Journal of

Clinical Medicine

Article
Comprehensive Lifestyle-Modification in Patients
with Ulcerative Colitis–A Randomized
Controlled Trial
Jost Langhorst 1,2, *, Margarita Schöls 2 , Zehra Cinar 2 , Ronja Eilert 2 , Kerstin Kofink 2 ,
Anna Paul 3 , Christina Zempel 3 , Sigrid Elsenbruch 4 , Romy Lauche 5 , Mohamed Ahmed 6 ,
Dirk Haller 6,7 , Holger Cramer 3 , Gustav Dobos 3 and Anna K. Koch 3
1 Department of Internal and Integrative Medicine, Sozialstiftung Bamberg, Germany, Chair for Integrative
Medicine, University of Duisburg-Essen, Buger Straße 80, 96049 Bamberg, Germany
2 Integrative Gastroenterology, University of Duisburg-Essen, Evang. Kliniken-Essen-Mitte, Am Deimelsberg
34 a, 45276 Essen, Germany; margarita_schoels@web.de (M.S.); zehra-cinar@gmx.de (Z.C.);
r.m.eilert@web.de (R.E.); kerstinkofink@gmx.de (K.K.)
3 Department of Internal and Integrative Medicine, Evang. Kliniken Essen-Mitte, Faculty of Medicine,
University of Duisburg-Essen, Am Deimelsberg 34 a, 45276 Essen, Germany; a.paul@kem-med.com (A.P.);
c.zempel@kem-med.com (C.Z.); h.cramer@kem-med.com (H.C.); g.dobos@kem-med.com (G.D.);
a.koch@kem-med.com (A.K.K.)
4 Department of Medical Psychology and Medical Sociology, Ruhr University Bochum, Universitätsstraße 150,
44801 Bochum, Germany; sigrid.elsenbruch@rub.de
5 National Centre for Naturopathic Medicine, Southern Cross University, Lismore, Lismore Campus, Military
Rd, Lismore, NSW 2480, Australia; romy.lauche@scu.edu.au
6 Technical University of Munich, Chair of Nutrition and Immunology, Gregor-Mendel-Str. 2,
85354 Freising-Weihenstephan, Germany; mohamed.ahmed@tum.de (M.A.); dirk.haller@tum.de (D.H.)
7 ZIEL-Institute for Food and Health, Technical University of Munich, 85354 Freising, Germany
* Correspondence: Jost.Langhorst@sozialstiftung-bamberg.de; Tel.: +49-(0)951-503-11251




Received: 29 July 2020; Accepted: 21 September 2020; Published: 24 September 2020


Abstract: Patients with ulcerative colitis suffer from impaired health-related quality of life
(HrQoL). Comprehensive lifestyle-modification might increase HrQoL and decrease disease activity.
Ninety-seven patients in clinical remission with impaired HrQoL were randomly assigned to a
10 week comprehensive lifestyle-modification program (LSM; n = 47; 50.28 ± 11.90 years) or control
(n = 50; 45.54 ± 12.49 years) that received a single workshop of intense training in naturopathic
self-help strategies. Primary outcome was HrQoL (Inflammatory Bowel Disease Questionnaire;
IBDQ) at week 12. Secondary outcomes included IBDQ subscales; generic HrQoL; disease activity
and microbiome. Both groups showed improvement in HrQoL from baseline to post-treatment at
week 12. The IBDQ sum score showed no significant group difference (p = 0.251). If patients attended
more than 50% of the training sessions, a significant group effect (p = 0.034) was evident in favor
of LSM. In addition, the SF-36 mental component summary (p = 0.002) was significantly different
between the groups in favor of LSM. Disease activity microbiome and adverse events did not differ.
Both a single workshop and a 10-week comprehensive lifestyle-modification program can improve
HrQoL in patients with ulcerative colitis in remission with no apparent effects on clinical disease
activity. A treatment difference was observed when examining a subsample of patients who attended
≥ 50% of sessions.

Keywords: ulcerative colitis; health-related quality of life; lifestyle-modification; randomized

controlled trial; integrative medicine

J. Clin. Med. 2020, 9, 3087; doi:10.3390/jcm9103087 www.mdpi.com/journal/jcm

J. Clin. Med. 2020, 9, 3087 2 of 16

1. Introduction
Ulcerative colitis represents a chronic inflammatory bowel disease with a high burden of disease
for the patients. In Europe, the prevalence is 2.2 million people with a steadily increasing incidence [1].
While the pathogenesis and pathological connections are not fully understood, a connection with
the western lifestyle has been suggested, given the higher prevalence in northern Europe and North
America [2]. According to the current pathogenetic model, it is assumed that while there is a genetic
risk for the disease, the onset and course are significantly influenced by environmental and lifestyle
factors [1].
One factor known to contribute to the pathogenesis of ulcerative colitis is psychosocial stress.
Seventy percent of patients with ulcerative colitis believe that temporary psychosocial stress may have
caused a flare, or at least influenced, the course of their disease in the past [3,4]. In addition, current
research gives evidence for bidirectional effects of inflammatory bowel disease (IBD) activity and
psychological disorders with promising implications for psychoeducative and psychosocial treatment
options in IBD [5]. Furthermore, ulcerative colitis is often associated with reduced quality of life, with
a higher level of perceived stress being a strong predictor of patients’ quality of life [6,7]. Quality of life
is particularly impaired during flares. In remission, findings are mixed regarding quality of life [8,9].
What is more, in IBD, the reporting of irritable bowel syndrome (IBS)-type symptoms by patients with
quiescent disease is common and is associated with psychological disorders, impaired quality of life,
and increased health-care use [10]. Our limited understanding of the role of psychosocial and lifestyle
factors have hindered the development of effective comprehensive therapeutic approaches. This has
further led to patients seeking complementary treatment options outside conventional medication
based medicine; often without informing their attending physician [4]. Here, complementary medicine
offers a variety of salutogenetic options, with patients reporting benefits beyond improved disease
control and beyond effects achieved from using mainly pharmacologic-driven medical approaches; for
example, increased quality of life and decreased anxiety [3,11,12].
A comprehensive lifestyle modification program integrates the relevant aspects of complementary
medicine (e.g., mind-body medicine, herbal medicine, nutrition, exercise and naturopathic self-help
strategies) with the aim of improving patients’ physical, as well as psychological, well-being, in addition
to stabilizing the course of disease [13]. Previous research has demonstrated that a multicomponent
intervention including mind-body medicine, self-care, stress management strategies, dietary counselling
with a focus on the Mediterranean diet, naturopathic self-help strategies and herbal medicine, positively
impacts on patients’ quality of life [14,15]. To develop the field, future studies should include patients
with higher disease activity and/or higher levels of psychological distress/psychiatric comorbidity [15].
Therefore, within the present study we focused on patients with impaired quality of life and assessed
the efficacy of a comprehensive lifestyle modification program on health-related quality of life and
disease activity in patients with ulcerative colitis in clinical remission.

