Abstract
BACKGROUND
Nonalcoholic fatty liver disease (NAFLD) has become the leading cause of chronic liver disease with increasing prevalence worldwide. Clostridioides difficile infection (CDI) remains the most common cause of nosocomial diarrhea in developed countries.
AIM
To assess the impact of NAFLD on the outcomes of hospitalized patients with CDI.
METHODS
This study was a retrospective cohort study. The Nationwide Inpatient Sample database was used to identify a total of 7239 adults admitted as inpatients with a primary diagnosis of CDI and coexisting NAFLD diagnosis from 2010 to 2014 using ICD-9 codes. Patients with CDI and coexisting NAFLD were compared to those with CDI and coexisting alcoholic liver disease (ALD) and viral liver disease (VLD), individually. Primary outcomes included mortality, length of stay, and total hospitalization charges. Secondary outcomes were in-hospital complications. Multivariate regression was used for outcome analysis after adjusting for possible confounders.
RESULTS
CDI with NAFLD was independently associated with lower rates of acute respiratory failure (2.7% vs 4.2%, P < 0.01; 2.7% vs 4.2%, P < 0.05), shorter length of stay (days) (5.75 ± 0.16 vs 6.77 ± 0.15, P < 0.001; 5.75 ± 0.16 vs 6.84 ± 0.23, P <0.001), and lower hospitalization charges (dollars) (38150.34 ± 1757.01 vs 46326.72 ± 1809.82, P < 0.001; 38150.34 ± 1757.01 vs 44641.74 ± 1660.66, P < 0.001) when compared to CDI with VLD and CDI with ALD, respectively. CDI with NAFLD was associated with a lower rate of acute kidney injury (13.0% vs 17.2%, P < 0.01), but a higher rate of intestinal perforation (P < 0.01) when compared to VLD. A lower rate of mortality (0.8% vs 2.7%, P < 0.05) but a higher rate of intestinal obstruction (4.6% vs 2.2%, P = 0.001) was also observed when comparing CDI with NAFLD to ALD.
CONCLUSION
Hospitalized CDI patients with NAFLD had more intestinal complications compared to CDI patients with VLD and ALD. Gut microbiota dysbiosis may contribute to the pathogenesis of intestinal complications.
Keywords: Nonalcoholic fatty liver disease, Clostridioides difficile infection, Gut microbiota, Intestinal complications, Alcoholic liver disease, Viral liver disease
Core Tip: This study demonstrated that patients hospitalized with Clostridioides difficile infection (CDI) and coexisting nonalcoholic fatty liver disease (NAFLD) had more favorable overall outcomes but higher rates of intestinal complications when compared to those with alcoholic liver disease and viral liver disease individually, which suggests altering gut microbiota may play an essential role in the pathogenesis of both CDI and NAFLD. NAFLD-associated metabolic syndrome may contribute significantly to gut dysbiosis and increase risk for CDI and its complications. This study provides potential directions for future prospective clinical research to identify the clinical meaningfulness of interactions between the gut microbiota, gut immunity and systemic inflammation.
INTRODUCTION
Nonalcoholic fatty liver disease (NAFLD) is a heterogeneous disease with a spectrum from simple steatosis to nonalcoholic steatohepatitis (NASH), cirrhosis, and hepatocellular carcinoma[1,2]. With a prevalence of 10 to 46 percent in the United States and 6% to 35% worldwide[3,4], NAFLD has become the leading cause of chronic liver disease, and its prevalence continues to increase, paralleled by the increase of obesity and type 2 diabetes[5].
Clostridioides difficile (C. difficile) is a gram-positive, spore-forming bacterium, known as the most common pathogen causing nosocomial diarrhea in developed countries[6]. Symptoms of C. difficile infection (CDI) range from mild to severe diarrhea, which can progress to sepsis, fulminant colitis, and bowel perforation[7]. Severe colitis may also present as ileus and megacolon, which are characterized by symptoms of intestinal obstruction[8,9]. Gut microbiota dysbiosis due to the administration of antibiotics is the most prominent risk factor for the development of CDI. Advanced age, prolonged hospitalization and gastric acid suppression are some common additional risk factors for CDI[10,11].
Recently, a number of animal and human studies have revealed the role of the gut microbiota in the pathophysiology of NAFLD. It is proposed that dysbiosis-induced dysregulation of the gut barrier function and translocation of the bacteria link the gut microbiome to NAFLD[12,13]. In addition, it has been well documented that patients with chronic liver disease are more susceptible to CDI due to frequent hospitalization and antibiotics use. Specifically, recent studies have observed that NAFLD is an independent risk factor for CDI by single-centered retrospective design[14,15].
Although a strong association between NAFLD and CDI has been observed, gut microbiota dysbiosis likely plays a vital role in the pathogenesis of both aforementioned diseases. However, the inpatient outcomes of CDI in the NAFLD population, have not been well studied in large populations. The aim of this nationwide study was to assess the impact of NAFLD on the outcomes of hospitalized patients with CDI.
MATERIALS AND METHODS
Data source and study population
The largest all-payer inpatient care database in the United States, the Nationwide Inpatient Sample (NIS) database was accessed. The NIS database represents approximately 20% of all inpatient hospitalizations. Weighted, it estimates more than 35 million hospitalizations nationally[16]. It includes demographic information (age, sex, race, income), hospital characteristics (e.g., bed size, type), insurance status, discharge status, diagnoses and procedures (identified by The International Classification of Diseases-Ninth Edition Revision Clinical Modification (ICD-9 CM) codes), total hospitalization charges, length of stay (LOS), severity and other comorbidity measures. Yearly sampling weights are applied to generate national estimates.
This retrospective cohort study examined all adult (18-90 years old) patients hospitalized with CDI as the primary diagnosis from 2010 to 2014. Within this CDI population, patients with NAFLD were selected to compare to those with viral liver disease (VLD) (including hepatitis B infection and hepatitis C infection) and those with alcoholic liver disease (ALD). Notably, CDI was identified by ICD-9 CM code 008.45. NAFLD was identified by ICD-9 CM code 571.80 with the exclusion of all diagnostic codes for previous organ recipients and donors as well as other causes of chronic liver disease including hepatitis B and hepatitis C infection, ALD, hemochromatosis, primary biliary cholangitis, autoimmune hepatitis, and other unspecified liver diseases. The diagnosis of VLD was identified by the ICD-9 CM codes for hepatitis B and C caused liver diseases with the exclusion of previous organ recipients and donors, as well as other causes of chronic liver disease including NAFLD, ALD, hemochromatosis, primary biliary cholangitis, autoimmune hepatitis, and other unspecified liver diseases. Similarly, ALD was identified by the ICD-9 CM codes for ALD with the exclusion of previous organ recipients and donors as well as other causes of chronic liver disease including NAFLD, VLD, hemochromatosis, primary biliary cholangitis, autoimmune hepatitis, and other unspecified liver diseases (see Supplementary Table 1, supplemental digital content 1, which demonstrates ICD-9 diagnostic and procedure codes). VLD and ALD were assessed as separate groups which excluded patients with concomitant diagnoses of VLD and ALD. Information such as patients’ demographics, comorbidities, disposition, selected outcomes and surgical interventions were extracted from the NIS database. Elixhauser Comorbidity Index (ECI)[17], which measures 29 general medical conditions, then assigns different weights to compile a longitudinal score, allowing for further description of comorbidity burden.
Primary outcomes included mortality, length of stay, and total hospitalization charges. Secondary outcomes were CDI related complications and interventions.
