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Real-world evidence of long-term survival and healthcare resource use in patients with hepatic encephalopathy receiving rifaximin-α treatment: a retrospective observational extension study with long-term follow-up (IMPRESS II)

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Objective To describe survival of patients with hepatic encephalopathy (HE), up to 5 years after initiation of rifaximin-α (RFX) treatment. Design/Method A retrospective, observational extension study within 9 National Health Service secondary/tertiary UK care centres. All patients had a clinical diagnosis of HE, were being treated with RFX and were included in the previous IMPRESS study which reported the 1-year experience. Demographics, clinical outcomes, selected cirrhosis-related complications, hospital admissions and attendances up to 5 years from RFX initiation were extracted from patient medical records and hospital electronic databases. The primary outcome measure was survival at 5 years post-initiation of RFX treatment. Results The study included 138 patients. The survival rate at 5 years post-initiation of RFX was 35% (95% CI 28.2% to 44.4%) overall and 36% (95% CI 26.1% to 45.4%) for patients with alcohol-related liver disease. Median survival from RFX initiation was 2.8 years (95% CI 2.0 to 3.8; n=136). Among 48 patients alive at 5 years, 69% remained on RFX treatment at the end of the observation period, 74% reported no cirrhosis-related complications and 24% (9/37) had received a liver transplant. Between 1 and 5 years post-initiation, total numbers of liver-related emergency department visits, inpatient admissions, intensive care unit admissions and outpatient visits were 84, 194, 3 and 709, respectively; the liver-related 30-day readmission rate was 37%. Conclusion Within UK clinical practice, RFX use in HE was associated with a 35% survival rate with high treatment adherence, 76% transplant-free survival rate, minimal healthcare resource and low rates of complications at 5 years post-initiation.
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AspinallRJ, etal. Frontline Gastroenterology 2022;0:1–8. doi:10.1136/flgastro-2022-102221
Original research
Real- world evidence of long- term
survival and healthcare resource use
in patients with hepatic
encephalopathy receiving
rifaximin-α treatment: a
retrospective observational
extension study with long- term
follow- up (IMPRESSII)
Richard J Aspinall,1 Mark Hudson,2 Stephen D Ryder,3 Paul Richardson,4
Elizabeth Farrington,5 Mark Wright ,6 Robert T Przemioslo,7
Francisco Perez,8 Melanie Kent,8 Roland Henrar,9 Joe Hickey,10
Debbie L Shawcross11
Liver
To cite: AspinallRJ,
HudsonM, RyderSD, etal.
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Correspondence to
Dr Richard J Aspinall, Queen
Alexandra Hospital, Cosham,
Portsmouth PO6 3LY, UK; r. j.
aspinall@ doctors. org. uk
Received 18 May 2022
Accepted 2 October 2022
© Author(s) (or their employer(s))
2022. Re- use permitted under
CC BY- NC. No commercial re-
use. See rights and permissions.
Published by BMJ.
ABSTRACT
Objective To describe survival of patients with
hepatic encephalopathy (HE), up to 5 years after
initiation of rifaximin-α (RFX) treatment.
Design/Method A retrospective, observational
extension study within 9 National Health
Service secondary/tertiary UK care centres. All
patients had a clinical diagnosis of HE, were
being treated with RFX and were included in
the previous IMPRESS study which reported
the 1- year experience. Demographics,
clinical outcomes, selected cirrhosis- related
complications, hospital admissions and
attendances up to 5 years from RFX initiation
were extracted from patient medical records
and hospital electronic databases. The primary
outcome measure was survival at 5 years post-
initiation of RFX treatment.
Results The study included 138 patients. The
survival rate at 5 years post- initiation of RFX was
35% (95% CI 28.2% to 44.4%) overall and
36% (95% CI 26.1% to 45.4%) for patients
with alcohol- related liver disease. Median
survival from RFX initiation was 2.8 years (95%
CI 2.0 to 3.8; n=136). Among 48 patients alive
at 5 years, 69% remained on RFX treatment
at the end of the observation period, 74%
reported no cirrhosis- related complications and
24% (9/37) had received a liver transplant.
Between 1 and 5 years post- initiation, total
WHAT IS ALREADY KNOWN ON THIS
TOPIC
A number of studies have suggested that
rifaximin-α (RFX) may improve survival,
but these results remain to be confirmed
in longer term multicentre studies.
WHAT THIS STUDY ADDS
This is the first UK real- world study to
evidence the long- term survival rate of
patients with hepatic encephalopathy (HE)
up to 5 years after initiating treatment
with RFX.
Yearly survival rates after initiation of RFX
appear improved in comparison to those
previously published for HE.
In patients surviving 5 years after RFX
initiation, treatment appeared well
tolerated with most patients remaining on
treatment at the end of the observation
period.
HOW THIS STUDY MIGHT AFFECT
RESEARCH, PRACTICE OR POLICY
The results reported here support the
long- term use and tolerability of RFX in
patients with HE and will provide clinical
decision- makers with further evidence of
the continued benefits of RFX to improve
clinical care.
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numbers of liver- related emergency department visits, inpatient
admissions, intensive care unit admissions and outpatient visits
were 84, 194, 3 and 709, respectively; the liver- related 30- day
readmission rate was 37%.
Conclusion Within UK clinical practice, RFX use in HE was
associated with a 35% survival rate with high treatment
adherence, 76% transplant- free survival rate, minimal
healthcare resource and low rates of complications at 5 years
post- initiation.
