A.A.
      • Azam K.
      • Eskandari M.H.
      • Djafarian K.
      Effect of probiotic and prebiotic vs placebo on psychological outcomes in patients with major depressive disorder: a randomized clinical trial.
      Probiotics have been shown to reduce systemic levels of inflammatory biomarkers and pro-inflammatory cytokines.
      • Qin N.
      • Yang F.
      • Li A.
      • Prifti E.
      • Chen Y.Y.
      • Shao L.
      • et al.
      Alterations of the human gut microbiome in liver cirrhosis.
      FMT aims to restore the microbiome of an unhealthy individual to a healthy state, via faecal bacteria transfer from a healthy donor. Whilst the use of FMT is still in its infancy, a recent systematic review, analysing the effect of FMT on psychiatric disorder symptoms from 28 pre-clinical and clinical studies, found a decrease in depressive symptoms post FMT in all studies.
      • Meyyappan A.C.
      • Forth E.
      • Wallace C.J.K.
      • Milev R.
      Effect of fecal microbiota transplant on symptoms of psychiatric disorders: a systematic review.

      Targeting the gut microbiome and inflammation in depression and liver disease

      Probiotic administration has been shown to improve quality of life, symptom burden and infection rates, but not mortality, in patients with cirrhosis.
      • Dalal R.
      • Mcgee R.G.
      • Riordan S.M.
      • Webster A.C.
      Probiotics for people with hepatic encephalopathy.
      ,
      • Mittal V.V.
      • Sharma B.C.
      • Sharma P.
      • Sarin S.K.
      A randomized controlled trial comparing lactulose, probiotics, and L-ornithine L-aspartate in treatment of minimal hepatic encephalopathy.
      Furthermore, probiotic administration has been associated with a decrease in pro-inflammatory cytokine levels, such as TNF-α, in patients with CLD.
      • Dhiman R.K.
      • Rana B.
      • Agrawal S.
      • Garg A.
      • Chopra M.
      • Thumburu K.K.
      • et al.
      Probiotic VSL#3 reduces liver disease severity and hospitalization in patients with cirrhosis: a randomized, controlled trial.
      A pre-clinical study found that administering VSL#3 (a proprietary name for a group of 8 probiotics) improved ‘fatigue-like’ behaviours in mice with liver inflammation, independent of changes in the severity of liver injury. Furthermore, the mice treated with VSL#3 had decreased levels of TNFα which was linked to reduced microglial activation, monocyte:CEC interactions and cerebral monocyte infiltration.
      • D’Mello C.
      • Ronaghan N.
      • Zaheer R.
      • Dicay M.
      • Le T.
      • MacNaughton W.K.
      • et al.
      Probiotics improve inflammation-associated sickness behavior by altering communication between the peripheral immune system and the brain.
      Such observations suggest that altering the gut microbiome can modify systemic immunity in liver disease, which can consequently affect the brain and behaviour.
      Similarly, in a cirrhotic mouse model, transfer of faecal material from patients with cirrhosis resulted in higher levels of neuroinflammation, microglial activation and dysbiosis than transfer of faecal material from healthy controls. There was no change in the severity of liver disease on histology. This neuroinflammation was then reduced significantly when faecal material obtained from the same patients 15 days after undergoing FMT from healthy controls was transplanted into the same mice.
      • Liu R.
      • Kang J.D.
      • Sartor R.B.
      • Sikaroodi M.
      • Fagan A.
      • Gavis E.A.
      • et al.
      Neuroinflammation in murine cirrhosis is dependent on the gut microbiome and is attenuated by fecal transplant.
      This demonstrated that the attenuation of neuroinflammation by FMT is independent of liver inflammation.
      Trials of FMT in cirrhosis are ongoing and have mainly focused on its safety. However, FMT has been shown to have a beneficial impact on patients with cirrhosis and HE, leading to an improvement in cognition, and on patients with alcohol-related cirrhosis and alcohol use disorder leading to improved cognition, improved psychosocial quality of life and a reduction in serum IL-6 levels.
      • Bajaj J.S.
      • Gavis E.A.
      • Fagan A.
      • Wade J.B.
      • Thacker L.R.
      • Fuchs M.
      • et al.
      A randomized clinical trial of fecal microbiota transplant for alcohol use disorder.
      As such, our exploration of the literature lends further weight to the hypothesis that the gut dysbiosis observed in cirrhosis, and resultant systemic inflammation, may explain the increased rates of depression seen (Fig. 1). The observations and trials described demonstrate the potential role of the gut microbiome and immune dysfunction in driving the behavioural changes and increased rates of depression observed in cirrhosis and highlight the need for further work, involving larger clinical trials investigating potential psychobiotic treatments (Fig. 2).
      Figure thumbnail gr1
      Fig. 1Role of gut-derived systemic inflammation in the pathophysiology of cirrhosis and depression.
      Gut dysbiosis occurs in cirrhosis with decreased microbial diversity, increased pathogenic microbes and small bowel bacterial overgrowth. This reduces intestinal barrier function resulting in increased translocation of bacteria (and their products [LPS, peptidoglycan, flagellin, bacterial DNA]) and PAMPs into the portal circulation leading to endotoxaemia. This results in systemic inflammation and increased levels of pro-inflammatory cytokines (TNF-α, IL-1β and IL-6). These cytokines communicate with the brain via neural pathways, CEC and CVO signalling and peripheral immune cell-to-brain signalling leading to microglial activation, changes in neural activity and ultimately depressive symptoms. In cirrhosis, reduced synthetic and reticuloendothelial function results in an acquired immunodeficiency and innate immune dysfunction which, coupled with systemic inflammation, is referred to as cirrhosis-associated immune dysfunction. CECs, cerebrovascular endothelial cells; CVOs, circumventricular organs; IL-, interleukin-; LPS, lipopolysaccharide; PAMP, pathogen-associated molecular pattern; TNF-α, tumour-necrosis factor-α.
      Figure thumbnail gr2
      Fig. 2Potential treatment options to restore gut eubiosis and treat depression in cirrhosis.
      The administration of prebiotics, probiotics and faecal microbiota transplant results in favourable gut microbiota composition, decreased bacterial translocation and reduced systemic inflammation. The consequent reduction in pro-inflammatory cytokines may lead to decreased microglial activation, improved cognition and mood and fewer depressive symptoms. IFN-γ, interferon-γ; IL-, interleukin-; TNF-α, tumour-necrosis factor-α.