2. Experimental Section

2.1. Study Design

The present study was a prospective randomized controlled trial. Patients were recruited through
newspaper and online announcements via a study announcement advertised by the German Crohn’s
Colitis Organization, as well as the Department of Internal and Integrative Medicine at the Kliniken
Essen-Mitte, Essen, Germany. Prospective participants were first screened via telephone for study
eligibility. Eligible patients were then invited to a clinic visit at the Kliniken Essen-Mitte where a
study physician provided patients with written information about the study and confirmed eligibility.
Eligible patients then gave written informed consent and were included in the study. The study was
approved by the Ethics Committee of the University of Duisburg-Essen (approval number 15-6554-BO),
registered on clinicaltrials.gov (ID: NCT02721823) and conducted in accordance with the declaration of
Helsinki and good clinical practice guidelines.
J. Clin. Med. 2020, 9, 3087 3 of 16

2.2. Study Procedure

The study was conducted at the Kliniken Essen-Mitte from early 2016 (first patient in) until late
2019. There were four consecutive study groups. The first group took part in the study from Feb 2016
to April 2018, the second from August 2016 to September 2018, the third from January 2017 to April
2019, and the fourth from August 2017 to October 2019.

2.3. Eligibility Criteria

Patients diagnosed with ulcerative colitis who had been in clinical remission for no longer than 12
months at the longest (Clinical Activity Index according to Rachmilewitz (CAI) ≤4 [16]), were aged
between 18 and 75 years and had impaired quality of life (Inflammatory Bowel Disease Questionnaire
(IBDQ) total score <170 at baseline [17]) were included. Exclusion criteria were: infectious or chronically
active colitis; glucocorticosteroids within the last three months (other than stable medication with
azathioprine: other pharmaceutical treatments according to the medical guideline were allowed, for
example, mesalazine or sulfasalazine); severe psychological illness requiring treatment (e.g., depression,
addiction or schizophrenia; severe comorbid somatic disease (e.g., diabetes mellitus or oncological
disease)), pregnancy or participation in another stress reduction program or clinical study testing a
psychological intervention. In line with current treatment guidelines [1], the inclusion criteria were
changed during recruitment to also include patients receiving immunosuppressive medication. Both
groups were opened for a stratified inclusion of patients using immunomodulatory medication after
the inclusion of 50% of the planned participants.

2.4. Randomization
Patients were randomized using stratified block randomization (strata: sex, azathioprine and
biologics) to either the comprehensive lifestyle-modification program group or the control group.
A biostatistician, not involved in patient recruitment or assessment, generated the random sequence for
allocation in a 1:1 ratio (intervention to control) using Random Allocation Software. Using a generated
random sequence, the study coordinator concealed the allocation (i.e., intervention or control) within
sealed, opaque envelopes by order of ascending number. If a patient met the inclusion and exclusion
criteria and agreed to participate, one of the study coordinators (PhD students) opened the envelope
with the lowest number and enrolled the patient into the respective group (i.e., intervention or control).

2.5. Interventions

2.5.1. Comprehensive Lifestyle-Modification Program

Patients randomized to the comprehensive lifestyle modification group participated in 10 weekly
group sessions, each six hours in duration. An experienced team of physicians and mind-body
instructors guided the sessions. The day clinic program took place on Thursdays, started at 13:00 with
a communal lunch and ended with relaxation therapy at 19:00. At the first appointment, a lecture on
the subject of mind-body medicine was given by the principal investigator (author J.L., an experienced
gastroenterologist specialized in integrative medicine) and participants were given an overview of the
course and objectives of the program. The following nine sessions (sessions 2–10) included theoretical
and practical activities on exercise, yoga, stress management, mindfulness, herbal medicines, home
remedies, communication, meaning of self-awareness and assessment of personal habits, as well as
cooking classes. All sessions were attended by the principal investigator, who gave participants the
opportunity to report on their week within a medical round. Patients were also given a variety of
information material and were asked to apply what they had learned at home. A detailed description
of the program and contents is available via request to the corresponding author.
J. Clin. Med. 2020, 9, 3087 4 of 16

2.5.2. Control
The control group received a single two-hour psychoeducational workshop, conducted by the
principal investigator, on the topic of naturopathic self-care strategies. Various self-care strategies,
mind-body techniques, herbal medicines and home remedies, were presented. Patients were also given
informational material in the form of a small booklet (KVC Verlag, “Was tun bei Colitis ulcerosa”;
Bauchredner 2/16 “Integrative Gesundheit bei chronisch entzündlichen Darmerkrankungen”) which
contains general information about the disease, mind-body medicine and self-help. Patients randomized
to the control group were offered the option to participate in the comprehensive lifestyle modification
program at the end of the study.

2.6. Measures
Outcomes were assessed at five different time-points within the lifestyle-modification group:
baseline measurement at week 0, postintervention measurement at week 12 and follow-up
measurements at weeks 24, 48 and 60. Within the control group, outcomes were assessed at six
time-points: baseline measurement at week 0, postintervention measurement at week 12, and follow-up
measurements at weeks 24 and 48. After week 48, patients in the control group received the lifestyle
modification program; hence the additional postintervention measurement at week 60 and follow-up
at week 108. Outcomes were assessed by experienced study nurses, physicians or doctoral students.
Sociodemographic and clinical characteristics were captured at baseline. The present manuscript reports
on baseline (week 0) and postintervention (week 12) measurements only. Subsequent publications will
report on follow-up measurements beyond week 12.