INTRODUCTION
Hepatic encephalopathy (HE), a frequent compli-
cation of cirrhosis, is associated with significant
morbidity and mortality rates higher than other
hepatic decompensation events.1–3 HE manifests as
a spectrum of neuropsychiatric abnormalities with a
significant socioeconomic burden for patients and
caregivers.4 Episodes of overt HE (displaying obvious
clinical symptoms) occur in approximately 30%–40%
of patients with cirrhosis, often require hospitalisa-
tion and can be triggered by infection, gastrointes-
tinal bleeding or surgery.2 4–6 Patients not effectively
treated after their first episode have an increased risk
of readmission, ongoing symptoms, complications and
mortality.7 Treatments for overt HE aim to resolve such
episodes and prevent recurrence.2 Previous studies
have reported a 1- year survival probability in patients
with HE of 36%–48.3%,1 8–10 reducing to 23% by year
38 and 15% by year 5.1
Rifaximin-α (RFX) is a minimally absorbed oral
antibiotic licensed for the reduction in recurrence of
episodes of overt HE and was recommended by the
National Institute for Health and Care Excellence for
routine use in the UK National Health Service (NHS)
in 2015.11 The action of RFX is focused within the
gut where it reduces ammonia- producing bacteria,
improves antimicrobial activity and promotes gut
barrier repair.12 13 The efficacy and safety of RFX
was evaluated in a meta- analysis of 28 randomised
controlled trials (RCTs) of RFX versus other active
drugs or placebo for patients with HE. In that anal-
ysis, RFX was shown to significantly reduce HE grade,
improve cognitive impairment and reduce recurrent
episodes but no significant improvement in mortality
was observed.14 Follow- up lengths for the included
RCTs ranged from 3 days to 6 months, leaving the long-
term effect of RFX treatment on survival unclear.14
RFX has been shown to reduce healthcare use
for patients receiving RFX treatment in multiple
studies,3 15–19 but the relationship between RFX and
mortality remains unclear. There is currently a lack of
real- world data on the long- term survival of patients
with HE receiving RFX in routine clinical settings.
IMPRESS- II is an extension study in a subgroup of
patients from the IMPRESS study that aimed to eval-
uate 5- year survival outcomes of RFX treatment in
patients with HE in real- world settings.17
MATERIALS AND METHODS
Study design
IMPRESS- II was a retrospective observational study
conducted in 9 of the 13 UK NHS centres included
in IMPRESS.17 The study population consisted of
patients with a clinical diagnosis of HE and who were
treated with RFX. Patients were eligible for inclusion
in IMPRESS- II if they were included in the original
IMPRESS study17; patients whose hospital records
were unavailable were excluded. As this was a retro-
spective observational study and patient- level data
were collected by members of the direct care team,
there was no requirement for patient consent.
Study objectives, outcomes and data collection
The primary objective was to describe survival up to
5 years after RFX initiation (defined as the ‘index
date’). Secondary objectives included: baseline demo-
graphics, clinical characteristics at baseline 2 and 5
years post- RFX initiation, RFX treatment patterns
and healthcare resource use (HCRU) between 1 and
5 years post- RFX initiation. Clinical data included:
Model for End- Stage Liver Disease (MELD)/Child-
Pugh/Albumin- Bilirubin (ALBI) scores, disease history,
RFX treatment and cirrhosis- related complications
(these included variceal bleeding, spontaneous bacte-
rial peritonitis (SBP), renal dysfunction/hepatorenal
syndrome and infections). Baseline Child- Pugh and
MELD scores were recorded within a window of
±1 month from RFX initiation. Treatment patterns
included: RFX discontinuation, reasons for discon-
tinuation, and subsequent reinitiation and concom-
itant treatment. HCRU included: inpatient admis-
sions including intensive care unit (ICU), length of
stay including ICU, reasons for hospitalisations (using
International Classification of Disease (ICD)- 10 codes
to identify liver- related and all- cause HCRU (online
supplemental table 1)17; hospitalisations not including
day cases), hospital visits (emergency department (ED),
outpatient), inpatient, ICU and 30- day readmission
rates. ALBI scores were included as an indication of
disease severity, given the low number of MELD and
Child- Pugh scores recorded in medical records during
the observation period.20
Relevant data from the original IMPRESS database
were included in IMPRESS- II. Additional pseudoan-
onymised data were collected from patient medical
records by members of the direct care team. Data
collection and management for IMPRESS- II was
carried out between March 2020 and October 2021.
Statistical analyses
All analyses were descriptive in nature. Categorical
variables are reported as number (percentage) and
quantitative data as mean (SD) or median (IQR), as
appropriate. Survival was analysed from the index
date using the Kaplan- Meier (KM) method, with the
event defined as death (all causes), reported as 5- year
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AspinallRJ, etal. Frontline Gastroenterology 2022;0:1–8. doi:10.1136/flgastro-2022-102221 3
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survival rates. Median survival was also analysed (95%
CIs, not including those lost to follow- up (n=136)).
Patients who were alive at 5 years and those lost to
follow- up at the end of the observation period were
censored at the end of the observation period and
on the date of last contact, respectively. Survival
rates were also analysed for the subgroup of partici-
pants with alcohol- related liver disease (ARLD). For
variables with missing data, analyses were performed
using the available data; denominators are presented
where data were missing. HCRU data are presented
for patients who were alive and receiving RFX treat-
ment at 1 year post- index. ALBI scores were calculated
from bilirubin and albumin results using the following
formula: ALBI = (log10 bilirubin (µmol/L)×0.66)+(al-
bumin (g/L)×−0.0852).20
RESULTS
Patient demographics and clinical characteristics
A total of 138 patients from 9 centres were included
in the study. Table 1 summarises patient baseline char-
acteristics, figure 1 shows the flow of patients through
the study and table 2 summarises liver- related clinical
characteristics at 1, 2 and 5 years post- index. Mean
(SD) age at index was 60.9 (11.6) years, 38% (53/138)
of patients were female, 79% (109/138) had an overt
HE phenotype and 70% (96/138) had ARLD. In total,
16% (21/131) of patients had a transjugular intrahe-
patic portosystemic shunt (TIPSS) pre- index.
Survival
Median survival from index was 2.8 (95% CI 2.0 to
3.8) years (n=136; see figure 2). Survival rates at 1,
3 and 5 years post- index were: 72% (95% CI 65.2%
to 80.2%), 49% (95% CI 41.0% to 57.9%) and 35%
(95% CI 28.2% to 44.4%), respectively. Of the 88
patients who died, cause of death was recorded for
45; of these, death was liver- related for 91% (n=41;
liver decompensation (n=16, 39%), liver cancer (n=7,
17%), infection (n=4, 10%) and other causes (n=18,
44%)). Among patients with ARLD (n=95), survival
rate at 1, 3 and 5 years post- index was 74% (95% CI
64.8% to 82.5%), 50% (95% CI 39.4% to 59.5%) and
36% (95% CI 26.1% to 45.4%).
