Infectious Diseases Diagnosis & Treatment (ISSN: 2577-1515)

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The Influence of a blend of Probiotic Lactobacillus and Prebiotic Inulin on the Duration and Severity of Symptoms among Individuals with Covid-19

Authors: Robert Thomas1,2*, Jeffrey Aldous3, Rachel Forsyth4, Angel Chater5,6, Madeleine Williams7

*Corresponding Author: Robert Thomas, Consultant Clinical Oncologist, Bedford & Addenbrooke’s Cambridge University NHS Trusts, UK

Received Date: November 01, 2021

Accepted Date: November 11, 2021

Published Date: November 16, 2021

Abstract

Background: Gut microfloral dysbiosis is known to affect the majority individuals suffering with a Covid-19 infection. This study evaluated whether a specific lactobacillus and inulin blend, which aimed to improve gut health, could reduce the severity of early and chronic Covid-19 symptoms.

Methods: From May 2020 to May 2021, we evaluated 126 participants with Covid-19, with an average duration of symptoms of 108 days, who were given 30 days of this pre and probiotic capsule within the ongoing UK national Phyto-v study. Symptoms were recorded using the validated Cough Symptom Score, the Subjective Well-Being questionnaire and the Chandler fatigue questionnaire. The group was analysed as a whole and then subdivided into 40 (32%) in an early phase of infection (average symptoms 10 days before baseline) and the 86 (68%) in a chronic phase (average symptoms 120 days before trial baseline).

Results: Cough, fatigue and subjective well-being scores significantly improved over the 30 days in both the early and chronic phase cohorts. Participants who were more likely to have gut dysbiosis at trial entry, such as sedentary, hospitalised, older males with GI symptoms, had a statistically significantly better response to the probiotics. Gut symptoms improved in 25 of 31 (82%) who reported them at baseline. Two (1.5%) patients reported mild increased bloating and diarrhoea.

Discussion: Following this nutritional intervention, participants had a significant improvement in GI and non-GI symptoms resulting in a meaningful improvement in overall well-being. Although some participants with early disease would have improved spontaneously, such a rapid improvement in the majority who had been experiencing symptoms for over 6 months, was clinically relevant and welcomed, especially among those more likely to have pre-existing gut dysbiosis. Going forward, our research group are now evaluating whether intake of this blend now known as yourgutplus+, could also enhance antibody titres levels post Covid vaccination.

Keywords: Probiotics; Prebiotics; Covid-19; Gut-health; Long-Covid symptoms; Yourgutplus+

Introduction and Background

As emerging evidence from clinical studies and experience from managing patients with Covid-19 (Covid) unfolds, the links between severity of symptoms, mortality and gut microbial dysbiosis has become increasingly apparent [1-5]. Depleted healthy strains of commensal bacteria such as Lactobacillus have been reported in the majority of patients with Covid expressing Gastrointestinal (GI) symptoms and especially those with persistent ongoing problems, coined long or chronic Covid [5-11]. Although most Covid cases have a mild self-limiting respiratory illness, individuals with co-morbidities and conditions, linked to poor gut health, such as being elderly, those living with obesity or diabetes do significantly worse [7,8,11,12]. The authors of these studies postulated microfloral dysbiosis contributes to symptoms via increased gut inflammation, impaired gut wall integrity which correspondingly leads to systemic inflammatory dysfunction, reduced immune surveillance leading to greater nongut symptoms as well [4-6,8,11,12]. In this situation, overgrowth of less favourable gut bacteria have been found in the systemic circulation and within pulmonary aspirates leading to an increased inflammatory response, causing cough and breathlessness [1317]. Excess inflammatory cytokines and pulmonary exudates are a feature of Acute Respiratory Distress Syndrome (ARDS) following a viral infection, hence the recently coined term cytokine storm [13-17]. The link between bowel dysbiosis and lung hyper inflammation has also been well documented in other chronic respiratory diseases including asthma and chronic bronchitis [1820].