2.7. Health-Related Quality of Life

The primary outcome total health-related quality of life at week 12 was assessed using the
validated IBDQ German version. [18,19] The IBDQ consists of 32 items with four subscales: bowel
(10 items; scale ranging from 10 to 70), systemic (five Items; scale ranging from 5 to 35), emotion
(12 items; scale ranging from 12 to 84), and social (five items; scale ranging from 5 to 35), all of which
were rated on a 7-point Likert scale (1 = worst rating, 7 = best rating). A total score was then calculated
ranging from 32 to 224, with higher scores indicating better health and scores above 170 indicating no
impairment to quality of life.

2.8. Generic Quality of Life

Generic health-related quality of life was assessed using the 36-Item Short Form Health Survey
(SF-36) which is validated and widely used across different health conditions [20,21]. The SF-36
contains eight sub-scores that are weighted sums of the questions for each section: physical functioning
(10 items), bodily pain (two items), general health perceptions (five items), physical role limitations
(four items), emotional role limitations (three items), social functioning (two items), vitality (four items)
and mental health (five items) that were rated on either 5-point Likert scales, 3-point Likert scales or
dichotomous items. Higher subscales indicated better health. Furthermore, two component summaries
(physical and mental) were calculated using weighted subscales. The eight domains were scored on a
0–100 scale while the two summary measures were norm-based T-scores, with a mean of 50 and SD of
10. In all cases, higher scores indicated better HRQoL.

2.9. Clinical Disease Activity

Clinical disease activity was assessed using the Colitis Activity Index (CAI) by Rachmilewitz [16].
The CAI assesses the severity of colitis based on stool frequency, abdominal pain or cramps, blood
in stool, extraintestinal manifestations of the disease and laboratory findings. A score higher than 4
indicates a flare; scores of 4 or below currently inactive disease.
J. Clin. Med. 2020, 9, 3087 5 of 16

2.10. Fecal Biomarkers

Inflammatory activity was monitored by noninvasive biomarkers fecal lactoferrin and fecal
calprotectin [22]. Stool specimens were collected by the patients and analyzed at an independent
laboratory (Labor L+S AG, Bad Bocklet-Großenbrach, Germany). Each specimen was tested
for lactoferrin and calprotectin with an enzyme-linked immunosorbent assay (ELISAKits from
Immundiagnostik, Bensheim, Germany for calprotectin; IBD-SCAN kit from Techlab, Blacksburg, USA
for lactoferrin).

2.11. Endoscopy and Histology

Voluntary endoscopies at weeks 0 and 12 were performed. The presence and degree of
active inflammation was quantified using the Endoscopic Score according to Rachmilewitz (EI) [16].
Six mucosal biopsies were taken from rectum and sigma. Biopsies were analyzed and scored by
a pathologist, who remained blind to the group allocation throughout the study, using the Riley
Score [23].

2.12. Clinical Parameters

Medications (Table 1).and blood parameters were assessed during a personal interview which
included a physical examination.

2.13. Microbiome
Participants were given a stool collection kit to collect stool specimens. Stool samples were
frozen at −80 ◦ C. Analyses were carried out at the Technical University of Munich, Chair of Nutrition
and Immunology, Freising, Germany. Bacterial DNA was isolated with an alteration of Godon and
colleagues’ method [24]. Basically 500 mg of autoclaved 0.1 mm silica beads (Roth) were added to
frozen fecal samples (100–800 mg). Microbial cells were then lysed mechanically (3 × 40 s at 6.5
m/s) using a FastPrep® -24 (MP Biomedicals) fitted with a 24 × 2 mL cooling adaptor, heat treated
(95 ◦ C, 5 min) and then centrifuged (15,000× g, 5 min, 4 ◦ C). Supernatants were then treated with RNase
(0.1 µg/µL) for 30 min at 37 ◦ C. Metagenomic DNA was purified using silica membrane-based columns
(Macherey-Nagel) following the manufacturer’s recommendations. Genomic DNA concentrations
and purity were measured using the NanoDrop® system (Thermo Scientific) and samples were then
stored at 4 ◦ C during library preparation, or at −20 ◦ C for longer storage. The V3/V4 region of the
16S ribosomal RNA (rRNA) genes was amplified using polymerase chain reaction (PCR, 25 cycles)
from 24 ng of metagenomic DNA using the bacteria-specific primers 341F and 785R [25], followed by a
two-step procedure to limit amplification bias [26]. After purification (AMPure XP system, Beckmann)
and pooling in an equimolar amount, the V3/V4 regions were sequenced in the paired-end modus
(PE275) using an MiSeq device (Illumina, Inc.), as per the manufacturer’s guidelines, and a final DNA
concentration of 10 pM and 15% (v/v) PhiX standard library. After sequencing, processed raw data
were assigned to their corresponding sample via demultiplexing using previously assigned barcode
pairs that were unique to each sample. Afterwards, data were analyzed using the Integrated Microbial
Next Generation Sequencing platform [27], which is based on the UPARSE method [28]. For each
sample, sequences were dereplicated and checked for chimeras using UCHIME [29]. Sequences from
all samples were merged and sorted by abundance, and operational taxonomic units (OTUs) were
picked at a threshold of 97% similarity. Finally, all sequences were mapped back to the representative
sequences resulting in one OTU table for all samples. Only those OTUs with a relative abundance
of above 0.5% total sequences in at least one sample were kept to avoid analysis of spurious OTUs.
SILVA (SILVA Incremental Aligner) [30] was used to assign taxonomic classification to the OTUs’
representative sequences. Specific OTUs with differential abundances between groups were further
identified using EzTaxon (https://www.ezbiocloud.net/). The OTU table was then refined to the
minimum count of sequences observed to prevent incorrect estimation of species richness due to
J. Clin. Med. 2020, 9, 3087 6 of 16

differential sequencing depth. Evaluating beta diversity (diversity between samples) was performed
by measuring the distances between microbial profiles using the generalized Unifrac procedure [31].
Beta diversity was visualized by metric multidimensional scaling (MDS) projections of the generalized
UniFrac distances. For quantifying alpha-diversity, richness was calculated as the value of present
OTUs within one sample. For downstream processing of the intermediate files generated by IMNGS, a
fully modular R-based pipeline (Rhea) was used for analysis of microbial profiles [32].