Statistical analysis
SAS Survey Procedures (SAS 9.4, SAS Institute Inc, Cary, NC, United States) was utilized for all statistical analyses. The national estimates were calculated after accounting for sample design elements (clusters, strata, and trend weights) provided by the NIS. Continuous variables were reported as weighted mean ± SE; categorical variables were reported as weighted numbers (n) and percentages (%). The SEs of weighted means were estimated using the Taylor linearization method that incorporated the sample design. Weighted Student’s t-tests were used to analyze the normally distributed continuous variables, while Rao-Scott modified chi-square tests were used to test the difference of distribution for categorical variables. Wilcoxon Rank-Sum Tests were used to test the variables that are not normally distributed. Multivariate linear regression was used to estimate the average change in LOS and total hospitalization charges after adjusting for patient demographics, hospital characteristics, insurance type, median household income, ECI score, obesity, diabetes, tobacco use disorder, hypertension, dyslipidemia, cirrhosis and its complications, numbers of cirrhosis complications, and hepatocellular carcinoma. Multivariate logistic regression was used to estimate the odds ratio (OR) of mortality, CDI complications and interventions after adjusting for the same confounding variables as noted above.
The statistical methods of this study were reviewed by Dr. Chunyi Wu, PhD of Epidemiology from University of Michigan Medical School.
RESULTS
Patient demographics and baseline characteristics
From 2010 to 2014, the numbers of patients hospitalized for CDI with coexisting NAFLD, VLD and ALD were 7239, 11857 and 5938, respectively. The CDI with NAFLD cohort in this study was predominantly Caucasian with an average age 56.3 years old. In the aforementioned cohort, 69.4% of the patients were female, 41.6% were admitted to southern hospitals, and 58.6% were admitted to large hospitals (Table 1). Compared to CDI with VLD or ALD individually, the CDI with NAFLD group had significantly more patients in the 18-39 and greater than 70-year-old age groups (P < 0.0001), were more likely to be female (P < 0.0001), from the southern hospital region (P < 0.0001), and less likely to be Medicaid insured (P < 0.0001). Additionally, the CDI with coexisting VLD group was associated with a higher percentage of African American patients and had less patients with a high household income (Q3 and Q4, median household income for ZIP code between 51th and 100th percentile) compared to the CDI with NAFLD group.
Table 1.
Comparison of demographic data for patients hospitalized with Clostridioides difficile infection with coexisting nonalcoholic fatty liver disease, viral liver disease and alcoholic liver disease
|
Variables
|
CDI with NAFLD
|
CDI with VLD
|
CDI with ALD
|
P
value
|
|
|
n
(weighted)
|
7239
|
11857
|
5938
|
CDI with NAFLD vs CDI with VLD
|
CDI with NAFLD vs CDI with ALD
|
| Age (yr) | 56.32 ± 0.42 | 57 ± 0.26 | 56.13 ± 0.37 | 0.15 | 0.73 |
| 18-39 | 1133 (15.6%) | 791 (6.7%) | 557 (9.4%) | < 0.0001 | < 0.0001 |
| 40-49 | 1290 (17.8%) | 1811 (15.3%) | 1051 (17.7%) | ||
| 50-59 | 1618 (22.4%) | 4873 (41.1%) | 2021 (34%) | ||
| 60-69 | 1620 (22.4%) | 2791 (23.5%) | 1439 (24.2%) | ||
| ≥ 70 | 1578 (21.8%) | 1591 (13.4%) | 870 (14.7%) | ||
| Sex | < 0.0001 | < 0.0001 | |||
| Female | 5023 (69.4%) | 5795 (48.9%) | 2300 (38.7%) | ||
| Race | < 0.0001 | 0.17 | |||
| Caucasian | 5427 (75%) | 6920 (58.4%) | 4358 (73.4%) | ||
| African American | 482 (6.5%) | 2773 (23.4%) | 525 (8.8%) | ||
| Hispanic | 648 (9%) | 1144 (9.6%) | 515 (8.7%) | ||
| Hospital bed size | 0.033 | 0.9 | |||
| Large | 4241 (58.6%) | 7414 (62.6%) | 3461 (58.3%) | ||
| Hospital region | < 0.0001 | < 0.0001 | |||
| Northeast | 1091 (15.1%) | 2618 (22.1%) | 1243 (20.9%) | ||
| Midwest | 1618 (22.3%) | 2514 (21.1%) | 1584 (26.7%) | ||
| South | 3008 (41.6%) | 4208 (35.5%) | 1671 (28.1%) | ||
| West | 1522 (21%) | 2517 (21.2%) | 1440 (24.3%) | ||
| Hospital type | < 0.0001 | 0.22 | |||
| Urban teaching | 3401 (47%) | 7207 (60.8%) | 3065 (51.6%) | ||
| Insurance | < 0.0001 | < 0.0001 | |||
| Medicare | 3086 (42.6%) | 5493 (46.3%) | 2239 (37.7%) | ||
| Medicaid | 914 (12.6%) | 3329 (28.1%) | 1261 (21.2%) | ||
| Private | 2526 (34.9%) | 1835 (15.5%) | 1391 (23.4%) | ||
| Median household income for ZIP Code, % | < 0.0001 | 0.61 | |||
| Q1 | 1790 (24.7%) | 4205 (35.5%) | 1592 (26.8%) | ||
| Q2 | 1824 (25.2%) | 3128 (26.4%) | 1407 (23.7%) | ||
| Q3 | 1926 (26.6%) | 2353 (19.8%) | 1503 (25.3%) | ||
| Q4 | 1511 (20.9%) | 1657 (14%) | 1252 (21.1%) | ||
Values reported as weighted mean ± SE and weighted number [n (%)]. CDI: Clostridioides difficile infection; NAFLD: Nonalcoholic fatty liver disease; VLD: Viral liver disease; ALD: Alcoholic liver disease; Q1: Quartile 1, 0-25th percentile; Q2: Quartile 2, 26th-50th percentile; Q3: Quartile 3, 51th-75th percentile; Q4: Quartile 4, 76th-100th percentile.
In regard to comorbidities (Table 2), when compared to the CDI with VLD or ALD groups individually, CDI patients with NAFLD had a greater prevalence of obesity (P < 0.0001, P < 0.0001), diabetes (P < 0.0001, P < 0.0001), hypertension (P = 0.0006, P < 0.0001) and dyslipidemia (P < 0.0001, P < 0.0001). CDI with NAFLD was also associated with a significantly lower rate of cirrhosis (P < 0.0001, P < 0.0001) when compared to the other two groups. None of the patients in the CDI with NAFLD group had cirrhosis-related ascites, esophageal varices bleeding, spontaneous bacterial peritonitis or hepatorenal syndrome. Moreover, a lower rate of hepatocellular carcinoma (P < 0.0001, P = 0.0217) was observed in the CDI with NAFLD group compared to the CDI with VLD or ALD groups individually.
Table 2.