In addition to dietary and behavioural measures, supplementary capsules are a convenient way to increase total intake of pro and prebiotics, as well as a way to spread their intake throughout the day. The most widely researched probiotics include lactic acid producing bacteria such as species of Lactobacillus, the colonisation of which is enhanced by concomitant intake with prebiotic soluble fibres such as inulin [21,22]. Numerous interventional studies in humans and animals have shown they can help improve mircrofloral biodiversity, correct GI symptoms such as bloating and diarrhoea and improve Immune efficiency [23-28]. Many of these studies, albeit most needing further confirmation, have shown they help modify a range of chronic diseases ranging from obesity, inflammatory bowel disease, diabetes, cardiovascular disease, hypertension, anxiety, depression, osteoporosis and dementia [21,28-37]. More relevant to this study, intervention studies have shown regular intake of live probiotics, particularly Lactobacilli strains, shortened the incidence duration and severity of upper respiratory tract infections in several studies [38-43]. This includes a summary of interventional studies published in the Cochrane Database which concluded that probiotics did reduce the number of symptomatic upper respiratory tract infections [43]. Another meta-analysis of small RCTs suggests that probiotics decreased the need for invasive mechanical ventilation due to development ARDS following viral pneumonia [44].

The reported mechanism of action of probiotic bacteria is multifactorial [45,46]. They encourage gut colonisation of antiinflammatory strains, which then out space pro-inflammatory (Firmicutes) bacteria. They encourage the fermentation of otherwise poorly digestible dietary carbohydrates into Short-Chain Fatty Acids (SCFA) such as butyrate. These have an important impact upon mucosal physiology, as they are an idea source of energy for gut cells so help improve gut health and hence gut wall integrity [45,47-49]. Probiotic bacteria also help the breakdown of polyphenols into more ready absorbed and more bioactive varieties [50,51]. Higher serum levels of polyphenols and other phytochemicals are linked to lower systemic inflammation, a lower risks of chronic degenerative disease [48,51-56] and cancer [52,53].

As well as their positive influence on immune balance, probiotics have been found to have a range of other potential mechanisms of actions [45,46]. They can enhance intracellular oxidative enzyme capacity and can help scavenge excess superoxide anions among patients with Covid [57]. This mechanism, in laboratory studies, was attributed to their ability to reduce oxidative stress via upregulating superoxide transferase and other anti-oxidant enzymes [58,59]. Excess oxidative stress is a linked to more aggressive pulmonary pathogenicity following Covid pneumonia [60,61]. Probiotics help increase vitamin D absorption and bioactivity [62-66]. Low vitamin D is associated with higher levels of unregulated hyper inflammatory cytokine production and ultimately more severe respiratory Covid related symptoms [6770]. Finally, there are reports of direct anti-viral actions of lactic acid producing bacteria such as lactobacillus via the production of antiviral inhibitory metabolites following induction of the expression of genes involved in antiviral immunity [71-75].

The Kings App study has reported that individuals, who have more symptoms initially, including bowel problems, were more at risk of long Covid [76]. In addition, people who took regular probiotics had a 14% lower risk of symptomatic Covid [77]. Many clinical trials are underway globally examining the role of pro and prebiotics in both prevention and treatment of Covid and some have reported benefits [1,8,57,78-82]. Considering this background of evidence, this study aimed to examine whether their administration could reduce the severity and longevity of symptomatic Covid infection, particularly those with ongoing symptom, via their gut health promoting, immunomodulatory and anti-inflammatory and direct actions.

Methods

This experimental trial was conducted at Bedford Hospital, part of the Addenbrooke’s Hospital Cambridge University Trust Network. All participants (n=126, 70 male, 56 female) had one or more symptoms related to their Covid infection at the time of trial entry. Participants were recruited between May 2020 and May 2021, approached either at the local post Covid clinic, or from the daily Covid ward round or had contacted the trials unit themselves directly after hearing about the study via word of mouth. For this analysis, we only included participants who were given a capsule containing a 5 species Lactobacillus probiotic blend with inulin prebiotic derived from chicory for at least one month. The daily dose (from 2 capsules) was 200 mg of Inulin and 10 Billion Colony Forming Units (CFU’s) of Lactobacillus plantarum (Lp90), Lactobacillus rhamnosus (LRa05), Lactobacillus bulgaricus (LB42), Lactococcus lactis (La61), Lactobacillus paracasei (LC86).