Table 1. Sociodemographic and clinical characteristics at baseline. Values are expressed as mean ±
standard deviation, unless indicated otherwise.

Lifestyle-Modification (n = 47) Control (n = 50)

Age years 50.28 ± 11.90 (18–74) 45.54 ± 12.49 (19–71)
Female n (%) 34 (72.3) 35 (70)
Weight 72.79 ± 14.90 (52–100) 70.24 ± 16.86 (49.6–150)
Height 171.19 ± 9.05 (152–196) 173.76 ± 9.94 (156–197)
Anamnestic pattern n (%)
Proctitis 14 (29.8) 15 (30)
Left-sided colitis 17 (36.2) 15 (30)
Pancolitis 13 (27.7) 17 (34)
Missing 3 (6.4) 3 (6)
Time since diagnosis in years 18.04 ± 12.00 (2–46) 14.76 ± 10.99 (1–43)
Prior integrative medicine
inpatient treatment at 13 (27.7) 12 (24)
Kliniken Essen-Mitte n (%)
Prior integrative medicine
day-care treatment at 7 (14.9) 3 (6)
Kliniken Essen-Mitte n (%)
Smokers n (%) 2 (4.3) 3 (6)
Married n (%) 33 (70.2) 39 (78)
Education n (%)
Secondary school 17 (36.1) 11 (22)
High school (“Abitur”) 12 (25.6) 14 (28)
University degree 18 (38.3) 25 (50)
Blood parameters
Leucocytes 6.40 ± 1.70 6.73 ± 4.38
Thrombocytes 272.26 ± 81.69 269.98 ± 72.68
Blood sedimentation rate 9.17 ± 10.55 9.54 ± 11.99
C-reactive protein 0.36 ± 0.67 0.29 ± 0.58
Medication intake n (%)
Steroids 2 (4.3) 1 (2)
Azathioprine 4 (8.5) 3 (6)
Mesalazine 33 (70.2) 34 (68)
Herbal medicine 7 (14.9) 15 (30)
Biologicals 3 (6.4) 3 (6)
Other 8 (17) 12 (24)

2.14. Safety
Patients were asked about adverse events at all study visits. Additionally, open-ended questions
were used in the questionnaires to assess any adverse events not mentioned to the study team by
the patients.

2.15. Sample Size Calculation

In previous studies, a difference of 16 points in the IBDQ was identified as a clinically relevant
difference [17,33]. To detect this difference using a two-sample t-test with a 5% significance level and
90% power, and assuming a standard deviation of 23.04 points (as reported for a previous sample [19]),
J. Clin. Med. 2020, 9, 3087 7 of 16

37 patients per group were needed. Accounting for a maximum dropout rate of 20%, at least 92 patients
needed to be enrolled.

2.16. Statistical Analyses

All analyses were conducted on an intention-to-treat basis, i.e., on all participants randomized
J. Clin. Med. 2020, 9, x FOR PEER REVIEW 7 of 16
irrespective of adherence to the study protocol. Missing values were replaced by multiple imputation
methods and 50 additional data sets were generated and averaged. In addition, a per-protocol
analysis was performed to explore the impact of adherence to the study protocol on study results.
analysis was performed to explore the impact of adherence to the study protocol on study results.
The primary outcome was evaluated using univariate analyses of covariance (ANCOVA) with group
The primary outcome was evaluated using univariate analyses of covariance (ANCOVA) with group
as the between‐subject factor and baseline values as covariates. Secondary outcomes were evaluated
as the between-subject factor and baseline values as covariates. Secondary outcomes were evaluated
exploratively also using ANCOVA with group as the between‐subject factor and baseline values as
exploratively also using ANCOVA with group as the between-subject factor and baseline values as
covariates with no adjusted p values for multiple testing. Partial eta‐squared (η22p) was reported as an
covariates with no adjusted p values for multiple testing. Partial eta-squared (η p ) was reported as an
effect‐size estimator. Baseline group differences were analyzed using Student’s t‐tests for continuous
effect-size estimator. Baseline group differences were analyzed using Student’s t-tests for continuous
data and chi‐square tests for categorical data. All analyses were performed using the Statistical
data and chi-square tests for categorical data. All analyses were performed using the Statistical Package
Package for Social Sciences software (IBM SPSS Statistics for Windows, release 25.0; IBM Corporation,
for Social Sciences software (IBM SPSS Statistics for Windows, release 25.0; IBM Corporation, Armonk,
Armonk, NY). A p‐value <0.05 was considered significant. Microbiome was analyzed using
NY). A p-value <0.05 was considered significant. Microbiome was analyzed using aPermutation
aPermutation Multivariate Analysis of Variance test to determine statistically significant differences
Multivariate Analysis of Variance test to determine statistically significant differences between groups
between groups for alpha and beta diversity analyses.
for alpha and beta diversity analyses.
3. Results
3. Results

3.1. Patients
3.1. Patients
336 patients
336 patients expressed
expressed their
their interest
interest to
to participate
participate in in the
the study
study (Figure
(Figure 1).
1). Ninety-seven
Ninety‐seven patients
patients
were invited for further assessment and were all included in the study after
were invited for further assessment and were all included in the study after providing written informed providing written
consent. Patients were randomized to either lifestyle modification (n = 47) or control (n = 50; Table(n1).
informed consent. Patients were randomized to either lifestyle modification (n = 47) or control =
50; baseline
No Table 1).differences
No baseline weredifferences
evident (allwere evident
p > 0.05) Seven (allpatients
p > 0.05) Seven
in the patients
lifestyle in the lifestyle
modification group,
modification group, and four patients in the control, dropped out before
and four patients in the control, dropped out before week 12. Due to changes between screening week 12. Due to changes
and
betweenworkup
baseline screening at and baseline workup
the beginning at thepatients
of the study, beginning who of (1)
thehad
study, patients
normal IBDQ who (1) had
scores (twonormal
in the
IBDQ scores and
intervention (twotwoin the intervention
in the and two
control group), or in
(2)the
werecontrol group), or
in remission for(2) were
more in remission
than 12 monthsfor more
(one in
than 12 months (one in the intervention and one in the control group), were
the intervention and one in the control group), were included in the study despite violation of the included in the study
despite violation
inclusion criteria. of the inclusion
Hence, criteria. Hence,
for the per-protocol for the10per‐protocol
analyses, patients of the analyses, 10 patients
intervention group,ofand
the
intervention group, and seven patients of the control
seven patients of the control group, were excluded from the analysis.group, were excluded from the analysis.