Comparison of comorbid conditions and complications for patients hospitalized with Clostridioides difficile infection with coexisting nonalcoholic fatty liver disease, viral liver disease and alcoholic liver disease
|
Variables
|
CDI with NAFLD
|
CDI with VLD
|
CDI with ALD
|
P
value
|
|
|
n
(weighted)
|
7239
|
11857
|
5938
|
CDI with NAFLD vs CDI with VLD
|
CDI with NAFLD vs CDI with ALD
|
| Number of Elixhauser comorbidities | < 0.0001 | < 0.0001 | |||
| 0 | 0 (0%) | 114 (1%) | - | ||
| 1 | 244 (3.4%) | 574 (4.8%) | 116 (2%) | ||
| 2 | 656 (9.1%) | 1409 (11.9%) | 354 (6%) | ||
| ≥ 3 | 6338 (87.6%) | 9760 (82.3%) | 5463 (92%) | ||
| Obesity | 2012 (27.8%) | 850 (7.2%) | 372 (6.3%) | < 0.0001 | < 0.0001 |
| Diabetes | 2750 (38%) | 3451 (29.1%) | 1170 (19.7%) | < 0.0001 | < 0.0001 |
| Hypertension | 4300 (59.4%) | 6347 (53.5%) | 2980 (50.2%) | 0.00058 | < 0.0001 |
| Dyslipidemia | 2619 (36.2%) | 1868 (15.8%) | 905 (15.2%) | < 0.0001 | < 0.0001 |
| Hepatocellular carcinoma | - | 253 (2.1%) | 45 (0.8%) | < 0.0001 | 0.0217 |
| Cirrhosis related comorbidities1 | |||||
| Cirrhosis | 401 (5.5%) | 2508 (21.2%) | 3407 (57.4%) | < 0.0001 | < 0.0001 |
| Number of cirrhosis complications | 0.0013 | < 0.0001 | |||
| 0 | 137 (34.2%) | 1773 (70.7%) | 2105 (61.8%) | ||
| 1 | 244 (60.8%) | 688 (27.4%) | 1104 (32.4%) | ||
| v ≥ 2 | 20 (5.0%) | 47 (1.9%) | 198 (5.8%) | ||
| Ascites | 0 (0%) | 0 (0%) | 0 (0%) | NA | NA |
| Esophageal varices bleeding | 0 (0%) | - | 20 (0.6%) | NA | NA |
| Hepatic encephalopathy | 110 (27.4%) | 60 (2.4%) | 569 (16.7%) | 0.003338 | < 0.0001 |
| Hepatorenal syndrome | 0 (0%) | 15 (0.6%) | 33 (1.0%) | NA | NA |
| Portal hypertension | 175 (43.6%) | 661 (26.4%) | 843 (24.7%) | < 0.0001 | < 0.0001 |
| Spontaneous bacterial peritonitis | 0 (0%) | 38 (1.5%) | 40 (1.2%) | NA | NA |
Value reported as percentage of all cirrhotic patients.
Values reported as weighted number [n (%)].-: Numbers were not displayed due to extremely small numbers were associated with increased risk for identification of persons; CDI: Clostridioides difficile infection; NAFLD: Nonalcoholic fatty liver disease; VLD: Viral liver disease; ALD: Alcoholic liver disease; NA: Not available.
Outcomes and regression analysis of CDI patients with NAFLD vs VLD
When compared to the CDI with NAFLD group, the CDI with VLD group was associated with higher rates of acute kidney injury (AKI) [adjusted OR (aOR) = 1.35, 95%CI: 1.10-1.67, P = 0.0041], respiratory failure (RF) (aOR = 1.83, 95%CI: 1.22-2.76, P = 0.0036), longer LOS (adjusted LOS ratio = 1.12, 95%CI: 1.06-1.18, P < 0.0001) and higher hospitalization charges (adjusted cost ratio = 1.13, 95%CI :1.06-1.2, P < 0.0001). However, a lower rate of intestinal perforation rate was observed in the CDI with VLD group (aOR = 0.12, 95%CI: 0.03-0.57, P = 0.0075). CDI with VLD was initially associated with higher rates of mortality, colectomy and ileostomy, however this difference no longer existed after adjusting for confounding factors (Table 3).
Table 3.
Multivariate regression analysis of outcomes for patients hospitalized for Clostridioides difficile infection with coexisting nonalcoholic fatty liver disease vs viral liver disease
|
Outcomes
|
CDI with NAFLD
|
CDI with VLD
|
Unadjusted ratio (95%CI)
|
P
value
|
Adjusted ratio1 (95%CI)
|
P
value
|
|
n
(weighted)
|
7239
|
11857
|
||||
| Hospital mortality | 59 (0.8%) | 186 (1.6%) | 1.94 (1.44, 2.6) | < 0.0001 | 1.87 (0.95, 3.7) | 0.071 |
| Acute kidney injury | 938 (13%) | 2035 (17.2%) | 1.39 (1.28, 1.51) | < 0.0001 | 1.35 (1.1, 1.67) | 0.0041 |
| Respiratory failure | 192 (2.7%) | 504 (4.2%) | 1.63 (1.37, 1.92) | < 0.0001 | 1.83 (1.22, 2.76) | 0.0036 |
| Septic shock | 39 (0.5%) | 115 (1%) | 1.8 (1.25, 2.59) | 0.0015 | 1.64 (0.67, 4.02) | 0.27 |
| Intestinal perforation | - | - | 0.3 (0.1, 0.89) | 0.03 | 0.12 (0.03, 0.57) | 0.0075 |
| Intestinal obstruction | 331 (4.6%) | 527 (4.4%) | 0.97 (0.84, 1.12) | 0.67 | 0.94 (0.66, 1.33) | 0.725 |
| Peritonitis | 61 (0.8%) | 106 (0.9%) | 1.06 (0.77, 1.45) | 0.71 | 0.72 (0.35, 1.52) | 0.39 |
| Colectomy | 45 (0.6%) | 105 (0.9%) | 1.43 (1.01, 2.03) | 0.044 | 1.38 (0.6, 3.15) | 0.44 |
| Ileostomy | - | 41 (0.3%) | 2.47 (1.24, 4.92) | 0.01 | 2.62 (0.66, 10.41) | 0.17 |
| LOS (days) | 5.75 ± 0.16 | 6.77 ± 0.15 | 1.11 (1.06, 1.16) | < 0.0001 | 1.12 (1.06, 1.18) | < 0.0001 |
| Total hospitalizationcharges (dollars) | 38150.34 ± 1757.01 | 46326.72 ± 1809.82 | 1.14 (1.07, 1.2) | < 0.0001 | 1.13 (1.06, 1.2) | < 0.0001 |
Adjusted for age, sex, race, primary insurance payer, hospital type, hospital bed size, hospital region, income quartile, Elixhauser Comorbidity Index score, obesity, diabetes, tobacco use disorder, hypertension, dyslipidemia, cirrhosis and its complications, numbers of cirrhosis complications, and hepatocellular carcinoma.
-: Numbers were not displayed due to extremely small numbers were associated with increased risk for identification of persons. Values reported as weighted mean ± SE and weighted numbers [n (%)]; CDI: Clostridioides difficile infection; NAFLD: Nonalcoholic fatty liver disease; VLD: Viral liver disease; CI: Confidence interval; LOS: Length of stay.
Outcomes and regression analysis of CDI patients with NAFLD vs ALD
When compared to CDI patients with NAFLD, CDI patients with ALD had higher rates of RF (aOR = 1.72, 95%CI: 1.09-2.72, P = 0.0201), mortality (aOR = 2.63, 95%CI: 1.25-5.51, P = 0.0107), longer LOS (adjusted LOS ratio = 1.18, 95%CI: 1.10-1.25, P < 0.0001) and higher hospitalization charges (adjusted cost ratio = 1.17, 95%CI: 1.09-1.26, P < 0.0001). However, a lower rate of intestinal obstruction (aOR = 0.45, 95%CI: 0.28-0.72, P = 0.0010) was found in the CDI with ALD group when compared to the CDI with NAFLD group. Higher rates of AKI and septic shock, and a lower rate of colectomy were initially observed in CDI with ALD group, but the difference no longer existed after adjusting for the aforementioned confounders (Table 4).
Table 4.