      Future developments in the field

      The gut-liver-immune axis in cirrhosis is well documented
      • Tranah T.H.
      • Edwards L.A.
      • Schnabl B.
      • Shawcross D.L.
      Targeting the gut-liver-immune axis to treat cirrhosis.
      and research into this area is growing exponentially. The microbiota-gut-brain axis has also been clearly demonstrated.
      • Cryan J.F.
      • O’Riordan K.J.
      • Cowan C.S.M.
      • Sandhu K.V.
      • Bastiaanssen T.F.S.
      • Boehme M.
      • et al.
      The microbiota-gut-brain Axis.
      Whilst our hypothesis that the high rates of depression seen in cirrhosis are a consequence of gut-derived systemic inflammation is logical, and certainly does not contradict current literature, there is a paucity of direct evidence. As depicted in Table 3, published studies examining the relationship between systemic inflammation, depression and liver disease are few, and arise from two research teams. One research group demonstrated the link between hepatic inflammation and sickness behaviour in bile duct ligated mice, with evidence of microglial activation.
      • D’Mello C.
      • Riazi K.
      • Le T.
      • Stevens K.M.
      • Wang A.
      • McKay D.M.
      • et al.
      P-selectin-mediated monocyte-cerebral endothelium adhesive interactions link peripheral organ inflammation to sickness behaviors.
      ,
      • D’Mello C.
      • Le T.
      • Swain M.G.
      Cerebral microglia recruit monocytes into the brain in response to tumor necrosis factora signaling during peripheral organ inflammation.
      Cross-sectional data from a separate team corroborated the relationship between depression and inflammation in cirrhosis, though the correlation was not strong.
      • Ko F.Y.
      • Yang A.C.
      • Tsai S.J.
      • Zhou Y.
      • Xu L.M.
      Physiologic and laboratory correlates of depression, anxiety, and poor sleep in liver cirrhosis.
      ,
      • Ko F.-Y.
      • Tsai S.-J.
      • Yang A.C.
      • Zhou Y.
      • Xu L.-M.
      Association of CD8 T cells with depression and anxiety in patients with liver cirrhosis.
      Further mechanistic work, including prospective longitudinal studies to assess the gut microbiome, immune system and depression (confirmed by clinical psychiatric evaluations such as the SCID) in patients with cirrhosis
      • First M.B.
      Structured clinical Interview for the DSM (SCID).
      are required to lend further support to this hypothesis.
      Therapeutic interventions that target dysbiosis are being investigated in cirrhosis and targeting the microbiome may be key to improving mood and alleviating depression in these patients.