Figure 1. Flow-chart.
Figure 1. Flow‐chart.

Patients
Patients in
in the
the lifestyle
lifestyle modification
modificationgroup
groupattended 8.06±± 2.70
attended8.06 2.70 classes
classes on
on average.
average.

3.2. Primary Outcome: Health‐Related Quality of Life After 12 Weeks

Patients’ IBDQ total after 12 weeks was not significantly different between groups when
analyzing the intention‐to‐treat sample (F(1, 94) = 1.336, p = 0.251, η2p = 0.014). After intervention, 40
 J. Clin. Med. 2020, 9, 3087 8 of 16

3.2. Primary Outcome: Health-Related Quality of Life After 12 Weeks

Patients’ IBDQ total after 12 weeks was not significantly different between groups when analyzing
the intention-to-treat sample (F(1, 94) = 1.336, p = 0.251, η2 p = 0.014). After intervention, 40 percent of
the control group and 48.94 percent of the intervention group had an IBDQ score above 170. In addition,
52 percent of the controls and 70.21 percent of the intervention group experienced a clinically relevant
J. improvement
Clin. Med. 2020, 9,of 16 points
x FOR or more. Within the per-protocol analysis, which included 37 patients
PEER REVIEW from
8 of 16
the lifestyle modification group and 43 patients from the control group, the IBDQ total score was
IBDQ total score
significantly was significantly
different between groups different
at 12 between
weeks in groups
favor ofatthe
12lifestyle
weeks in favor of thegroup
modification lifestyle
(F(1,
modification
77) = 4.66, p group
= 0.034, (F(1,
η2 p 77) = 4.66,
= 0.06) p = 0.034,
(Figure η p =intervention,
2
2). After 0.06) (Figure39.53
2). After intervention,
percent 39.53group
of the control percentand
of54.05
the control
percent of the intervention group had an IBDQ score above 170. In addition, 51.16 percent of In
group and 54.05 percent of the intervention group had an IBDQ score above 170. the
addition, 51.1675.68
controls and percent of the
percent controls
of the and 75.68
intervention grouppercent of the aintervention
experienced group experienced
clinically significant improvement a
clinically significant
of 16 points or more. improvement of 16 points or more.

Comprehensivelifestyle‐modification
Figure2.2.Comprehensive
Figure lifestyle-modificationprogramprogramand andself‐care
self-care(control)
(control)on onhealth‐related
health-related
qualityofoflife
quality lifemeasured
measuredwithwiththe
thesum
sumscore
scoreofofthe
theGerman
Germanversion
versionofofthe
theInflammatory
InflammatoryBowel BowelDisease
Disease
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Questionnaire. Bothgroups
groupsdemonstrated
demonstratedincreases
increasesininhealth‐related
health-relatedquality
qualityofoflife
lifewith
withnonosignificant
significant
differencebetween
difference betweenthe thegroups
groupswithin
withinthetheintention‐to‐treat
intention-to-treatanalysis (ITT;NN==97;
analysis(ITT; 97;pp==0.251).
0.251).Within
Withina a
per-protocol analysis (PP; n = 80), improvement in health-related quality of
per‐protocol analysis (PP; n = 80), improvement in health‐related quality of life was significantly life was significantly
higherininthe
higher thelifestyle
lifestylemodification group(p(p= =0.034);
modificationgroup 0.034);Values
Valuesexpressed mean± ±
expressedasasmean standard
standard deviation.
deviation.
Asterisks indicate
Asterisks indicate significant
significantgroup
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differences. TheThe
dotted line represents
dotted the cut-off
line represents the of 170 indicating
cut‐off of 170
no impairment
indicating to qualityto
no impairment ofquality
life. of life.

3.3. Secondary Outcomes

3.3. Secondary Outcomes
3.3.1. Health-Related Quality of Life Subscales
3.3.1. Health‐Related Quality of Life Subscales
Within the intention-to-treat analysis, the IBDQ bowel subscale, systemic subscale and social
Within
subscale were thenot
intention‐to‐treat analysis,
significantly different the IBDQ
between bowel subscale,
the groups. systemic
The emotional subscale
subscale and social
at week 12 was
subscale were not significantly different between the groups. The emotional subscale
significantly different between the two groups (F(1, 94) = 4.14, p = 0.045, η p = 0.042) in favor of
2 at week 12 was
the
significantly different between
lifestyle-modification the twothe
group. Within groups (F(1, 94)analysis,
per-protocol = 4.14, pthe
= 0.045, η p subscale
2
systemic = 0.042) in favor
(F(1, 77)of= the
4.66,
lifestyle‐modification
p = 0.034, η2 p = 0.057)group.and theWithin the per‐protocol
emotional analysis,
subscale differed the systemic
between groups atsubscale
week 12(F(1,
(F(1, 77)
77) ==4.66,
8.713,
p p= =0.034, η 2 p2= 0.057) and the emotional subscale differed between groups at week 12 (F(1, 77) = 8.713,
0.004, η p = 0.102) in favor of the lifestyle modification group. The bowel and social subscale were
p not
= 0.004, η2p = 0.102)
significantly in favor
different of the lifestyle
between modification
groups (Figure 3). group. The bowel and social subscale were
not significantly different between groups (Figure 3).
 J. Clin. Med. 2020, 9, 3087 9 of 16
J. Clin. Med. 2020, 9, x FOR PEER REVIEW 9 of 16