Multivariate regression analysis of outcomes for patients hospitalized for Clostridioides difficile infection with coexisting nonalcoholic fatty liver disease vs alcoholic liver disease
|
Outcomes
|
CDI with NAFLD
|
CDI with ALD
|
Unadjusted ratio (95%CI)
|
P
value
|
Adjusted ratio1 (95%CI)
|
P
value
|
|
n
(weighted)
|
7239
|
5938
|
||||
| Hospital mortality | 59 (0.8%) | 159 (2.7%) | 3.34 (2.48, 4.52) | < 0.0001 | 2.63 (1.25, 5.51) | 0.0107 |
| Acute kidney injury | 938 (13%) | 935 (15.8%) | 1.26 (1.14, 1.39) | < 0.0001 | 1.2 (0.93, 1.54) | 0.15 |
| Respiratory failure | 192 (2.7%) | 249 (4.2%) | 1.61 (1.33, 1.94) | < 0.0001 | 1.72 (1.09, 2.72) | 0.0201 |
| Septic shock | 39 (0.5%) | 79 (1.3%) | 2.48 (1.69, 3.64) | < 0.0001 | 2.14 (0.84, 5.46) | 0.109 |
| Intestinal perforation | - | 0 (0%) | NA | NA | NA | NA |
| Intestinal obstruction | 331 (4.6%) | 133 (2.2%) | 0.48 (0.39, 0.59) | < 0.0001 | 0.45 (0.28, 0.72) | 0.0010 |
| Peritonitis | 61 (0.8%) | 69 (1.2%) | 1.38 (0.97, 1.95) | 0.071 | 0.54 (0.25, 1.18) | 0.12 |
| Colectomy | 45 (0.6%) | 15 (0.3%) | 0.42 (0.23, 0.74) | 0.003 | 0.44 (0.14, 1.39) | 0.16 |
| Ileostomy | - | - | 0.65 (0.23, 1.85) | 0.42 | 0.99 (0.15, 6.61) | 0.98 |
| LOS (days) | 5.75 ± 0.16 | 6.84 ± 0.23 | 1.14 (1.08, 1.21) | < 0.0001 | 1.18 (1.1, 1.25) | < 0.0001 |
| Totalhospitalizationcharges (dollars) | 38150.34 ± 1757.01 | 44641.74 ± 1660.66 | 1.14 (1.07, 1.22) | < 0.0001 | 1.17 (1.09, 1.26) | < 0.0001 |
Adjusted for age, sex, race, primary insurance payer, hospital type, hospital bed size, hospital region, income quartile, Elixhauser Comorbidity Index score, obesity, diabetes, tobacco use disorder, hypertension, dyslipidemia, cirrhosis and its complications, numbers of cirrhosis complications, and hepatocellular carcinoma.
Values reported as weighted mean ± SE and weighted numbers [n (%)]. -: Numbers were not displayed due to extremely small numbers were associated with increased risk for identification of persons. CDI: Clostridioides difficile infection; NAFLD: Nonalcoholic fatty liver disease; ALD: Alcoholic liver disease; LOS: Length of stay.
DISCUSSION
This nationwide retrospective cohort study investigated the inpatient clinical characteristics and outcomes of CDI in hospitalized patients with coexisting liver diseases, with comparisons between NAFLD, VLD and ALD. We demonstrated that patients hospitalized with CDI and coexisting NAFLD had overall more favorable outcomes including a lower rate of RF, lower hospitalization charges and a shorter LOS when compared to those with ALD and VLD individually. Interestingly, higher rates of intestinal complications were observed in the CDI with NAFLD group when compared to the CDI with ALD or VLD groups. Specifically, a significantly higher rate of intestinal obstruction was seen in the CDI with NAFLD group when compared to the CDI with ALD group, and a higher rate of intestinal perforation was seen when compared to CDI patients with concomitant VLD.
Our findings of worse intestinal complications in patients hospitalized with CDI and coexisting NAFLD compared to CDI patients with VLD and ALD, linked the gut pathology to the liver. The crosstalk between the gut and liver is increasingly recognized as the gut-liver axis[18]. Receiving more than 70% of the blood supply from the intestinal venous outflow, the liver represents the first line of defense against gut derived antigens with a broad array of immune cells[19]. The liver also releases many bioactive mediators into the systemic circulation, allowing for communication with the intestine. In the intestine, the endogenous and exogenous products from host and microbial metabolism translocate to the liver through the portal venous system, ultimately influencing liver function[20].
How does NAFLD influence the intestinal complications of CDI through the gut-liver axis? Convincing evidence has shown that NAFLD is associated with significantly increased gut permeability and inflammation in both animal[21] and human models. Miele et al[22] found that NAFLD patients had significantly increased gut permeability measured by urine radiolabeled markers and immunohistochemical analysis of zona occludens -1 expression in intestinal biopsy specimens, compared with healthy volunteers. They also discovered that both gut permeability and the prevalence of small intestinal bacterial overgrowth are correlated with the severity of steatosis. Verdam et al[23] found that plasma immunoglobulin G levels against endotoxin were increased in NASH patients, which positively correlated with the severity of inflammation. Furthermore, transmission electron microscopy observed irregular microvilli and widened tight junctions in the gut mucosa of the NAFLD patients[24]. In addition, decreased numbers of CD4+ and CD8+ T lymphocytes and increased levels of TNF-α, IL-6 and IFN-γ were detected in the NAFLD patient group compared to healthy control. All of these results suggested impaired gut permeability and increased levels of inflammation at both the tissue and cellular levels in NAFLD disease models.
The gut microbiota-mediated inflammation, the related disturbance of the intestinal integrity and the impairment in mucosal immune function have been reported to play important roles, not only in the pathophysiology of CDI[25] but also in the pathogenesis of NAFLD[13,24,26]. The gut microbiota normally exerts significant influence on intestinal epithelial cell health, nutrient metabolism and mucosal defense[19,27]. Early evidence in animal studies demonstrated that altered gut microbiota composition[28] independently contributed to the development of NAFLD in mice. In addition, altered interaction between the gut and the host (produced by defective inflammasome sensing in inflammasome-deficient mouse models) may govern the rate of progression of multiple metabolic syndrome-associated abnormalities[29]. With the recent developments in genome sequencing technologies, bioinformatics, and culturomics; it has been recognized that NAFLD and NASH are associated with decreased richness of the gut flora and increased risk of pathogenic flora in pediatric and adult patients[30-34], which are both well known risk factors for CDI. Although it is still unclear which specific microorganisms are harmful given conflicting results in human and animal studies[35], it is believed that gut microbiota-derived signatures extracted by whole-genome shotgun sequencing of DNA can be used for diagnosis of advanced fibrosis in NAFLD[36], and modification of gut microbiota analyzed by 16S ribosomal RNA pyrosequencing can be used for therapeutic purposes in NASH patients[37]. Additionally, increased pathogenic flora in NAFLD and NASH further disturb the immune balance and cause worsened dysbiosis through various mechanisms involving short-chain fatty acids[38], lipopolysaccharide[21], choline metabolism[39], bile acid metabolism[40] and bacteria-derived ethanol[41]. Collectively, NAFLD and NASH related alterations of gut microbiota and its downstream dysbiosis pathways may contribute to CDI risk and worse intestinal complications.
On the other end, we sought to identify the characteristics of gut microbiota changes in ALD and VLD. Compared to NAFLD, ALD is remarkably similar histologically[42] and initiated directly from the gut by alcohol intake or binges. It has been well documented that alcohol intake can lead to changes in gut microbiota composition[43] and gut permeability[44] early on, even before the development of liver disease. These alterations involve multiple physical and biochemical layers of defense in the intestinal barrier[19]. In VLD, the gut microbiome works as an effective tool early on for immunity against the hepatitis virus, and helps with viral clearance[45]. In chronic VLD, large translocations of intestinal microbiota were observed and thought to contribute to not only dysregulation of immune cells and dysfunction of the intestinal barrier, but also viral replication[27]. Comparison analysis revealed that, compared to other cirrhosis etiologies, alcoholic cirrhosis is associated with worse gut dysbiosis after adjusting for Model For End-Stage Liver Disease score and body mass index[46]. In two other studies[47,48], which primarily compared the gut microbiota composition in HBV/HCV related and alcoholic cirrhosis, no difference was observed at the phylum and class level.