People were excluded if they had known sensitivities and allergies to the investigational foods, were immune-suppressed or were too ill to take oral capsules. The average age 53 years (range 16-82). Eighty-three (66%) were smokers, 42 (34%) non-smokers. The average BMI was 28.7 Kg/m2 , 47 (37.3%) were normal weight (BMI 18-<25 Kg/m2 ), 79 (62.7%) were in the overweight or obese range (BMI >25 Kg/m2) (30% overweight, 32.7% obese).

The average time from Covid diagnosis to trial entry was 108 days (range 2-467). The group was analysed as a whole and then subdivided into 40 (32%) in the Early Phase (EP) of infection (within 30 days of diagnosis) and 86 (68%) in a Chronic Phase (CP) of persistent symptoms (>30 days from diagnosis). Of the individuals in this chronic phase Covid group, the average time from diagnosis and trial entry was 120 days and for the individuals in the early phase this was 10 days.

Symptoms were recorded at trial entry and at 30 days 3 using validated questionnaires (The Cough Symptom Score, the Subjective Well-Being questionnaire and the Chandler fatigue questionnaire) [83-85]. All other symptoms were recorded using the NCI Common Toxicity Checklist.

Manufacture

The food supplement was made specifically for this trial by Park-acre, Lincoln, DN21 5TJ and The Oxford Health Company Ltd, Oxfordshire, OX26 5AH. Certified to conform to Good Manufacturing Practice (GMP-FSSC 22000, ISO 22000), UK and International food production laws [www.tohc.co.uk]. They are also certified organic by the Organic Food Federation. There in-house Research and Development department, for each batch tested for contamination with yeast, mould, E. coli, Salmonella. They measured lead, arsenic, cadmium, mercury and pesticides then excluded batches, which did not abide by international threshold guidance and law. A unit of the supplements are securely stored by the Trust Secretary and can be sent to any regulatory body at their request in the future.

Statistical analysis

The primary end points for this analysis were mean cough, fatigue and subjective well-being symptoms scores on one day one and day 30, for the whole cohort and then split into early phase and chronic phase groups. Statistical analysis was performed using IBM SPSS Statistics (IBM Corp., Amonk, NY, United States). All dependent variables were checked for normal distribution using Quantile-Quantile (Q-Q) Plots and were deemed plausible in all instances. All data was presented as mean ± SD with 95% confidence intervals (95%CI). A dependent paired sample t-test was used to assess the mean differences in cough, subjective wellbeing and fatigue scores at day 1 compared with day 30. The two-tailed alpha level was set as P<0.05. Cohen’s d effect size were used to show the magnitude of change for each significant difference using the following thresholds; 0.2-0.49 small, 0.5-0.79 moderate, >0.8 large).

A predetermined subgroup determined which participants had the most benefit to the intervention by comparing the change in mean symptoms scores from baseline to day 30 between male versus (vs) female; normal weight versus overweight or obese; <60 years vs >60 years; ethnic group (White British vs other); Exercise levels (<3 hours a week v >3 hours a week); hospitalised vs not; history of bowel symptoms vs not, gastrointestinal symptoms at baseline vs not. An independent t-test was used to determine the differences in scores between normally distributed subgroups. A between groups one way analysis of variance (ANOVA) were used to determine differences for all other sub-group analysis. Assumptions of both tests were checked via the homogeneity of variance, which were not violated for any variables. In the instance of a significant main effect, a Bonferroni pairwise comparison was used to locate significant differences. The two-tailed alpha level was set as p<0.05.

Results

 Formal Symptoms Scores

Table 1 summarises the changes in formal cough, fatigue and well-being scores over the 30 days intervention for the whole cohort and separately for the patients who received probiotics in the acute and chronic phases of Covid (Table. 2).