Comprehensivelifestyle‐modification
Figure 3. Comprehensive
Figure lifestyle-modificationprogram
programand and self‐care
self-care (control)
(control) on
on subscales
subscales ofof
health-related quality
health‐related quality of
of life
life measured
measured with
with the
the German
German version
version ofof the
the inflammatory
inflammatory bowel
bowel disease
disease
questionnaire. Within
questionnaire. Withinthe
theintention-to-treat-analysis
intention‐to‐treat‐analysis (ITT; N =N97),
(ITT; significant
= 97), group
significant differences
group in favor
differences in
of lifestyle-modification were found for the emotional subscale (Emotional (ITT); p
favor of lifestyle‐modification were found for the emotional subscale (Emotional (ITT); p = 0.045);= 0.045); within
the per-protocol
within the per‐protocol (PP; n = (PP;
analysisanalysis 80), significant group differences
n = 80), significant in favor of lifestyle-modification
group differences in favor of lifestyle‐
were evident were
modification for the emotional
evident (Emotional
for the emotional (PP); p = 0.004);
(Emotional andpthe
(PP); systemic
= 0.004); andsubscale (Systemic
the systemic (PP);
subscale
p = 0.034). No further group differences were found (all p > 0.05). Values expressed as mean
(Systemic (PP); p = 0.034). No further group differences were found (all p > 0.05). Values expressed as ± standard
deviation.
mean Asterisks
± standard indicateAsterisks
deviation. significant groupsignificant
indicate differences.group differences.

3.3.2. Generic Quality of Life

3.3.2. Generic Quality of Life
The SF-36 mental component summary score differed significantly between groups at week 12
The SF‐36 mental component summary score differed significantly between groups at week 12
(F(1, 94) = 9.820, p = 0.002, η2 = 0.095) in favor of the lifestyle modification group. The SF-36 physical
(F(1, 94) = 9.820, p = 0.002, η2pp= 0.095) in favor of the lifestyle modification group. The SF‐36 physical
component summary score did not differ significantly between the two groups. Per-protocol analysis
component summary score did not differ significantly between the two groups. Per‐protocol analysis
confirmed the differences regarding the SF-36 mental component summary score (F(1, 77) = 11.641,
confirmed the differences regarding the SF‐36 mental component summary score (F(1, 77) = 11.641, p
p = 0.001, η2 = 0.131) but did not reveal significant differences in the SF-36 physical component
= 0.001, η2p =p 0.131) but did not reveal significant differences in the SF‐36 physical component
summary but significant group differences in favor of lifestyle-modification were further evident for
summary but significant group differences in favor of lifestyle‐modification were further evident for
physical role limitations (p = 0.047), general health perceptions (p = 0.003), vitality (p = 0.004), emotional
physical role limitations (p = 0.047), general health perceptions (p = 0.003), vitality (p = 0.004),
role limitations (p = 0.026), and mental health (p = 0.004; Figure 4).
emotional role limitations (p = 0.026), and mental health (p = 0.004; Figure 4).
J.J.Clin.
Clin. Med. 2020, 9,
Med. 2020, 9, 3087
x FOR PEER REVIEW 10 of
10 of 16
16

Figure 4. Comprehensive lifestyle-modification program and self-care (control) on generic quality of

Figure 4. Comprehensive lifestyle‐modification program and self‐care (control) on generic quality of
life measured with the German version of the 36-item Short Form Health Survey, (A) mental health
life measured with the German version of the 36‐item Short Form Health Survey, (A) mental health
index score; (B) physical health index score; (C) subscales: PF = physical functioning; PRL = physical
index score; (B) physical health index score; (C) subscales: PF = physical functioning; PRL = physical
role limitations; BP = bodily pain; GHP = general health perceptions; VT = vitality; ERL = emotional
role limitations; BP = bodily pain; GHP = general health perceptions; VT = vitality; ERL = emotional
role limitations; MH = mental health; SF = social functioning. Values expressed as mean ± standard
role limitations; MH = mental health; SF = social functioning. Values expressed as mean ± standard
deviation. Asterisks indicate significant group differences.
deviation. Asterisks indicate significant group differences.
3.4. Disease Activity
3.4. Disease Activity
There were no significant differences in disease activity (EI, Riley Score, CAI, fecal lactoferrin, or
There were
calprotectin; Tableno2).significant differences in disease activity (EI, Riley Score, CAI, fecal lactoferrin,
or calprotectin; Table 2).
3.5. Microbiome Diversity
Table 2. Disease activity as measured by the clinical activity index, fecal lactoferrin, and fecal
Microbial beta diversity (diversity between samples) was analyzed via generalized UniFrac
calprotectin. Values are expressed as median (minimum‐maximum), unless indicated otherwise.
distance measurement (a distance matrix for microbial communities assessment) and it was visualized
by multidimension scaling (MDS). No nsignificant differences wereWeek
Baseline
evident
12
between
Groupthe microbial
Differences
profiles of the lifestyle-modification and control group at week 12 (Figure 5), even after p η2 p
controlling
Rachmilewitz Endoscopic Score (M ± SD)
for immunosuppressant medications. Furthermore, there were no significant differences observed in
Lifestyle‐modification ITT 15 2.47 ± 2.77 2.73 ± 2.49
differential abundance of the operational16
taxonomic 0.451 and 0.020
Control ITT 2.19units
± 2.48between the3.13
lifestyle-modification
± 3.20 control
group. The bacterial communities
Lifestyle‐modification PP did not
13 show2.62
any± 2.96
noticeable differences
2.62 ± 2.47 at different phylogenetic
0.227 0.063
Controlfamily
resolutions (phylum, PP and genus).13 2.62 ± 2.57 3.69 ± 3.30
Riley Score (M ± SD)
Lifestyle‐modification ITT 15 4.89 ± 4.55 5.53 ± 4.96
0.406 0.025
Control ITT 16 5.00 ± 4.23 4.31 ± 4.81
Lifestyle‐modification PP 13 5.14 ± 4.78 5.77 ± 5.25
0.586 0.013
Control PP 13 5.77 ± 4.34 5.08 ± 5.04
CAI (M ± SD)
Lifestyle‐modification ITT 47 2.30 ± 1.21 1.74 ± 1.78
0.239 0.015
Control ITT 50 2.12 ± 1.27 2.12 ± 2.00
Lifestyle‐modification PP 37 2.38 ± 1.11 1.65 ± 1.93
0.179 0.023
Control PP 43 2.19 ± 1.34 2.19 ± 2.12
Fecal lactoferrin
Lifestyle‐modification ITT 45 3.85 (0.13–97.47) 8.42 (0.12–61.96)
0.648 0.002
Control ITT 48 3.83 (0.08–85.16) 4.03 (0.08–60.79)
Lifestyle‐modification PP 37 4.97 (0.13–97.47) 4.53 (0.12–61.69)
0.510 0.006
Control PP 43 3.47 (0.08–85.16) 3.91 (0.08–60.79)
J. Clin. Med. 2020, 9, 3087 11 of 16