Intriguingly, in our study, the majority (94.5%) of patients in CDI with NAFLD group were non-cirrhotic; the percentage of cirrhotic patients in CDI with NAFLD group was significantly less than those in CDI with ALD or VLD group. CDI with NAFLD group was associated with a higher rate of intestinal complications after adjusting for cirrhosis and its complications. These results suggested that NAFLD is associated with altered gut microbiota that is predisposed to CDI and its complications, likely independent from the liver disease severity. In fact, NAFLD has been reported as an independent risk factor for CDI[14]. Although ALD and VLD cirrhosis was previously found to be associated with worse gut dysbiosis than NAFLD cirrhosis, this finding should be treated cautiously for non-cirrhotic patients, because the alteration of the gut microbiome is associated with the severity of liver disease, as significant differences in gut microbiota have been found between non-cirrhotic, compensated and decompensated cirrhotic patients[49,50]. Importantly, the standard of care therapies in cirrhotic patients such as lactulose, rifaximin, antibiotics and acid-suppressants that can affect the gut microbiota, may be playing a critical role[51]. In summary, our study suggested that NAFLD may be associated with worse dysbiosis in early liver disease stages and therefore a higher risk for CDI and its complications compared to ALD and VLD.
Aside from aforementioned gut microbiota changes that directly link NAFLD to CDI and intestinal complications, NAFLD related metabolic syndrome and systemic inflammation also play crucial roles in intestinal pathology. Recently, metabolic dysfunction-associated fatty liver disease has been proposed as a more appropriate name to replace NAFLD by an international panel of experts, with emphasis on the underlying metabolic dysfunction[52,53]. Clinical evidence has demonstrated that NAFLD, along with other components of metabolic syndrome, such as diabetes and obesity, are associated with an increased prevalence of small intestinal bacterial overgrowth (SIBO)[54,55] by insulin resistance, oxidative stress and chronic low grade inflammation[56]. Subsequently, the dysmotility induced by SIBO can further promote SIBO in NAFLD patients, causing a vicious cycle[57]. In fact, dysmotility itself is associated with NAFLD and may be a potential therapeutic target for NAFLD from a Japanese study[58,59]. Moreover, diabetes, a component of metabolic syndrome which may cause vasculopathies and neuropathies in the intestines, also contributes to dysmotility[60]. Additionally, diverticular disease, irritable bowel disease[61] and inflammatory bowel disease[62], together with SIBO and dysmotility have all been shown to have increased prevalence in NAFLD patients. Not surprisingly, the structural and functional abnormalities in the gut associated with NAFLD and metabolic dysfunction further increase the risk of CDI and its complications.
The strengths of this study include the utilization of the NIS database to provide a unique opportunity to investigate a nationwide population hospitalized for CDI. To the best of our knowledge, this study is a leading clinical research analysis that provided a comprehensive nationwide comparison of outcomes between NAFLD and other common chronic liver diseases, ALD and VLD, in hospitalized CDI patients. There are also limitations in this study. Particularly, NIS data acquisition relies on the accuracy ICD-9-CM codes for medical diagnoses and no lab results, biopsy or image studies were available for NAFLD diagnosis and severity stratification. It is also difficult to determine which cases of CDI were hospital acquired or community acquired because ICD-9 codes are assigned at discharge. To strengthen the validity of ICD-9 codes for NAFLD, VLD and ALD, we used not only diagnostic codes but also excluded the codes for all other chronic liver diseases (Supplementary Table 1)[63]. The ICD-9 codes for CDI were validated previously with good diagnostic accuracy[64,65].
CONCLUSION
In conclusion, this study found more favorable overall outcomes but higher rates of intestinal complications in patients hospitalized with CDI and coexisting NAFLD, compared to CDI with coexisting ALD and VLD, individually. These results suggested that NAFLD may be associated with a higher risk of CDI associated intestinal complications through alteration of gut microbiota. Our study also suggested that NAFLD associated metabolic syndrome may contribute significantly to the gut dysbiosis even in the early liver disease stages and cause increased risk for CDI and its complications. During the last few years, the novel and rapidly evolving research technologies for the gut microbiome have been opening up an exciting era in the microbiota therapeutics for different disease models[66]. Tremendous progress has been observed in the treatment of NAFLD and CDI through gut microbiome manipulation. Our study may help increase awareness and diagnose intestinal complications in patients with two common diseases: CDI and NAFLD. Unraveling the significance of interactions between gut microbiota, gut immunity and systemic metabolic impact of NAFLD with prospective studies will provide more insights into the future microbiota therapeutics for CDI and NAFLD.
ARTICLE HIGHLIGHTS
Research background
The ongoing exploration of liver-gut axis has discovered strong association between gut dysbiosis and nonalcoholic fatty liver disease (NAFLD) in both basic science and clinical research. Small-scaled studies have observed that NAFLD is an independent risk factor for Clostridioides difficile infection (CDI).
Research motivation
CDI, as the most common cause of nosocomial diarrhea in developed countries, carries high hospitalization burden. NAFLD, as the leading cause of chronic liver disease, is commonly seen in hospitalized patients with CDI. So far the inpatient outcomes of CDI in the NAFLD population have not been well studied.
Research objectives
The authors aimed to examine the impact of NAFLD on the inpatient outcomes of hospitalized patients with CDI, by comparing the effect of NAFLD with alcoholic liver disease (ALD) and viral liver disease (VLD) individually.
Research methods
This nationwide retrospective cohort study was conducted according to STROBE statement using the National Inpatient Sample database. Inpatient CDI with coexisting NAFLD cases were selected using ICD-9 codes. Multivariate regression analysis was used with adjustment for a large group of possible confounders. Elixhauser Comorbidity Index (ECI) was used for a full description of comorbidity burden.
Research results
CDI with NAFLD was independently associated with lower rates of acute respiratory failure, shorter length of stay and lower hospitalization charges when compared to CDI with VLD and CDI with ALD. However, CDI with NAFLD was associated with a higher rate of intestinal perforation when compared to VLD, and a higher rate of intestinal obstruction when compared to ALD.
Research conclusions
CDI and coexisting NAFLD is associated with favorable overall outcomes, but higher rates of intestinal complications compared to CDI with coexisting ALD and VLD, individually.
Research perspectives
This finding suggests that alteration of gut microbiota may play an important role in the pathogenesis of both CDI and NAFLD. NAFLD associated metabolic syndrome may contribute significantly to the gut dysbiosis and cause increased risk for CDI and its complications. This study provides potential directions for future prospective clinical research to identify the clinical meaningfulness of interactions between gut microbiota, gut immunity and systemic inflammation. The study may open the door for potential microbiota therapeutic targets and manipulation as future treatment options for chronic liver diseases.
ACKNOWLEDGEMENTS
The authors thank Dr. Chunyi Wu, PhD of Epidemiology from University of Michigan Medical School for her assistance with the statistical analysis.
Footnotes
Institutional review board statement: This retrospective cohort study did not directly involve any patients in the data collection process and the National Inpatient Sample (NIS) database is de-identified and available for the public. Therefore, Institutional Review Board approval was not required.
Conflict-of-interest statement: The authors have no conflicts of interest related to this publication.
STROBE statement: The authors have read the STROBE Statement, and the manuscript was prepared and revised according to the STROBE Statement.
Provenance and peer review: Unsolicited article; Externally peer reviewed.
Peer-review started: June 14, 2021
First decision: July 27, 2021
Article in press: September 19, 2021
Specialty type: Gastroenterology and hepatology
Country/Territory of origin: United States
Peer-review report’s scientific quality classification
Grade A (Excellent): A
Grade B (Very good): 0
Grade C (Good): 0
Grade D (Fair): 0
Grade E (Poor): 0
P-Reviewer: Nseir WB S-Editor: Ma YJ L-Editor: A P-Editor: Guo X
Contributor Information
Yi Jiang, Department of Medicine, Rutgers New Jersey Medical School, Newark, NJ 07101, United States.
Salil Chowdhury, Department of Medicine, Rutgers New Jersey Medical School, Newark, NJ 07101, United States.
Bing-Hong Xu, Liver Center and Center for Asian Health, RWJBH-Saint Barnabas Medical Center, Florham Park, NJ 07932, United States.