Treatment patterns
Of the 48 patients alive at 5 years, 33 were on RFX
treatment at the end of the observation period. Of
these 33 patients, 9 had discontinued and subse-
quently reinitiated RFX treatment, and 24 remained
on treatment throughout the observation period. 114
patients discontinued RFX treatment during the obser-
vation period (66 between 1 and 5 years post- index).
Of these, 105 patients discontinued permanently (48
due to death) and 9 subsequently reinitiated treatment.
The most common reasons for discontinuation in
living patients were liver transplantation (n=3), reso-
lution of encephalopathy (n=6), clinical improvement
Table 1 Demographic and clinical characteristics at initiation of
RFX treatment
Demographic and clinical characteristics
(n=138 unless specified otherwise)
Female (n, %) 53 (38%)
Age, years (mean (±SD))
At diagnosis of cirrhosis 58.2 (12.1)
At diagnosis of HE 60.2 (11.7)
At initiation of RFX 60.9 (11.6)
Phenotype (n, %)
Overt 109 (79%)
Covert 29 (21%)
Time from cirrhosis diagnosis to initiation of RFX,
months
Mean (SD), n=133 32.3 (36.5)
Median (IQR), n=133 21.1 (6.7–47.2)
Time from HE diagnosis to initiation of RFX, months
Mean (SD) 9.0 (17.6)
Median (IQR) 3.1 (0.4–10.5)
Underlying liver disease aetiology (not mutually
exclusive, n (%))
Alcohol- related liver disease 96 (70%)
Non- alcoholic steatohepatitis 32 (23%)
Hepatitis B or C 14 (10%)
Autoimmune hepatitis 2 (1%)
Non- alcoholic fatty liver disease 2 (1%)
Cryptogenic 4 (3%)
Other 3 (2%)
On liver transplant list at initiation (n, %)
Yes 6 (4%)
No 132 (96%)
Proportion of patients with prior TIPSS at initiation of
RFX (n, % n=131)
Yes procedural 21 (16%)
No 110 (84%)
Not recorded 7
Child- Pugh score (n, % n=55)
A 4 (7%)
B 32 (58%)
C 19 (35%)
Not recorded 83
MELD score (n, % n=100)
<10 12 (12%)
10<15 37 (37%)
15<20 19 (19%)
20<25 11 (11%)
25 or higher 21 (21%)
Not recorded 38
ALBI score (n, % n=127)
≤−2.60 (grade 1) 12 (9%)
>−2.60 to ≤ −1.39 (grade 2) 63 (50%)
>−1.39 (grade 3) 52 (41%)
Not recorded 11
Alcohol use status (n, % n=117)
Currently drinking alcohol 23 (20%)
Continued
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(n=4) or being moved to end- of- life care (n=4; online
supplemental table 3). In patients who were alive at 5
years post- index and did not undergo liver transplan-
tation (n=37), the median time to RFX discontinua-
tion was 0.8 (IQR 0.2–1.7) years. The median (IQR)
time to RFX discontinuation in patients who discon-
tinued due to HE resolution or clinical improvement
(n=10) and in those who discontinued without HE
resolution or clinical improvement (n=27) was 0.7
(IQR 0.3–1.3) and 0.8 (IQR 0.1–1.8) years, respec-
tively. Use of concomitant laxatives is summarised in
online supplemental table 4.
In patients who were alive at 2 years post- index
(n=80), 93% reported no clinically relevant events,
4% reported variceal bleeding, 3% reported infections
and 1% reported SBP between 1 and 2 years post-
index. In patients who were alive at 5 years (n=50),
74% reported no clinically relevant events, 6%
reported variceal bleeding, 14% reported infections,
4% reported SBP and 2% reported renal dysfunc-
tion/hepatorenal syndrome between 2 and 5 years
post- index. The reported events were not mutually
exclusive.
Healthcare resource use
The total numbers of liver- related (all- cause) ED visits,
inpatient admissions, ICU admissions and outpatient
visits between 1 and 5 years post- index were 84 (156),
194 (310), 3 (6) and 709 (1123), respectively (online
supplemental table 5). The median (IQR) lengths of
stay for inpatient and ICU admissions from 1 to 5 years
post- index for liver- related/all- cause HCRU were 4.0
(2.0–10.0)/3.0 (1.0–9.0) and 2.0 (1.5–3.5)/4.9 (2.0–
5.0) days, respectively. Of all liver- related (all- cause)
ED visits in the 1–5 years post- index, 66%–95%
resulted in inpatient admissions, 0%–2% resulted in
ICU admissions, and in 5%–33%, the patient was
discharged home. For inpatient admissions in the 1–5
years post- index, between 93% and 95% resulted in
the patient being discharged home, 0%–1% resulted
in admission to ICU and 4%–7% resulted in deaths.
Of the total 138 patients, 20% of patients recorded
a subsequent liver- related admission and 30- day read-
mission within 1–5 years post- index. Of this 20%,
9% were before 2 years, 10% after 2 years and 1%
recorded readmissions both before and after 2 years.
The total number of readmissions was 76, with 41%
of these between 1 and 2 years and 59% between 2
and 5 years. The 30- day liver- related readmission rate
between year 1 and year 5 was 37% (76/206 admis-
sions).
DISCUSSION
This retrospective 5- year follow- up study aimed to
provide evidence of long- term survival of patients
with HE receiving RFX treatment. We have previously
reported 12 months outcomes in this cohort.17 The
current results at 5 years post- initiation of RFX treat-
ment show a survival rate of 35% and a 76% transplant-
free survival rate. Additional findings suggest relatively
low numbers of ED visits, inpatient and ICU admis-
sions between 1 and 5 years post- initiation, suggesting
a possible positive impact of RFX treatment on HCRU.