      FMT

      FMT has shown beneficial effects in patients with cirrhosis, with improved cognition in patients with HE, reduction in episodes of overt HE
      • Bajaj J.S.
      • Kassam Z.
      • Fagan A.
      • Gavis E.A.
      • Liu E.
      • Cox I.J.
      • et al.
      Fecal microbiota transplant from a rational stool donor improves hepatic encephalopathy: a randomized clinical trial.
      ,
      • Bajaj J.S.
      • Salzman N.H.
      • Acharya C.
      • Sterling R.K.
      • White M.B.
      • Gavis E.A.
      • et al.
      Fecal microbial transplant capsules are safe in hepatic encephalopathy: a phase 1, randomized, placebo-controlled trial.
      and improved quality of life.
      • Bajaj J.S.
      • Gavis E.A.
      • Fagan A.
      • Wade J.B.
      • Thacker L.R.
      • Fuchs M.
      • et al.
      A randomized clinical trial of fecal microbiota transplant for alcohol use disorder.
      The effect of FMT on psychiatric disorder symptoms in other illnesses, such as depression and irritable bowel syndrome, is promising,
      • Meyyappan A.C.
      • Forth E.
      • Wallace C.J.K.
      • Milev R.
      Effect of fecal microbiota transplant on symptoms of psychiatric disorders: a systematic review.
      but has not been evaluated in cirrhosis. The upcoming UK multicentre randomised controlled PROMISE (PROspective double-blind placebo-controlled multicentre trial of faecal MIcrobiota tranSplantation to improve outcomEs in patients with cirrhosis) [https://fundingawards.nihr.ac.uk/award/NIHR130730] trial will assess the efficacy of encapsulated FMT to reduce infection and mortality in alcohol-related liver disease and NAFLD cirrhosis. The primary endpoint is time to hospitalisation with infection, however secondary endpoints include change in depression and anxiety (measured by HADS score) and change in quality of life (measured by EQ-5D-3L score). As such, this study should yield crucial data on the effect of FMT on depression in cirrhosis.

      Rifaximin

      Rifaximin is an oral non-absorbable gut-selective antibiotic, used effectively to treat HE in cirrhosis.
      • Bass N.M.
      • Mullen K.D.
      • Sanyal A.
      • Poordad F.
      • Neff G.
      • Leevy C.B.
      • et al.
      Rifaximin treatment in hepatic encephalopathy.
      It has been shown to modulate the gut microbiome, reduce endotoxemia and improve cognitive performance in patients with cirrhosis,
      • Bajaj J.S.
      • Heuman D.M.
      • Sanyal A.J.
      • Hylemon P.B.
      • Sterling R.K.
      • Stravitz R.T.
      • et al.
      Modulation of the metabiome by rifaximin in patients with cirrhosis and minimal hepatic encephalopathy.
      raising its potential as a psychobiotic-like treatment. The recently published RIFSYS trial, a placebo-controlled RCT of rifaximin in patients with cirrhosis and HE, revealed significantly reduced TNF-α levels at 30 days in the treatment arm, in conjunction with a reduction in markers of gut-derived systemic inflammation, abundance of metagenomic species in both faecal and salivary compartments and resolution of HE.
      • Patel V.
      • Lee S.
      • McPhail M.
      • Da Silva K.
      • Guilly S.
      • Zamalloa A.
      • et al.
      Rifaximin reduces gut-derived inflammation and mucin degradation in cirrhosis and encephalopathy: RIFSYS randomised controlled trial.

      Non-selective beta-blockers

      Non-selective beta-blockers (NSBBs) are a well-established treatment for portal hypertension and reduce splanchnic blood flow. NSBBs ameliorate intestinal permeability and reduce bacterial translocation by modulating gut motility,
      • Senzolo M.
      • Cholongitas E.
      • Burra P.
      • Leandro G.
      • Thalheimer U.
      • Patch D.
      • et al.
      beta-Blockers protect against spontaneous bacterial peritonitis in cirrhotic patients: a meta-analysis.
      demonstrated by lower levels of IL-6 and lipopolysaccharide-binding protein in patients with cirrhosis receiving NSBBs.
      • Reiberger T.
      • Ferlitsch A.
      • Payer B.A.
      • Mandorfer M.
      • Heinisch B.B.
      • Hayden H.
      • et al.
      Non-selective betablocker therapy decreases intestinal permeability and serum levels of LBP and IL-6 in patients with cirrhosis.
      The M-BOP (mechanism of beta-blockade on bacterial translocation in portal hypertension) mechanistic sub-study to the current UK multicentre randomised controlled BOPPP trial (NCT03776955), investigating the use of NSBBs or placebo for primary prophylaxis of oesophageal varices, will further explore the effect of NSBBs on bacterial translocation and risk of decompensation in BOPPP participants.