Cough scores significantly decreased over the 30 days from a mean of 1.25 (± 1.99) to 0.42 (± 1.01) (t124 = 5.331, p<0.001; 95%CI: 0.52 to 1.14, d=0.48). Fatigue scores were significantly improved from a mean of 21.37 (± 5.59) to 16.57 (± 6.80), (t118=5.178, P<0.001; 95%CI: 3.58 to 6.01, d=1.36) by a large magnitude (d=1.36)). Subjective wellbeing demonstrated a significant improvement by a large magnitude from a mean of 24.05 (± 8.47) to 28.38 (± 6.95) (t124=7.823, p<0.001; 95%CI: -5.98 to -2.67, d=1.10).

Both fatigue and subjective wellbeing scores were significantly improved in the acute (fatigue: t39=4.120, P<0.001, 95%: 2.88 to 8.61, d=1.8; Subjective wellbeing: t39=3.585, P=0.001, 95%: 2.80 to 10.17, d=1.6) and chronic (fatigue: t95=6.618, P<0.001, 95%: 3.13 to 5.82, d=1.3; Subjective wellbeing: t95=3.840, P<0.001, 95%: 0.70 to 5.33, d=0.9) phase groups by a large magnitude. Furthermore, cough scores were significantly improved by a moderate effect size in the acute (t39=3.060, P=0.004, 95%: 0.42 to 2.07, d=0.6) phase group and by a small magnitude in the chronic (t95=4.472, P<0.001, 95%: 0.38 to 0.98, d=0.4) phase group.

Self-reported symptoms

The top 7 self-reported symptoms were fatigue, shortness of breath, pains, altered sense of smell, bowels symptoms, cough and headache (Table 3). Table 4 (excluding cough and fatigue) summarised how these self-reported symptoms changed over the 30 days of the intervention with bowel symptoms improving the most.

Subgroup analysis

Subgroups were predetermined to evaluate whether some individuals had a greater or lesser benefit from the intervention. These subgroups included gender, Body Mass Index (BMI), age, ethnic group, exercise levels, whether hospitalised, whether they had a history of GI symptoms and whether they had new GI symptoms at trial entry. Although there was no difference in relative benefit between different ethnic groups or BMI levels, it appeared that males, those <60 years, those exercising more than 3 hours a week, those previously hospitalised, no prior indigestion, new or worse GI symptoms at trial entry had a statistically greater benefit for one or more measurable outcomes (Table 5).

Safety and adverse events

The assessment of safety was based on the frequency of adverse events reported by the investigator in the Case Report File. The level of adverse events attributable to the probiotics were very low (Table 6) with only two (1.5%) patients reported mild increased bloating and diarrhoea. At trial entry, it was also observed that, of the participants who were overweight or obese, 15% indicated they never exercised as opposed to 2% in the normal weight group. In the overweight or obese group, 15% ate meat less than 3 times a week compared to 28% in the normal weight group. Likewise, 15% of the overweight or obese participants added more than 2 spoons of sugar in their tea or coffee as opposed to 4% in the normal weight group.

Discussion

This study highlights the wide variety of symptoms patients suffer following a Covid-19 infection and draws attention to the high prominence of those of Gastro-Intestinal (GI) origin. Selfreported GI symptoms of indigestion, bloating, nausea, diarrhoea and constipation were reported to have developed or increased from their usual level in over a quarter of patients at baseline. Previous publications have highlighted that patients with GI symptoms at presentation had worse non-GI symptoms, particularly fatigue, during their Covid episode, and had a greater risk of developing chronic on going symptoms [4,5,7,8]. GI symptoms have been attributed to direct viral growth within the gut mucosa causing inflammation and dysbiosis in the gut bacterial flora [4,5,7,8,80].