Survival
Survival was 72% at 1 year, in line with the original
IMPRESS study (73%)13 and higher than the 42%8
and 44%10 reported in patients with HE not receiving
RFX treatment. It is also higher than the 1- year
survival reported in HE cohorts where RFX treatment
was mixed (48.3%)9 or where RFX treatment status
was not clarified (36%).1 Importantly, RFX use was
associated with reduced risk of death when included in
a multivariable Cox model of survival in patients with
HE .9 The observed 5- year survival rate of 35% is also
higher than the previously reported 5- year survival rate
of patients with HE (15%).1 Importantly, for compar-
ison, the cohort studied by Jepsen et al had ARLD,1
while the cohort here was mixed. The 36% survival
rate in the comparable ARLD subgroup studied here
lends weight to the suggestion that long- term RFX
treatment may be associated with improved survival.
Demographic and clinical characteristics
(n=138 unless specified otherwise)
Not currently drinking alcohol 94 (80%)
Not recorded 21
ALBI, albumin- bilirubin; HE, hepatic encephalopathy; MELD, model
for end- stage liver disease; NAFLD, non- alcoholic fatty liver disease;
NASH, non- alcoholic steatohepatitis; RFX, rifaximin; TIPSS, transjugular
intrahepatic portosystemic shunt.
Table 1 Continued
Figure 1 Study flow (RFX denotes rifaximin-α).
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The 1- year survival rate observed (72%) is lower than
that previously reported at 2 years (81%).21 Baseline
MELD scores in the previous study had a maximum
score of 24 (reflective of more restrictive inclusion/
exclusion criteria), while in this real- world study, a
fifth of patients had scores of 25 and above. Given
higher MELD scores are associated with increased
mortality, inclusion of these patients may account for
the lower survival rate observed.22 Additionally, both
the observed 3- year and 5- year survival rates with
RFX treatment (49% and 35%, respectively) are much
higher than the 23% previously reported without RFX
at 3 years, in line with the observation that RFX may
be associated with increased survival.1 8 9
Although limited by low numbers of observations,
prognostic scores (Child- Pugh, MELD and ALBI)
appear to decrease in severity from index to year 2
(plateauing between 2 and 5 years). This may reflect
deaths or liver transplantation in those with more
severe liver disease, as was observed by Orr et al who
Table 2 Liver- related clinical characteristics at 1, 2 and 5 years post- index
Characteristic 1 year 2 years 5 years
Liver transplant status n (%=87) n (%=67) n (%=37)
Received transplant 3 (3%) 6 (9%) 9 (24%)
Not received transplant 84 (97%) 61 (91%) 28 (76%)
Not recorded 11 11 11
Not applicable* 38 58 88
Child- Pugh score n (%=44) n (%=18) N (%=7)
A 15 (34%) 11 (61%) 4 (57%)
B 25 (57%) 6 (33%) 2 (29%)
C 4 (9%) 1 (6%) 1 (14%)
Not recorded 56 62 43
Not applicable* 38 58 88
MELD score n (%=62) n (%=16) N (%=7)
<10 11 (18%) 7 (44%) 4 (57%)
10<15 27 (44%) 7 (44%) 2 (29%)
15<20 15 (24%) 2 (13%) 1 (14%)
20<25 3 (5%) 0 (0%) 0 (0%)
25 or higher 6 (10%) 0 (0%) 0 (0%)
Not recorded 38 64 43
Not applicable* 38 58 88
ALBI score n (%=91) n (%=65) n (%=40)
≤−2.60 (grade 1) 9 (10%) 12 (18%) 12 (30%)
>−2.60 to ≤−1.39 (grade 2) 63 (69%) 41 (63%) 21 (53%)
>−1.39 (grade 3) 19 (21%) 12 (18%) 7 (18%)
Not recorded 10 15 10
Not applicable* 37 58 88
Alcohol use status n (%=76) n (%=38) n (%=28)
Currently drinking alcohol 11 (14%) 5 (13%) 5 (18%)
Not currently drinking alcohol 65 (86%) 33 (87%) 23 (82%)
Not recorded 24 42 22
Not applicable* 38 58 88
*Not applicable due to death.
ALBI, albumin- bilirubin; MELD, model for end- stage liver disease.
Figure 2 Kaplan- Meier estimates of survival at 5 years post-
rifaximin-α treatment. Crosshairs represent patients from whom data
were censored.
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reported that patients with HE on RFX who died
within 12 months follow- up had a significantly higher
baseline MELD score than those who were alive at 1
year.16 Alternatively, the data could indicate patients
are improving on treatment or have stopped drinking
alcohol. Further research is warranted to explore the
long- term impact of RFX on prognostic scores.
It is unclear whether RFX directly improves survival
in patients with HE, with conflicting results reported
in two independent meta- analyses when compared
with active treatments or placebo.14 23 Other studies
have suggested that RFX treatment may improve
survival, but this remains to be substantiated by larger
RCTs.24–27
Treatment patterns
Discontinuation of therapy was common in those
patients alive over 5 years (48%), with liver disease
recovery with resolution of HE being the most common
reason why treatment was stopped. Other studies
report short- term discontinuation rates from 37% at
6 months to 10% at a year.15 16 A high percentage of
patients alive at 5 years (69%) remained on treatment,
which is in line with previous findings of RFX being
well tolerated in this patient group in both RCT and
real- world settings up to 2 years,15 21 and suggests that
the long- term tolerability of RFX remains good up to
5 years.
Healthcare resource use
Hospital outpatient visits were the most frequent type
of healthcare contact in the 1–5 years post- index, with
much lower numbers of ED visits and ICU admissions
reported. The rate of cirrhosis complications reported
is consistent with the clinical benefit of RFX treatment
in HE that has been observed in previous studies.25 27
Alternatively, the rates of complications could posi-
tively relate to the observed levels of alcohol abstinence
(82%–87% between year 1 and year 5) in the ARLD
cohort in which a low rate of complications might also
be expected.28 Published rates of 30- day readmission
due to liver- related causes vary between 18% and 37%
and thus the observed rate of 37% between 1 and 5
years is at the higher end of this range.7 29–31 However,
the cohorts for the majority of these studies captured
the readmission rates of all patients with cirrhosis,
while this study focused on those with HE (known
to increase the likelihood of rehospitalisation). Taken
together with previous observations of reduced HCRU
post- RFX initiation,16 17 the combined benefit of low
recurrence of HE episodes, low number of compli-
cations and observed low rates of HCRU (outside of
outpatient visits) support the rationale that RFX may
provide a long- term economic benefit.14 31
Strengths and limitations
The study was conducted in ‘real- world’ settings and
recruited from a geographically diverse range of acute
centres including regional hospitals and transplant
centres. The patient cohort displayed baseline demo-
graphics in line with the previous studies15–17 and of
UK patients with advanced liver disease,32 suggesting
they are broadly representative of the intended clin-
ical population. The study is a retrospective design
and is thus limited to routinely collected data recorded
in medical records. Potential limitations of our study
include that the reported results may be open to
confounding effects and measures of HCRU did not
include telemedicine or primary care. Additionally,
while the inclusion of patients with covert HE in the
study reflects real- world practice, it could potentially
impact on the reported survival.