Mohamad Aghaie Meybodi, Department of Medicine, Rutgers New Jersey Medical School, Newark, NJ 07101, United States.
Konstantinos Damiris, Department of Medicine, Rutgers New Jersey Medical School, Newark, NJ 07101, United States.
Samanthika Devalaraju, Department of Medicine, Rutgers New Jersey Medical School, Newark, NJ 07101, United States.
Nikolaos Pyrsopoulos, Department of Medicine, Gastroenterology and Hepatology, Rutgers New Jersey Medical School, Newark, NJ 07101, United States. pyrsopni@njms.rutgers.edu.
Data sharing statement
Technical appendix, statistical code, and dataset available from the corresponding author at pyrsopni@njms.rutgers.edu. Participants gave informed consent for data sharing.
References
- 1.Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M. Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology. 2016;64:73–84. doi: 10.1002/hep.28431. [DOI] [PubMed] [Google Scholar]
- 2.Huang DQ, El-Serag HB, Loomba R. Global epidemiology of NAFLD-related HCC: trends, predictions, risk factors and prevention. Nat Rev Gastroenterol Hepatol. 2021;18:223–238. doi: 10.1038/s41575-020-00381-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Williams CD, Stengel J, Asike MI, Torres DM, Shaw J, Contreras M, Landt CL, Harrison SA. Prevalence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis among a largely middle-aged population utilizing ultrasound and liver biopsy: a prospective study. Gastroenterology. 2011;140:124–131. doi: 10.1053/j.gastro.2010.09.038. [DOI] [PubMed] [Google Scholar]
- 4.Vernon G, Baranova A, Younossi ZM. Systematic review: the epidemiology and natural history of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults. Aliment Pharmacol Ther. 2011;34:274–285. doi: 10.1111/j.1365-2036.2011.04724.x. [DOI] [PubMed] [Google Scholar]
- 5.Younossi ZM. Non-alcoholic fatty liver disease - A global public health perspective. J Hepatol. 2019;70:531–544. doi: 10.1016/j.jhep.2018.10.033. [DOI] [PubMed] [Google Scholar]
- 6.Evans CT, Safdar N. Current Trends in the Epidemiology and Outcomes of Clostridium difficile Infection. Clin Infect Dis. 2015;60 Suppl 2:S66–S71. doi: 10.1093/cid/civ140. [DOI] [PubMed] [Google Scholar]
- 7.Rupnik M, Wilcox MH, Gerding DN. Clostridium difficile infection: new developments in epidemiology and pathogenesis. Nat Rev Microbiol. 2009;7:526–536. doi: 10.1038/nrmicro2164. [DOI] [PubMed] [Google Scholar]
- 8.McDonald LC, Gerding DN, Johnson S, Bakken JS, Carroll KC, Coffin SE, Dubberke ER, Garey KW, Gould CV, Kelly C, Loo V, Shaklee Sammons J, Sandora TJ, Wilcox MH. Clinical Practice Guidelines for Clostridium difficile Infection in Adults and Children: 2017 Update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA) Clin Infect Dis. 2018;66:e1–e48. doi: 10.1093/cid/cix1085. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Nwachuku E, Shan Y, Senthil-Kumar P, Braun T, Shadis R, Kirton O, Vu TQ. Toxic Clostridioides (formerly Clostridium) difficile colitis: No longer a diarrhea associated infection. Am J Surg. 2021;221:240–242. doi: 10.1016/j.amjsurg.2020.06.026. [DOI] [PubMed] [Google Scholar]
- 10.Kistangari G, Lopez R, Shen B. Frequency and Risk Factors of Clostridium difficile Infection in Hospitalized Patients With Pouchitis: A Population-based Study. Inflamm Bowel Dis. 2017;23:661–671. doi: 10.1097/MIB.0000000000001057. [DOI] [PubMed] [Google Scholar]
- 11.Czepiel J, Dróżdż M, Pituch H, Kuijper EJ, Perucki W, Mielimonka A, Goldman S, Wultańska D, Garlicki A, Biesiada G. Clostridium difficile infection: review. Eur J Clin Microbiol Infect Dis. 2019;38:1211–1221. doi: 10.1007/s10096-019-03539-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Safari Z, Gérard P. The links between the gut microbiome and non-alcoholic fatty liver disease (NAFLD) Cell Mol Life Sci. 2019;76:1541–1558. doi: 10.1007/s00018-019-03011-w. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Aron-Wisnewsky J, Vigliotti C, Witjes J, Le P, Holleboom AG, Verheij J, Nieuwdorp M, Clément K. Gut microbiota and human NAFLD: disentangling microbial signatures from metabolic disorders. Nat Rev Gastroenterol Hepatol. 2020;17:279–297. doi: 10.1038/s41575-020-0269-9. [DOI] [PubMed] [Google Scholar]
- 14.Nseir WB, Hussein SHH, Farah R, Mahamid MN, Khatib HH, Mograbi JM, Peretz A, Amara AE. Nonalcoholic fatty liver disease as a risk factor for Clostridium difficile-associated diarrhea. QJM. 2020;113:320–323. doi: 10.1093/qjmed/hcz283. [DOI] [PubMed] [Google Scholar]
- 15.Papić N, Jelovčić F, Karlović M, Marić LS, Vince A. Nonalcoholic fatty liver disease as a risk factor for Clostridioides difficile infection. Eur J Clin Microbiol Infect Dis. 2020;39:569–574. doi: 10.1007/s10096-019-03759-w. [DOI] [PubMed] [Google Scholar]
- 16.Agency for Healthcare Research and Quality. Healthcare Cost and Utilization Project (HCUP). 2019. Available from: https://www.ahrq.gov/data/hcup/index.html . [PubMed]
- 17.Moore BJ, White S, Washington R, Coenen N, Elixhauser A. Identifying Increased Risk of Readmission and In-hospital Mortality Using Hospital Administrative Data: The AHRQ Elixhauser Comorbidity Index. Med Care. 2017;55:698–705. doi: 10.1097/MLR.0000000000000735. [DOI] [PubMed] [Google Scholar]
- 18.Tripathi A, Debelius J, Brenner DA, Karin M, Loomba R, Schnabl B, Knight R. The gut-liver axis and the intersection with the microbiome. Nat Rev Gastroenterol Hepatol. 2018;15:397–411. doi: 10.1038/s41575-018-0011-z. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Son G, Kremer M, Hines IN. Contribution of gut bacteria to liver pathobiology. Gastroenterol Res Pract. 2010;2010 doi: 10.1155/2010/453563. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Stärkel P, Schnabl B. Bidirectional Communication between Liver and Gut during Alcoholic Liver Disease. Semin Liver Dis. 2016;36:331–339. doi: 10.1055/s-0036-1593882. [DOI] [PubMed] [Google Scholar]
- 21.Mao JW, Tang HY, Zhao T, Tan XY, Bi J, Wang BY, Wang YD. Intestinal mucosal barrier dysfunction participates in the progress of nonalcoholic fatty liver disease. Int J Clin Exp Pathol. 2015;8:3648–3658. [PMC free article] [PubMed] [Google Scholar]
- 22.Miele L, Valenza V, La Torre G, Montalto M, Cammarota G, Ricci R, Mascianà R, Forgione A, Gabrieli ML, Perotti G, Vecchio FM, Rapaccini G, Gasbarrini G, Day CP, Grieco A. Increased intestinal permeability and tight junction alterations in nonalcoholic fatty liver disease. Hepatology. 2009;49:1877–1887. doi: 10.1002/hep.22848. [DOI] [PubMed] [Google Scholar]