This intervention, which aimed to improve gut health with a combination of lactobacillus probiotics and inulin prebiotics, demonstrated a clear improvement in fatigue, cough, subjective wellbeing and self-reported GI symptoms after their initiation. For patients within the early phase of an infection (less than 30 days), this result was largely expected as most patients improve within a month of an acute infection, although the same cannot with said for participants with chronic persistent Covid-related symptoms [78,79].

In this cohort, participants had ongoing symptoms for an average of 120 days months pre-entry and therefore, improvement in symptoms seen within 30 days of the intervention, would unlikely to have happened spontaneously. This improvement was considered clinically relevant and welcomed by participants. This finding supports similar benefits from probiotic interventions, reported in patients, mainly with other respiratory tract viral infections, but more recently in patient with Covid [1,4,8,54,73,76,77,81]. Furthermore, it supports findings from the Kings App study, which established a link between people who took probiotics and a lower risk of Covid [76].

In terms of a subgroup differences, patients admitted to hospital had a greater improvement after this intervention compared to non-hospitalised patients. A possible explanation for this is that, gut dysbiosis is aggravated by treatments such as dexamethasone and antibiotics, often administered to patients during their hospital Covid management, so we suggest that an intervention to improve gut health has an even greater impact on these patients [86-88]. Likewise, benefit from this intervention was greater in the older participants and those who exercised less, also factors known to be linked to less favourable gut microfloral profile [47,89]. Males difference [90].

The mechanism of action of the probiotics, for non-GI symptoms, was not addressed in this study but the improvement in respiratory symptoms may be explained by improvement in the gut-lung axis highlighted in the introduction [13-17]. The cause of fatigue, common during a viral infection and particularly Covid, is not certain. Some postulate there is an evolutionary advantage for fatigue within the innate immune related response as it reduces movement and interaction with other people and hence spread of the virus [91]. It is well known that poor gut health has a link to chronic fatigue [85,92-94]. Previous interventions with lactobacillus supplements reduced fatigue related behaviour in laboratory animals [63]. In humans, there have been reported improvements in fatigue and memory following probiotic interventions which also demonstrated reductions in systemic inflammatory cytokines and improvements in gut integrity [63,93,94]. Some studies have shown a microbial-neuroendocrine relationship between certain dysbiotic flora species and the resultant adverse change in hormones and neurotransmitters such as acetylcholine and Gamma-Amino Butyrate (GABA), serotonin and dopamine and that administration of lactobacillus probiotics helped reverse these changes [64,92-96]. Although these are all a possible mechanisms, further research is required to establish whether these biochemical changes are responsible for the profound fatigue in those with long Covid.

Going forward, these data suggests that, in terms of Covid, greater emphasis should be placed on eating behaviour, nutritional factors and exercise which improve gut biodiversity. Various studies have shown these factors include stopping smoking, reducing processed sugar, exercising more, eating more live probiotic bacteria within yogurt, kefir, sauerkraut and kimchi, eating more fermentable soluble fibres such as inulin, oligosaccharides and beta-glucans found in chicory, artichoke, grains, beans and mushrooms and prebiotic polyphenols found in nuts, onions, fruit pomegranate and herbs [22,52,53,87]. In addition, this study suggest that concentrating elements of these foods into capsules has a beneficial role. Nutritional supplement are certainly a convenient way to boost probiotic and prebiotic intake throughout the day. Many laboratory and some human studies that show probiotic capsules improve mirocrofloral biodiversity, improve immune efficiency, correct GI symptoms and modify a range of chronic diseases [21,28,34-36]. Other intervention trials have shown they can reduce the incidence of upper respiratory tract viral and flu like infections [38-44]. We believe, our data is one of the first to report the potential benefit for patients with symptoms post Covid.

In terms of safety, thousands of studies, have reported a high safety record among millions of healthy people who have consumed probiotic capsules for years, particularly the lactobacillus varieties [64,97-103]. More relevant to this study, the intake of lactobacillus probiotics has been shown to be particularly safe and beneficial among patients with several different medical condition including those on chemotherapy, those with irritable bowel syndrome and premature infants as well as elderly and even immunocompromised patients, hence a rationale for their inclusion in this study [102104]. We add to this data by reporting this lactobacillus blend was safe in patients who had ongoing symptoms following a Covid infection. Only two patients discontinued their capsules because of an increase in bloating although it was not certain whether this was related to the intervention.