Conclusions
This study provides real- world data from a geograph-
ically dispersed range of treatment centres on the
long- term survival rates associated with RFX treat-
ment in patients diagnosed with HE up to 5 years
post- initiation. The favourable long- term outcomes,
minimal HCRU and low rates of complications
reported from this extension study further support the
use of RFX in patients with HE.
Author affiliations
1Department of Gastroenterology & Hepatology, Portsmouth Hospitals
University NHS Trust, Portsmouth, UK
2Formerly Liver Unit, Freeman Hospital, Newcastle upon Tyne, UK
3NIHR Biomedical Research Unit in Gastrointestinal and Liver Diseases at
Nottingham University Hospitals NHS Trust and the University of Nottingham,
Nottingham, UK
4Department of Gastroenterology and Hepatology, Royal Liverpool &
Broadgreen University Hospitals NHS Trust, Liverpool, UK
5Department of Gastroenterology & Hepatology, Royal Cornwall Hospital,
Cornwall, UK
6Department of Hepatology, University Hospital Southampton, Southampton,
UK
7Department of Gastroenterology, Southmead Hospital, Bristol, UK
8Department of Gastroenterology, University Hospital of North Durham,
Durham, UK
9Global Medical Affairs, Norgine, Harefield, UK
10OPEN Health, Marlow, UK
11Institute of Liver Studies, Inflammation Biology, School of Immunology
and Microbial Sciences, Faculty of Life Sciences and Medicine, King’s College
London, London, UK
Twitter Mark Wright @marktheliverdoc
Acknowledgements The authors thank the following for their
contribution to study data collection: Ms Alison Dimmer and
Ms Beverley Longhurst at Portsmouth Hospitals University
NHS Trust, Portsmouth. Mr David Tyrer and Ms Giovanna
Bretland at Royal Liverpool & Broadgreen University Hospitals
NHS Trust, Liverpool. Mr Andrew Ayers at King’s College
Hospital, London. Ms Eleanor King at Royal Cornwall
Hospital, Cornwall. Mr Varinder Kaur Ryan at Nottingham
University Hospitals NHS Trust. Ms Charlotte Cranfield,
Ms Louise Jennings and Ms Danielle Gervaise- Brazier at
Southmead Hospital, Bristol. Ms Stefanie Hobson at University
Hospital of North Durham, Durham. Ms Gabriella Campos
and Ms Loredana- Julieta Gergely at The Freeman Hospital,
Newcastle Upon Tyne. Ms Mariya Shaji and Ms Sanchia
Triggs at University Hospital Southampton, Southampton. We
would like to thank the patients whose data were included in
the study. The authors also thank Will Cottam PhD of OPEN
Health, Marlow, who provided medical writing support
(funded by Norgine).
on November 11, 2022 by guest. Protected by copyright.http://fg.bmj.com/Frontline Gastroenterol: first published as 10.1136/flgastro-2022-102221 on 10 November 2022. Downloaded from
AspinallRJ, etal. Frontline Gastroenterology 2022;0:1–8. doi:10.1136/flgastro-2022-102221 7
Liver
Contributors RJA and MH contributed to the
conceptualisation, methodology, investigation, writing—
original draft, writing—review and editing, supervision and
project administration of the study. SDR, PR, EF, MW, RP,
FP, MK and DLS contributed to the investigation and the
writing—review and editing of the study. RH contributed
resources, writing—review and editing, supervision and
project administration of the study. JH contributed to the
methodology, formal analysis, resources, writing—original
draft, writing—editing and reviewing and visualisation of
the study. All authors critically reviewed the manuscript and
approved the final version for publication. RJA is the study
guarantor.
Funding This study was sponsored and funded by Norgine.
Competing interests RJA has previously consulted for, received
speaker fees, and participated on advisory boards for Norgine.
MH has previously received speaker fees from Norgine. RH is
an employee of Norgine. JH is an employee of OPEN Health,
which was commissioned by Norgine to provide support with
the design and conduct of the study, data analysis and medical
writing. DLS has participated in advisory boards/consulted
for Norgine, EnteroBiotix, Kaleido Biosciences, Mallinckrodt,
Shionogi and ONO Pharma UK; received honoraria from
Norgine, Falk Pharma, Alfa Sigma and Aska Pharmaceuticals.
SDR, PR, EF, MW, RP, FP and MK have no competing
interests.
Patient consent for publication Not applicable.
Provenance and peer review Not commissioned; externally
peer reviewed.
Data availability statement Data are available on reasonable
request. Data are available upon reasonable request. The data
described in this article will be shared upon reasonable request
from the corresponding author.
Supplemental material This content has been supplied by the
author(s). It has not been vetted by BMJ Publishing Group
Limited (BMJ) and may not have been peer- reviewed. Any
opinions or recommendations discussed are solely those of
the author(s) and are not endorsed by BMJ. BMJ disclaims
all liability and responsibility arising from any reliance
placed on the content. Where the content includes any
translated material, BMJ does not warrant the accuracy and
reliability of the translations (including but not limited to
local regulations, clinical guidelines, terminology, drug names
and drug dosages), and is not responsible for any error and/
or omissions arising from translation and adaptation or
otherwise.
Open access This is an open access article distributed in
accordance with the Creative Commons Attribution Non
Commercial (CC BY- NC 4.0) license, which permits others
to distribute, remix, adapt, build upon this work non-
commercially, and license their derivative works on different
terms, provided the original work is properly cited, appropriate
credit is given, any changes made indicated, and the use is non-
commercial. See: http://creativecommons.org/licenses/by-nc/4.