- 23.Verdam FJ, Rensen SS, Driessen A, Greve JW, Buurman WA. Novel evidence for chronic exposure to endotoxin in human nonalcoholic steatohepatitis. J Clin Gastroenterol. 2011;45:149–152. doi: 10.1097/MCG.0b013e3181e12c24. [DOI] [PubMed] [Google Scholar]
- 24.Jiang W, Wu N, Wang X, Chi Y, Zhang Y, Qiu X, Hu Y, Li J, Liu Y. Dysbiosis gut microbiota associated with inflammation and impaired mucosal immune function in intestine of humans with non-alcoholic fatty liver disease. Sci Rep. 2015;5:8096. doi: 10.1038/srep08096. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Theriot CM, Koenigsknecht MJ, Carlson PE Jr, Hatton GE, Nelson AM, Li B, Huffnagle GB, Z Li J, Young VB. Antibiotic-induced shifts in the mouse gut microbiome and metabolome increase susceptibility to Clostridium difficile infection. Nat Commun. 2014;5:3114. doi: 10.1038/ncomms4114. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Campo L, Eiseler S, Apfel T, Pyrsopoulos N. Fatty Liver Disease and Gut Microbiota: A Comprehensive Update. J Clin Transl Hepatol. 2019;7:56–60. doi: 10.14218/JCTH.2018.00008. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Sehgal R, Bedi O, Trehanpati N. Role of Microbiota in Pathogenesis and Management of Viral Hepatitis. Front Cell Infect Microbiol. 2020;10:341. doi: 10.3389/fcimb.2020.00341. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Le Roy T, Llopis M, Lepage P, Bruneau A, Rabot S, Bevilacqua C, Martin P, Philippe C, Walker F, Bado A, Perlemuter G, Cassard-Doulcier AM, Gérard P. Intestinal microbiota determines development of non-alcoholic fatty liver disease in mice. Gut. 2013;62:1787–1794. doi: 10.1136/gutjnl-2012-303816. [DOI] [PubMed] [Google Scholar]
- 29.Henao-Mejia J, Elinav E, Jin C, Hao L, Mehal WZ, Strowig T, Thaiss CA, Kau AL, Eisenbarth SC, Jurczak MJ, Camporez JP, Shulman GI, Gordon JI, Hoffman HM, Flavell RA. Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity. Nature. 2012;482:179–185. doi: 10.1038/nature10809. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Tsai MC, Liu YY, Lin CC, Wang CC, Wu YJ, Yong CC, Chen KD, Chuah SK, Yao CC, Huang PY, Chen CH, Hu TH, Chen CL. Gut Microbiota Dysbiosis in Patients with Biopsy-Proven Nonalcoholic Fatty Liver Disease: A Cross-Sectional Study in Taiwan. Nutrients. 2020;12 doi: 10.3390/nu12030820. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31.Schwimmer JB, Johnson JS, Angeles JE, Behling C, Belt PH, Borecki I, Bross C, Durelle J, Goyal NP, Hamilton G, Holtz ML, Lavine JE, Mitreva M, Newton KP, Pan A, Simpson PM, Sirlin CB, Sodergren E, Tyagi R, Yates KP, Weinstock GM, Salzman NH. Microbiome Signatures Associated With Steatohepatitis and Moderate to Severe Fibrosis in Children With Nonalcoholic Fatty Liver Disease. Gastroenterology. 2019;157:1109–1122. doi: 10.1053/j.gastro.2019.06.028. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32.Del Chierico F, Nobili V, Vernocchi P, Russo A, De Stefanis C, Gnani D, Furlanello C, Zandonà A, Paci P, Capuani G, Dallapiccola B, Miccheli A, Alisi A, Putignani L. Gut microbiota profiling of pediatric nonalcoholic fatty liver disease and obese patients unveiled by an integrated meta-omics-based approach. Hepatology. 2017;65:451–464. doi: 10.1002/hep.28572. [DOI] [PubMed] [Google Scholar]
- 33.Shen F, Zheng RD, Sun XQ, Ding WJ, Wang XY, Fan JG. Gut microbiota dysbiosis in patients with non-alcoholic fatty liver disease. Hepatobiliary Pancreat Dis Int. 2017;16:375–381. doi: 10.1016/S1499-3872(17)60019-5. [DOI] [PubMed] [Google Scholar]
- 34.Wang B, Jiang X, Cao M, Ge J, Bao Q, Tang L, Chen Y, Li L. Altered Fecal Microbiota Correlates with Liver Biochemistry in Nonobese Patients with Non-alcoholic Fatty Liver Disease. Sci Rep. 2016;6:32002. doi: 10.1038/srep32002. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 35.Jennison E, Byrne CD. The role of the gut microbiome and diet in the pathogenesis of non-alcoholic fatty liver disease. Clin Mol Hepatol. 2021;27:22–43. doi: 10.3350/cmh.2020.0129. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 36.Loomba R, Seguritan V, Li W, Long T, Klitgord N, Bhatt A, Dulai PS, Caussy C, Bettencourt R, Highlander SK, Jones MB, Sirlin CB, Schnabl B, Brinkac L, Schork N, Chen CH, Brenner DA, Biggs W, Yooseph S, Venter JC, Nelson KE. Gut Microbiome-Based Metagenomic Signature for Non-invasive Detection of Advanced Fibrosis in Human Nonalcoholic Fatty Liver Disease. Cell Metab. 2017;25:1054–1062.e5. doi: 10.1016/j.cmet.2017.04.001. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 37.Wong VW, Tse CH, Lam TT, Wong GL, Chim AM, Chu WC, Yeung DK, Law PT, Kwan HS, Yu J, Sung JJ, Chan HL. Molecular characterization of the fecal microbiota in patients with nonalcoholic steatohepatitis--a longitudinal study. PLoS One. 2013;8:e62885. doi: 10.1371/journal.pone.0062885. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 38.Cani PD, Possemiers S, Van de Wiele T, Guiot Y, Everard A, Rottier O, Geurts L, Naslain D, Neyrinck A, Lambert DM, Muccioli GG, Delzenne NM. Changes in gut microbiota control inflammation in obese mice through a mechanism involving GLP-2-driven improvement of gut permeability. Gut. 2009;58:1091–1103. doi: 10.1136/gut.2008.165886. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 39.Dumas ME, Barton RH, Toye A, Cloarec O, Blancher C, Rothwell A, Fearnside J, Tatoud R, Blanc V, Lindon JC, Mitchell SC, Holmes E, McCarthy MI, Scott J, Gauguier D, Nicholson JK. Metabolic profiling reveals a contribution of gut microbiota to fatty liver phenotype in insulin-resistant mice. Proc Natl Acad Sci U S A. 2006;103:12511–12516. doi: 10.1073/pnas.0601056103. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 40.Parséus A, Sommer N, Sommer F, Caesar R, Molinaro A, Ståhlman M, Greiner TU, Perkins R, Bäckhed F. Microbiota-induced obesity requires farnesoid X receptor. Gut. 2017;66:429–437. doi: 10.1136/gutjnl-2015-310283. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 41.Aragonès G, González-García S, Aguilar C, Richart C, Auguet T. Gut Microbiota-Derived Mediators as Potential Markers in Nonalcoholic Fatty Liver Disease. Biomed Res Int. 2019;2019:8507583. doi: 10.1155/2019/8507583. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 42.Brunt EM, Tiniakos DG. Histopathology of nonalcoholic fatty liver disease. World J Gastroenterol. 2010;16:5286–5296. doi: 10.3748/wjg.v16.i42.5286. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 43.Bajaj JS. Alcohol, liver disease and the gut microbiota. Nat Rev Gastroenterol Hepatol. 2019;16:235–246. doi: 10.1038/s41575-018-0099-1. [DOI] [PubMed] [Google Scholar]