      Albumin

      Whilst human albumin solution is commonly used for various indications in cirrhosis, it has further immune-restorative effects that may prove beneficial in cirrhosis.
      • China L.
      • Maini A.
      • Skene S.S.
      • Shabir Z.
      • Sylvestre Y.
      • Colas R.A.
      • et al.
      Albumin counteracts immune-suppressive effects of lipid mediators in patients with advanced liver disease.
      Trials of albumin infusion in decompensated cirrhosis have shown conflicting results. The open-label randomised ANSWER trial reported a 38% reduction in the hazard ratio for mortality in patients with cirrhosis receiving weekly albumin infusions.
      • Caraceni P.
      • Riggio O.
      • Angeli P.
      • Alessandria C.
      • Neri S.
      • Foschi F.G.
      • et al.
      Long-term albumin administration in decompensated cirrhosis (ANSWER): an open-label randomised trial.
      The recent UK multicentre randomised open-label ATTIRE study investigated the effect of intravenous 20% albumin infusions in hospitalised patients with cirrhosis (targeting a serum albumin level ≥30 g/L) compared to standard of care. Conversely, there was no benefit, and no difference in composite end point (new infection, renal dysfunction and death at 15 days) was observed.
      • China L.
      • Freemantle N.
      • Forrest E.
      • Kallis Y.
      • Ryder S.D.
      • Wright G.
      • et al.
      A randomized trial of albumin infusions in hospitalized patients with cirrhosis.
      The current MICROB-PREDICT study, which aims to validate microbiome-based markers to predict treatment response to albumin, may shed further light on this area.

      Conclusion

      The prevalence of depression is high in liver disease. Importantly, a comorbid diagnosis of depression appears to have an adverse impact on outcomes in cirrhosis.
      Gut dysbiosis results in increased permeability of the intestinal mucosa, resulting in increased bacterial translocation culminating in the activation of circulating immune cells, cytokine production and systemic inflammation. Such pathways are central to CAID and are implicated in the increased incidence of infection in cirrhosis, disease progression and the development of organ failure and complications. Peripheral inflammation can extend to the CNS and brain via neural mechanisms, CEC and circumventricular organ signalling, and peripheral immune cell-to-brain signalling resulting in depressive symptoms. The overt systemic inflammation present in cirrhosis may therefore explain the high rates of depression.
      Whilst the mechanism underlying the crucial link between depression and cirrhosis remains to be fully elucidated, and given the various psychosocial and other biological factors involved, is likely to be multifactorial, the role of the gut microbiome and inflammation requires further exploration and consideration as a target for therapy.

      Abbreviations

      ACLF, acute-on-chronic liver failure; AST, aspartate aminotransferase; BBB, blood brain barrier; BDI, Beck Depression Inventory; BDI-II, Beck Depression Inventory second edition; CAID, cirrhosis-associated immune dysfunction; CECs, cerebrovascular endothelial cells; CLD, chronic liver disease; CNS, central nervous system; CRP, C-reactive protein; DSM, Diagnostic and Statistical Manual of Mental Disorders; FMT, faecal microbial transplantation; HE, hepatic encephalopathy; IFN, interferon; IL-, interleukin; IR, insulin resistance; NAFL, non-alcoholic fatty liver; NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis; NSBB, non-selective beta-blocker; PAMPs, pathogen-associated molecular patterns; PBC, primary biliary cholangitis; PRRs, pattern recognition receptors; RCT, randomised controlled trial; SCFA, short-chain fatty acid; SCID, Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders 5; SSRI, selective serotonin reuptake inhibitors; TNF-α, tumour necrosis factor alpha.

      Financial support

      No funding was received for the preparation of this manuscript.

      Authors’ contributions

      VTK drafted the manuscript. THT designed the figures. The manuscript was then revised extensively by THT, CP and DLS. All authors approved the final manuscript prior to submission.

      Conflict of interest

      CP is funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London. CP has received research funding from Johnson & Johnson as part of a research programme on depression and inflammation, and from the Medical Research Council (UK) and the Wellcome Trust for research on depression and inflammation as part of two large consortia that also include Johnson & Johnson, GSK and Lundbeck; however, the present paper is independent from this funding. DLS has participated in advisory boards for Norgine Pharmaceuticals Ltd, EnteroBiotix, Kaleido Biosciences, Mallinckrodt and Shionogi and has delivered paid lectures for Norgine Pharmaceuticals Ltd, Falk Pharma and Alfa Sigma. THT and DLS have also received funding for an investigator-initiated study (EMITTIC Study) from Norgine Pharmaceuticals Ltd. THT has also received funding from the Medical Research Council (MRC). VTK has no COI to declare.
      Please refer to the accompanying ICMJE disclosure forms for further details.

      Supplementary data

      The following is the supplementary data to this article:

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