0/.
ORCID iD
Mark Wright http://orcid.org/0000-0001-7046-241X
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Article
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Alcohol use can cause hepatic necroinflammation and worsening portal hypertension in patients with cirrhosis. We aimed to evaluate the associations between degree of alcohol use and clinical liver-related outcomes according to etiol- ogy of cirrhosis. In this retrospective cohort analysis, 44,349 U.S. veterans with cirrhosis from alcohol-associated liver disease (ALD), chronic hepatitis C virus (HCV) infection, or nonalcoholic fatty liver disease were identified who com- pleted the Alcohol Use Disorders Identification Test Consumption questionnaire in 2012. Based on this score, level of alcohol use was categorized as none, low level, or unhealthy. Multivariable Cox proportional hazards regression was used to assess for associations between alcohol use and mortality, cirrhosis decompensation (new ascites, encephalopa- thy, or variceal bleeding), and hepatocellular carcinoma (HCC). At baseline, 36.4% of patients endorsed alcohol use and 17.1% had unhealthy alcohol use. During a mean 4.9 years of follow-up, 25,806 (57.9%) patients died, 9,409 (21.4%) developed a new decompensation, and 4,733 (11.1%) developed HCC. In patients with ALD-cirrhosis and HCV-cirrhosis, unhealthy alcohol use, compared with no alcohol use, was associated with higher risks of mortality (adjusted hazard ratio [aHR] = 1.13, 95% confidence interval [CI] = 1.07-1.19 and aHR = 1.14, 95% CI = 1.08-1.20, respectively) and decompensation (aHR = 1.18, 95% CI = 1.07-1.30 and aHR = 1.08, 95% CI = 1.00-1.16, respec- tively). Alcohol use was not associated with HCC, regardless of cirrhosis etiology. Conclusion: Unhealthy alcohol use was common in patients with cirrhosis and was associated with higher risks of mortality and cirrhosis decompensa- tion in patients with HCV-cirrhosis and ALD-cirrhosis. Therefore, health care providers should make every effort to help patients achieve abstinence. The lack of association between alcohol use and HCC merits further investigation.
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Objective: Rifaximin has been approved for use as a first-line therapy for secondary prophylaxis of hepatic encephalopathy (HE). This article is to update existing evidence on efficacy and safety of rifaximin treatment and prevention for HE. Methods: We systematically searched multiple databases until Jan 31 2021. The studies compared rifaximin versus placebo or other active drugs (i.e., nonabsorbable disaccharides, other antibiotics, LOLA, and probiotics) for patients with overt HE (OHE), minimal HE (MHE), and recurrent HE. Results: Twenty-eight randomized controlled trials with a total of 2979 patients were included. Compared with the controls, rifaximin significantly reduced HE grade (OHE: RR = 1.11, 95% CI = 1.02–1.21), improved the cognitive impairments (MHE: RR = 1.82, 95% CI = 1.12–2.93) and prevented the risk of HE recurrent episodes (RR = 1.33, 95% CI = 1.18–1.49). No statistical difference was observed in mortality between rifaximin and their controls (RR = 0.82, 95% CI = 0.54–1.24). The incidence of total adverse events in rifaximin-treated groups was significantly lower than that in the controls during the treatment period (RR = 0.73, 95% CI = 0.54–0.98). In addition, rifaximin treatment was better than other active drugs in improving psychometric indicators (mental state, flapping tremor and PSE index) and reducing the risk of rehospitalization in HE patients. Conclusion: Rifaximin therapy is effective and well-tolerated in different types of HE, which might be recommended as an alternative to conventional oral drugs in clinical settings.
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Background: Rifaximin is efficacious in the prevention of recurrent hepatic encephalopathy (HE) but its mechanism of action remains unclear. We postulated that rifaximin reduces gut microbiota-derived endotoxemia and systemic inflammation, a known driver of HE. Design: A randomised placebo-controlled double-blind mechanistic study of rifaximin versus placebo was performed in cirrhotic patients with HE. Rifaximin-α 550mg (TARGAXAN) twice daily (n=19) or placebo (n=19) was administered for 90-days. Primary outcome: 50% reduction in neutrophil oxidative burst (OB) at 30-days. Secondary outcomes: Psychometric Hepatic Encephalopathy Scale (PHES), shotgun metagenomic sequencing of saliva and faeces, plasma and faecal metabolome, blood bacterial DNA, neutrophil toll-like receptor (TLR)-2/4/9 and interleukin-8 expression, and plasma and faecal cytokine analysis. Results: Patients were well-matched: median MELD [11 rifaximin-α versus 10 placebo]. Day 30 HE grade normalised on rifaximin-α but not placebo (p=0.014) with an improvement in PHES score; p=0.009. Rifaximin-α reduced circulating neutrophil TLR-4 expression on day-30 (p=0.021) with a reduction in plasma tumour necrosis factor-α (TNF-α); p<0.001. Rifaximin-α suppressed oralisation of the gut, reducing the mucin-degrading sialidase-rich species Streptococcus spp, Veillonella atypica and parvula, Akkermansia and Hungatella. Rifaximin-α promoted a TNF-α and IL-17E enriched intestinal microenvironment augmenting anti-bacterial responses to invading pathobionts and promoting gut barrier repair. Those on rifaximin-α were less likely to develop infection [odds ratio 0.21(0.05-0.96)]. Conclusion: Rifaximin-treated patients were less likely to develop infection with resolution of overt and covert HE. Rifaximin-α reduced oralisation of the gut with mucin-degrading species attenuating systemic inflammation. These data link rifaximin-α as having a role in gut barrier repair as a mechanism by which it ameliorates bacterial translocation and systemic endotoxemia in cirrhosis. Lay summary: This clinical trial examined the underlying mechanism of action of an antibiotic called rifaximin which has been shown to be an effective treatment for a complication of chronic liver disease which effects the brain (termed encephalopathy). It shows that rifaximin suppresses gut bacteria that translocate from the mouth to the intestine which causes the intestinal wall to become leaky by breaking down the protective mucus barrier. This resolves encephalopathy and reduces inflammation in the blood preventing the development of infection. Clinical trial number: ClinicalTrials.gov NCT02019784.