Table 2. Disease activity as measured by the clinical activity index, fecal lactoferrin, and fecal
calprotectin. Values are expressed as median (minimum-maximum), unless indicated otherwise.

Group Differences
n Baseline Week 12
p η2 p
Rachmilewitz Endoscopic Score
(M ± SD)
Lifestyle-modification ITT 15 2.47 ± 2.77 2.73 ± 2.49
0.451 0.020
Control ITT 16 2.19 ± 2.48 3.13 ± 3.20
Lifestyle-modification PP 13 2.62 ± 2.96 2.62 ± 2.47
0.227 0.063
Control PP 13 2.62 ± 2.57 3.69 ± 3.30
Riley Score (M ± SD)
Lifestyle-modification ITT 15 4.89 ± 4.55 5.53 ± 4.96
0.406 0.025
Control ITT 16 5.00 ± 4.23 4.31 ± 4.81
Lifestyle-modification PP 13 5.14 ± 4.78 5.77 ± 5.25
0.586 0.013
Control PP 13 5.77 ± 4.34 5.08 ± 5.04
CAI (M ± SD)
Lifestyle-modification ITT 47 2.30 ± 1.21 1.74 ± 1.78
0.239 0.015
Control ITT 50 2.12 ± 1.27 2.12 ± 2.00
Lifestyle-modification PP 37 2.38 ± 1.11 1.65 ± 1.93
0.179 0.023
Control PP 43 2.19 ± 1.34 2.19 ± 2.12
Fecal lactoferrin
3.85 8.42
Lifestyle-modification ITT 45
(0.13–97.47) (0.12–61.96) 0.648 0.002
3.83 4.03
Control ITT 48
(0.08–85.16) (0.08–60.79)
4.97 4.53
Lifestyle-modification PP 37
(0.13–97.47) (0.12–61.69) 0.510 0.006
3.47 3.91
Control PP 43
(0.08–85.16) (0.08–60.79)
Fecal calprotectin
100.59 80.81
Lifestyle-modification ITT 45
(2.48–1375.50) (10.48–1232.40) 0.751 0.001
99.49 95.53
Control ITT 48
(6.92–1900.10) (28.51–1660.50)
114.32 75.15
Lifestyle-modification PP 37
(2.48–1375.50) (10.48–1232.40) 0.855 0.000
101.53 95.43
Control PP 43
(6.92–1900.10) (28.51–1660.50)
Note. p-values are based on univariate analyses of covariance with group as the between-subject factor and baseline
values as covariates. CAI = clinical activity index; M = mean; SD = standard deviation; ITT = intention-to-treat
analysis; PP = per-protocol analysis.
J. Clin. Med. 2020, 9, 3087 12 of 16

A B
Figure 5. Dimension scaling (MDS) plot shows the generalized unifrac distances of the microbial
profiles of the intervention and nonintervention groups at Week 12: No significant difference between
the intervention and nonintervention groups at week 12 (A) even if controlling for immunosuppressant
medications (B).

3.6. Safety
Three patients in the lifestyle-modification group and one patient in control group reported one
serious adverse event each. The serious adverse event reported in the control group was hospitalization
for an acute flare with anemia. Serious adverse events reported in the lifestyle modification group
included an abortion with hospitalization, inguinal hernia surgery and surgery for anal stenosis, and
were not related to the intervention. Nineteen patients in the lifestyle modification group and twelve
patients in the control group reported nonserious adverse events (p = 0.188). Nonserious adverse
events included, for example, common colds, herpes infection or cystitis.

4. Discussion
This paper conveys three messages we believe to be important. Firstly, the results imply that a
comprehensive lifestyle-modification program is safe and feasible in patients with ulcerative colitis.
Secondly, the program significantly improves health-related quality of life in patients with ulcerative
colitis who had mild clinical disease activity and significantly impaired health-related quality of life.
Finally, a treatment difference was observed when examining a subsample of patients who attended
more than 50% of sessions
The topic of health-related quality of life is of great importance for patients with ulcerative
colitis. Although quality of life impairment is strongly related to disease activity, it is also limited
during phases of mild disease activity or even in remission [34–37]. Therefore, the need to improve
the quality of life, and thus relieve the overall disease burden, is very high and oftentimes not part
of standard medical treatment [5,10,14]. In the present randomized controlled trial, patients with
ulcerative colitis who regularly attended a 10-week comprehensive lifestyle modification program
showed significantly better health-related quality of life outcomes after 12 weeks than patients who
received a single workshop on naturopathic self-help strategies. Further, compared with controls,
comprehensive lifestyle modification improved patients’ emotional symptoms (IBDQ emotional
subscale) and, if patients attended regularly, their systemic symptoms. Lifestyle modification, however,
had no effect on disease activity (as measured by CAI, fecal lactoferrin fecal calprotectin, EI, and Riley
score) in this group of patients with relatively low clinical activity, or even complete clinical remission
J. Clin. Med. 2020, 9, 3087 13 of 16