- 44.Parlesak A, Schäfer C, Schütz T, Bode JC, Bode C. Increased intestinal permeability to macromolecules and endotoxemia in patients with chronic alcohol abuse in different stages of alcohol-induced liver disease. J Hepatol. 2000;32:742–747. doi: 10.1016/s0168-8278(00)80242-1. [DOI] [PubMed] [Google Scholar]
- 45.Xu D, Huang Y, Wang J. Gut microbiota modulate the immune effect against hepatitis B virus infection. Eur J Clin Microbiol Infect Dis. 2015;34:2139–2147. doi: 10.1007/s10096-015-2464-0. [DOI] [PubMed] [Google Scholar]
- 46.Bajaj JS, Heuman DM, Hylemon PB, Sanyal AJ, White MB, Monteith P, Noble NA, Unser AB, Daita K, Fisher AR, Sikaroodi M, Gillevet PM. Altered profile of human gut microbiome is associated with cirrhosis and its complications. J Hepatol. 2014;60:940–947. doi: 10.1016/j.jhep.2013.12.019. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 47.Chen Y, Yang F, Lu H, Wang B, Chen Y, Lei D, Wang Y, Zhu B, Li L. Characterization of fecal microbial communities in patients with liver cirrhosis. Hepatology. 2011;54:562–572. doi: 10.1002/hep.24423. [DOI] [PubMed] [Google Scholar]
- 48.Kakiyama G, Pandak WM, Gillevet PM, Hylemon PB, Heuman DM, Daita K, Takei H, Muto A, Nittono H, Ridlon JM, White MB, Noble NA, Monteith P, Fuchs M, Thacker LR, Sikaroodi M, Bajaj JS. Modulation of the fecal bile acid profile by gut microbiota in cirrhosis. J Hepatol. 2013;58:949–955. doi: 10.1016/j.jhep.2013.01.003. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 49.Qin N, Yang F, Li A, Prifti E, Chen Y, Shao L, Guo J, Le Chatelier E, Yao J, Wu L, Zhou J, Ni S, Liu L, Pons N, Batto JM, Kennedy SP, Leonard P, Yuan C, Ding W, Hu X, Zheng B, Qian G, Xu W, Ehrlich SD, Zheng S, Li L. Alterations of the human gut microbiome in liver cirrhosis. Nature. 2014;513:59–64. doi: 10.1038/nature13568. [DOI] [PubMed] [Google Scholar]
- 50.Qin N, Le Chatelier E, Guo J, Prifti E, Li L, Ehrlich SD. Qin et al. reply. Nature. 2015;525:E2–E3. doi: 10.1038/nature14852. [DOI] [PubMed] [Google Scholar]
- 51.Bajaj JS, Betrapally NS, Gillevet PM. Decompensated cirrhosis and microbiome interpretation. Nature. 2015;525:E1–E2. doi: 10.1038/nature14851. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 52.Eslam M, Newsome PN, Sarin SK, Anstee QM, Targher G, Romero-Gomez M, Zelber-Sagi S, Wai-Sun Wong V, Dufour JF, Schattenberg JM, Kawaguchi T, Arrese M, Valenti L, Shiha G, Tiribelli C, Yki-Järvinen H, Fan JG, Grønbæk H, Yilmaz Y, Cortez-Pinto H, Oliveira CP, Bedossa P, Adams LA, Zheng MH, Fouad Y, Chan WK, Mendez-Sanchez N, Ahn SH, Castera L, Bugianesi E, Ratziu V, George J. A new definition for metabolic dysfunction-associated fatty liver disease: An international expert consensus statement. J Hepatol. 2020;73:202–209. doi: 10.1016/j.jhep.2020.03.039. [DOI] [PubMed] [Google Scholar]
- 53.Eslam M, Sanyal AJ, George J International Consensus Panel. MAFLD: A Consensus-Driven Proposed Nomenclature for Metabolic Associated Fatty Liver Disease. Gastroenterology. 2020;158:1999–2014.e1. doi: 10.1053/j.gastro.2019.11.312. [DOI] [PubMed] [Google Scholar]
- 54.Ferolla SM, Armiliato GN, Couto CA, Ferrari TC. The role of intestinal bacteria overgrowth in obesity-related nonalcoholic fatty liver disease. Nutrients. 2014;6:5583–5599. doi: 10.3390/nu6125583. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 55.Ghoshal UC, Goel A, Quigley EMM. Gut microbiota abnormalities, small intestinal bacterial overgrowth, and non-alcoholic fatty liver disease: An emerging paradigm. Indian J Gastroenterol. 2020;39:9–21. doi: 10.1007/s12664-020-01027-w. [DOI] [PubMed] [Google Scholar]
- 56.Augustyn M, Grys I, Kukla M. Small intestinal bacterial overgrowth and nonalcoholic fatty liver disease. Clin Exp Hepatol. 2019;5:1–10. doi: 10.5114/ceh.2019.83151. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 57.Wu WC, Zhao W, Li S. Small intestinal bacteria overgrowth decreases small intestinal motility in the NASH rats. World J Gastroenterol. 2008;14:313–317. doi: 10.3748/wjg.14.313. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 58.Kessoku T, Imajo K, Kobayashi T, Ozaki A, Iwaki M, Honda Y, Kato T, Ogawa Y, Tomeno W, Kato S, Higurashi T, Yoneda M, Kirikoshi H, Kubota K, Taguri M, Yamanaka T, Usuda H, Wada K, Kobayashi N, Saito S, Nakajima A. Lubiprostone in patients with non-alcoholic fatty liver disease: a randomised, double-blind, placebo-controlled, phase 2a trial. Lancet Gastroenterol Hepatol. 2020;5:996–1007. doi: 10.1016/S2468-1253(20)30216-8. [DOI] [PubMed] [Google Scholar]
- 59.Schattenberg JM. Intestinal motility: a therapeutic target for NAFLD? Lancet Gastroenterol Hepatol. 2020;5:957–958. doi: 10.1016/S2468-1253(20)30204-1. [DOI] [PubMed] [Google Scholar]
- 60.Gotfried J, Priest S, Schey R. Diabetes and the Small Intestine. Curr Treat Options Gastroenterol. 2017;15:490–507. doi: 10.1007/s11938-017-0155-x. [DOI] [PubMed] [Google Scholar]
- 61.Weaver MJ, McHenry SA, Sayuk GS, Gyawali CP, Davidson NO. Bile Acid Diarrhea and NAFLD: Shared Pathways for Distinct Phenotypes. Hepatol Commun. 2020;4:493–503. doi: 10.1002/hep4.1485. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 62.Reddy SK, Zhan M, Alexander HR, El-Kamary SS. Nonalcoholic fatty liver disease is associated with benign gastrointestinal disorders. World J Gastroenterol. 2013;19:8301–8311. doi: 10.3748/wjg.v19.i45.8301. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 63.Bush H, Golabi P, Otgonsuren M, Rafiq N, Venkatesan C, Younossi ZM. Nonalcoholic Fatty Liver is Contributing to the Increase in Cases of Liver Disease in US Emergency Departments. J Clin Gastroenterol. 2019;53:58–64. doi: 10.1097/MCG.0000000000001026. [DOI] [PubMed] [Google Scholar]
- 64.Dubberke ER, Reske KA, McDonald LC, Fraser VJ. ICD-9 codes and surveillance for Clostridium difficile-associated disease. Emerg Infect Dis. 2006;12:1576–1579. doi: 10.3201/eid1210.060016. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 65.Scheurer DB, Hicks LS, Cook EF, Schnipper JL. Accuracy of ICD-9 coding for Clostridium difficile infections: a retrospective cohort. Epidemiol Infect. 2007;135:1010–1013. doi: 10.1017/S0950268806007655. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 66.Khoruts A, Staley C, Sadowsky MJ. Faecal microbiota transplantation for Clostridioides difficile: mechanisms and pharmacology. Nat Rev Gastroenterol Hepatol. 2021;18:67–80. doi: 10.1038/s41575-020-0350-4. [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
Technical appendix, statistical code, and dataset available from the corresponding author at pyrsopni@njms.rutgers.edu. Participants gave informed consent for data sharing.