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Overt hepatic encephalopathy is a generally reversible neurologic complication of cirrhosis. Overt hepatic encephalopathy has been associated with poor hospitalization- and mortality-related outcomes, important given increasing hepatic encephalopathy–related hospitalizations over time. The aim of this narrative review is to provide an overview of hospital- and mortality-related outcomes in patients with overt hepatic encephalopathy and the pharmacologic therapies that may improve these outcomes. Guideline-recommended prophylaxis with lactulose (first-line therapy) or secondary prophylaxis with rifaximin plus lactulose decreases hospital admissions and mortality rates. Rifaximin or lactulose treatment was beneficial for reducing the hospitalization rate in patients with hepatic encephalopathy compared with no treatment. Further, retrospective studies have shown that rifaximin with or without lactulose was effective for decreasing the number of hepatic encephalopathy episodes, hepatic encephalopathy–related hospitalizations, and duration of hospitalization. Ornithine phenylacetate, an ammonia-reducing agent currently in development, is also being investigated in hospitalized patients with hepatic encephalopathy. Overall, data support that prophylaxis for the prevention of hepatic encephalopathy recurrence improves outcomes in patients with cirrhosis and a history of hepatic encephalopathy.
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Background Liver disease is an increasing burden on population health globally. Aims To characterise burden of liver disease among general internal medicine inpatients at seven Toronto-area hospitals and compare it to other common medical conditions. Methods Data from April 2010 to October 2017 were obtained from hospitals participating in the GEMINI collaborative. Using these cohort data from hospital information systems linked to administrative data, we defined liver disease admissions using most responsible discharge diagnoses categorised according to international classification of diseases, 10th Revision—enhanced Canadian version (ICD-10-CA). We identified admissions for heart failure, chronic obstructive pulmonary disease (COPD) and pneumonia as comparators. We calculated standardised mortality ratios (SMRs) as the ratio of observed to expected deaths. Results Among 239 018 discharges, liver disease accounted for 1.7% of most responsible discharge diagnoses. Liver disease was associated with marked premature mortality, with SMR of 8.84 (95% CI 8.06-9.67) compared to 1.06 (95% CI 0.99-1.12) for heart failure, 1.05 (95% CI 0.96-1.15) for COPD and 1.28 (95% CI 1.20-1.37) for pneumonia. The majority of deaths were among patients younger than 65 years (57.7%) compared to 3.3% in heart failure, 5.6% in COPD and 10.7% in pneumonia. Liver disease patients presented with worse Laboratory-Based Acute Physiology Scores, were more frequently admitted to the intensive care unit (14.4%), incurred higher average total costs (median $6723 CAD), had higher in-hospital mortality (11.4%), and were more likely to be a readmission from 30 days prior (19.8%). Non-alcoholic fatty liver disease admissions increased from 120 in 2011-2012 to 215 in 2016-2017 (P < 0.01). Conclusion In Canada's largest urban centre, liver disease admissions resulted in premature morbidity and mortality with higher resource use compared to common cardio-respiratory conditions. Re-evaluation of approaches to caring for inpatients with liver disease is timely and justified.
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Rifaximin is an oral non‐systemic antibiotic, with minimal gastrointestinal absorption and broad‐spectrum antibacterial activity covering both grampositive and gramnegative organisms. Rifaximin is currently worldwide used in patients with cirrhosis for preventing recurrent hepatic encephalopathy because its efficacy and safety has been proved by large randomized clinical trials. In the last decade, experimental and clinical evidence suggest that rifaximin could have other beneficial effects on the course of cirrhosis by modulating the gut microbiome and affecting the gut‐liver axis, which, in turn, can interfere with major events of the pathophysiological cascade underlying decompensated cirrhosis, such as systemic inflammatory syndrome, portal hypertension, and bacterial infections. However, the use of rifaximin for prevention or treatment of other complications, including spontaneous bacterial peritonitis or other bacterial infections, is not accepted as evidence by clinical trials is still very weak. The present review deals in the first part with the potential impact of rifaximin on pathogenic mechanisms in liver diseases, whereas, in the second part, its clinical effects are critically discussed. It clearly emerges that, due to its potential activity on multiple pathogenic events, the efficacy of rifaximin in the prevention or management of complications other than hepatic encephalopathy deserves to be investigated extensively. The results of double‐blinded, adequately powered randomized clinical trials assessing the effect of rifaximin, alone or in combination with other drugs, on hard clinical endpoints, such as decompensation of cirrhosis, acute‐on‐chronic liver failure and mortality, are therefore eagerly awaited.
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BACKGROUND Hepatic encephalopathy (HE) is a reversible neuropsychiatric complication of liver cirrhosis and occurs in up to 50% of cirrhotic patients. Studies examining the prognostic significance of HE are limited despite the high prevalence in cirrhosis. AIM To define the clinical outcomes of patients after an episode of HE treated with current standards-of-care. METHODS All patients hospitalised with HE requiring Rifaximin to 3 tertiary centres over 46-mo (2012–2016) were identified via pharmacy dispensing records. Patients with hepatocellular carcinoma and those prescribed Rifaximin prior to admission were excluded. Medical records were reviewed to determine baseline characteristics and survival. The Kaplan-Meier method was used to calculate survival probability. Univariate survival analysis was performed with variables reaching statistical significance included in a multivariate analysis. The primary outcome was 12-mo mortality following commencement of Rifaximin. RESULTS 188 patients were included. Median age was 57 years (IQR 50-65), 71% were male and median model for end stage liver disease and Child Pugh scores were 25 (IQR 18-31) and 11 (IQR 9-12) respectively. The most common causes of cirrhosis were alcohol (62%), hepatitis C (31%) and non-alcoholic fatty liver disease (20%). A precipitating cause for HE was found in 92% patients with infection (43%), GI bleeding (16%), medication non-compliance (15%) and electrolyte imbalance (14%) the most common. During a mean follow up period of 12 ± 13 mo 107 (57%) patients died and 32 (17%) received orthotopic liver transplantation. The most common causes of death were decompensated chronic liver disease (57%) and sepsis (19%). The probability of survival was 44% and 35% at 12- and 24-mo respectively. At multivariate analysis a model for end stage liver disease > 15 and international normalised ratio reached statistical significance in predicting mortality. CONCLUSION Despite advances made in the management of HE patients continue to have poor survival. Thus, in all patients presenting with HE the appropriateness of orthotopic liver transplantation should be considered.