at baseline. Similarly, no therapy effects on patients’ microbiome were found. Adverse events occurred
to a similar extent in both groups.
It was concluded from a previous randomized controlled trial conducted by our group that the
effects of a mind-body intervention on ulcerative colitis with mild clinical activity, or in remission, were
evident but limited, possibly given the recruitment of a small sample of patients with on average no, or
only small, impairments in health-related quality of life [15].Thus, within the present study, recruitment
was restricted to patients with existing reduced health-related quality of life. As in the prior study, no
effects on disease activity were found. Hence, it may be concluded that multicomponent treatment
approaches with a focus on mind-body therapy are effective primarily on measures of quality of life,
particularly regarding emotional and systemic symptoms, rather than clinical disease parameters in
this group of patients in clinical remission [14]. However, the fact that the included patients were in
clinical remission at baseline might support a floor effect. However, interestingly, patients reported that
the program had an effect on systemic symptoms of fatigue, malaise and sleep and weight issues, all of
which were physical, albeit nonspecific, symptoms. This finding complements the results of Casellas et
al. [38]. They described that with inactive disease, systemic symptoms are predominant symptoms that
require special attention in therapy. The comprehensive lifestyle-modification program may not have
a strong effect on disease activity in colitis patients while in remission, but it may affect nonspecific
physical symptoms, thereby alleviating distressing physical conditions of the disease. Future studies
should examine this more closely. Further, some effects were significant only in the per-protocol, but
not in the intention-to-treat, analysis. Within the per-protocol analysis, only patients who attended
at least half of the intervention sessions and did not present as screening failures during the study,
were analyzed. These differences in PP analysis were also robust when only those patients with less
than 50% participation were excluded from the analysis. Since the control group received a single
workshop of intense training in naturopathic self-help strategies, which was also a component of the
lifestyle modification program, regular participation in the intervention sessions might have been
crucial for the lifestyle modification program to exert its full effects, compared to control. Of note, the
control group also showed an improvement in their health-related quality of life after the workshop.
One could postulate that the group setting in itself could have had a positive effect beyond that of
the actual program content. However, previous studies evaluating the effects of group settings found
that group settings are well accepted by patients but do not exert positive effects beyond the actual
training content [39,40]. Of course, it is also conceivable that the contents of the workshop itself, as
well as positive expectations, had beneficial effects. The comprehensive lifestyle-modification program
actively aims to strengthen patients’ coping resources (e.g., social skills, social support and control
beliefs).
During the 10-week program, in addition to treatments specific to ulcerative colitis such as
diet, home remedies and herbal medicines, patients also learned generally about health-promoting
techniques such as stress management, internal and external communication skills, social network
reflection and perception of assessment habits which were intended to strengthen patients’ resources.
Although patients were encouraged to incorporate the learned skills into their daily lives, patient
compliance was not recorded in this regard. Future studies should address the question of how
improvements can be maintained in the long-term; for example, evaluation of nutrition counselling
provided. The fact that we could not demonstrate any changes in patients’ microbiomes as a potential
indicator of changes in patients’ dietary intake might be caused by an unsuitable time interval to show
changes in the microbiome. Moreover, it was hardly possible to calculate the necessary sample sizes.
Due to the high interpersonal variability, the required sample size would probably have been very
large, so that the size available may not have been sufficient to identify differences [41].
Strengths of the study included the randomized, controlled study design and the assessment of
subjective patient-reported outcomes using validated questionnaires in addition to clinical assessments
and objective laboratory parameters. The dropout rate was low with only 11.34% attrition after
12 weeks (n = 7 in intervention, n = 4 in control). There were also limitations in this study. Due to
J. Clin. Med. 2020, 9, 3087 14 of 16

administrative problems at the beginning of the study, the per-protocol analysis was reported in
extenso. Furthermore, this study was designed to evaluate changes in total health-related quality of
life as measured by the IBDQ post intervention. In addition, study results are limited to a specific
group of patients with ulcerative colitis with mild clinical activity or during remission, an interest in
complementary treatment approaches and diminished quality of life, which restrict generalizability.
In summary, the study showed that patients with ulcerative colitis might benefit from defined
nonpharmacological treatment modules. A comprehensive lifestyle-modification program is safe,
feasible and a treatment difference was observed when examining a subsample of patients who
attended more than 50% of the training sessions, without effects on disease activity.

Author Contributions: Conceptualization, J.L., A.P., C.Z., H.C., R.L., G.D. and A.K.K.; methodology, J.L., A.P.,
C.Z., H.C., R.L., G.D. and A.K.K.; validation, J.L.; formal analysis, J.L., A.K.K., D.H., and M.A.; investigation,
J.L., M.S., K.K., Z.C., R.E., C.Z., and A.K.K.; resources, J.L., G.D., D.H., and M.A.; data curation, A.K.K., D.H.,
and M.A; writing—original draft preparation, J.L., A.K.K.; writing—review & editing, J.L., M.S., Z.C., R.E., K.K.,
A.P., C.Z., S.E., R.L., M.A., D.H., H.C., G.D., A.K.K.; visualization, J.L., D.H., M.A., A.K.K.; supervision, J.L.;
project administration, J.L., A.K.; funding acquisition, J.L., R.L. & A.K.K. All authors have read and agreed to the
published version of the manuscript.
Funding: This research was funded by the Karl and Veronica Carstens-Foundation, grant number KVC 0/0088/2016,
the Deichmann Foundation, and the Raßfeld Foundation, grant numbers T0425–28.636 and T0425–32.540
Acknowledgments: The authors thank Annette Tengelmann and Denise Eisenbarth-Wiener for participating in
patient recruitment and data assessment.
Conflicts of Interest: J.L. was a speaker for Repha GmbH, Techlab Inc., Falk Foundation, Takeda, Celegene GmbH
and Willmar Schwabe and received research funding from Repha GmbH, Techlab Inc, Falk Foundation and
Willmar Schwabe. No conflict of interest: Romy Lauche, Kerstin Kofink, Anna Katharina Koch, Anna Paul. The
sponsors had no role in the design, execution, interpretation or writing of the study.

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