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Background Hepatic encephalopathy is a devastating complication of cirrhosis. Aim To describe the outcomes after developing hepatic encephalopathy among contemporary, aging patients. Methods We examined data for a 20% random sample of United States Medicare enrolees with cirrhosis and Part D prescription coverage from 2008 to 2014. Among 49 164 persons with hepatic encephalopathy, we evaluated the associations with transplant‐free survival using Cox proportional hazard models with time‐varying covariates (hazard ratios, HR) and incidence rate ratios (IRR) for healthcare utilisation measured in hospital‐days and 30‐day readmissions per person‐year. We validated our findings in an external cohort of 2184 privately insured patients with complete laboratory values. Results Hepatic encephalopathy was associated with median survivals of 0.95 and 2.5 years for those ≥65 or <65 years old and 1.1 versus 3.9 years for those with and without ascites. Non‐alcoholic fatty‐liver disease posed the highest adjusted risk of death among aetiologies, HR 1.07 95% CI (1.02, 1.12). Both gastroenterology consultation and rifaximin utilisation were associated with lower mortality, respective adjusted‐HR 0.73 95% CI (0.67, 0.80) and 0.40 95% CI (0.39, 0.42). Thirty‐day readmissions were fewer for patients seen by gastroenterologists (0.71 95% CI [0.57‐0.88]) and taking rifaximin (0.18 95% CI [0.08‐0.40]). Lactulose alone was associated with fewer hospital‐days, IRR 0.31 95% CI (0.30‐0.32), than rifaximin alone, 0.49 95% CI (0.45‐0.53), but the optimal therapy combination was lactulose/rifaximin, IRR 0.28 95% CI (0.27‐0.30). These findings were validated in the privately insured cohort adjusting for model for endstage liver disease‐sodium score and serum albumin. Conclusions Hepatic encephalopathy remains morbid and associated with poor outcomes among contemporary patients. Gastroenterology consultation and combination lactulose‐rifaximin are both associated with improved outcomes. These data inform the development of care coordination efforts for subjects with cirrhosis.
Article
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Background: After 5 years since the registration of rifaximin-α as a secondary prophylaxis for overt hepatic encephalopathy (HE) in the Netherlands, we aimed to evaluate the use of hospital resources and safety of rifaximin-α treatment in a real-world setting. Methods: We carried out prospective identification of all patients using rifaximin-α for overt HE. We assessed hospital resource use, bacterial infections, and adverse events during 6-month episodes before and after rifaximin-α initiation. Results: During 26 months we included 127 patients [71.7% male; median age 60.8 years (interquartile range: 56.2-66.1); median model for end-stage liver disease (MELD) score 15.0 (interquartile range: 12.1-20.4); 98% using lactulose treatment]. When comparing the first 6 months after rifaximin-α initiation with the prior 6 months, HE-related hospital admissions decreased (0.86 to 0.41 admissions/patient; p < 0.001), as well as the mean length of stay (8.85 to 3.79 bed days/admission; p < 0.001). No significant differences were found regarding HE-related intensive care unit admissions (0.09 to 0.06 admission/patient; p = 0.253), stay on the intensive care unit (0.43 to 0.57 bed days/admission; p = 0.661), emergency department visits (0.66 to 0.51 visits/patient; p = 0.220), outpatient clinic visits (2.49 to 3.30 bed visits/patient; p = 0.240), or bacterial infections (0.41 to 0.35 infections/patient; p = 0.523). Adverse events were recorded in 2.4% of patients. Conclusions: The addition of rifaximin-α to lactulose treatment was associated with a significant reduction in the number and length of HE-related hospitalizations for overt HE. Rifaximin-α treatment was well tolerated.
Article
Background: Rifaximin has been shown to reduce the incidence of hepatic encephalopathy and other complications in patients with cirrhosis. However, few studies have investigated the effect of rifaximin in cirrhotic patients with refractory ascites. Aim: To evaluate the effects of rifaximin in the treatment of refractory ascites and to preliminarily explore its possible mechanism. Methods: A total of 75 cirrhotic patients with refractory ascites were enrolled in the study (50 in a rifaximin and 25 in a control group). Patients in the rifaximin group were divided into two subgroups according to the presence of spontaneous bacterial peritonitis and treatment with or without other antibiotics (19 patients treated with rifaximin and 31 patients treated with rifaximin plus intravenous antibiotics). All patients received conventional treatment for refractory ascites, while patients in the rifaximin group received oral rifaximin-α 200 mg four times daily for at least 2 wk. The ascites grade, fasting weight, liver and kidney function, and inflammatory factors in the plasma were evaluated before and after treatment. In addition, the gut microbiota was determined by metagenomics sequencing to analyse the changes in the characteristics of the gut microbiota before and after rifaximin treatment. The patients were followed for 6 mo. Results: Compared with the control group, the fasting weight of patients significantly decreased and the ascites significantly subsided after treatment with rifaximin (P = 0.011 and 0.009, respectively). The 6-mo survival rate of patients in the rifaximin group was significantly higher than that in the control group (P = 0.048). The concentration of interferon-inducible protein 10 decreased significantly in the rifaximin group compared with that in the control group (P = 0.024). The abundance of Roseburia, Haemophilus, and Prevotella was significantly reduced after rifaximin treatment, while the abundance of Lachnospiraceae_noname, Subdoligranulum, and Dorea decreased and the abundance of Coprobacillus increased after treatment with rifaximin plus intravenous antibiotics. The gene expression of virulence factors was significantly reduced after treatment in both subgroups treated with rifaximin or rifaximin plus intravenous antibiotics. Conclusion: Rifaximin mitigates ascites and improves survival of cirrhotic patients with refractory ascites. A possible mechanism is that rifaximin regulates the structure and function of intestinal bacteria, thus improving the systemic inflammatory state.