Data from this study would have been more robust if a randomised design was used, however, despite the high number of Covid cases in our hospital at the start of the trial, it became clear that participants would buy their own probiotics, over the counter, negating the any comparative data. Considering these factors and following feedback from patients, the trials committee decided to provide the probiotic to all participants, with the design limitations acknowledged.

Conclusion

This study highlights the wide range of symptoms people suffer following a Covid infection, in particular, those related to GI tract. As it is known that patients with Covid with GI symptoms and other factors linked to gut dysbiosis have more severe and more persistent of symptoms, it would be wise to encourage lifestyle and nutritional factors, which improve the gut microbiome. In addition, this study strongly suggests that this specific probiotic supplement, enhances recovery from Covid especially for individuals who have symptoms or conditions suggestive of poor gut health. This blend of pro and prebiotics was safe and well tolerated, is now freely available as an over the counter supplement known as yourgutplus+ but it must be noted that it is classified as a food so cannot be licenced or prescribed by medical practitioners. Further research on this trial cohort will evaluate whether the addition of a phytochemical rich whole food supplement will further enhance the benefits of this intervention, which will be reported separately. Going forward, our research group are now designing a study to evaluate whether yourgutplus+ could also enhance antibody titres post Covid vaccination.

Acknowledgements

The interventional capsules, subsequently known as yourgutplus+, were designed by the scientific committee specifically for this study, made by The Oxford Health Company Ltd, and donated free by Keep-healthy Ltd, Isle of Man who we would like to thank, as without their generous support this study would have not been possible. We are grateful to the post Covid clinic, Bedford Hospital for their vital help in recruiting patients.

Declaration of Interest

This was a non-commercial trial and no direct funding has been received from external organisations although the probiotics was supplied free of charge to the trials unit as mentioned above. The research team involved in the study were not being paid to recruit patients into the study, had no other financial incentives and have no connection with the manufactures. There are no intellectual patent issues on any of the investigational products as these are freely available over-the-counter. Information generated by the trial will be published in the public domain and the authors have no other conflict of interest.

Certification

This trial was approved by the Health Research Authority (REC reference: 20/YH/0164), sponsored and approved by Bedfordshire Hospitals NHS trust and its Research and Development committee. The Medicines and Health Regulatory Agency (MHRA) gave formally authority to proceed with the trial as no medical products license is required for food products.


Tables

Symptom Score

Mean & SD
(Day 1 vs 30)

Difference
(Day 1 vs 30)

95%CI

p value

Cough

1.25 ± 1.99 
vs
0.42 ± 1.01

0.83 ± 1.74

0.52 to 1.14

p<0.001

Fatigue

21.37 ± 5.59
vs
16.57 ± 6.80

4.74 ± 6.85

3.58 to 6.01

p<0.001

Subjective wellbeing

24.05 ± 8.47
vs
28.38 ± 6.95

4.11 ± 9.62

5.98 to -2.67

p<0.001

Table 1: Changes in symptoms from day 1 to 30 days (all patients, n=126).

Symptom Scores

Mean & SD
(Day 1 vs 30)

Difference
(Day 1 vs 30)

95% CI

p value

Early Covid cohort  (n=40)
(symptoms developed within one month of trial entry (mean 14 days)

Cough

1.84 ± 2.33
vs
0.61 ± 1.27

1.24 ± 2.33

0.42 to 2.07

p=0.004

Fatigue

20.19 ± 5.69
vs
14.44 ± 4.53

4.70 ± 6.90

2.88 to 8.61

p<0.001

Subjective wellbeing

24.45 ± 9.69 
vs
 30.94 ± 6.06

6.48 ± 10.39

10.17 to -2.8

p=0.001

Chronic Covid cohort (n=96)
Symptoms persistent > 1 month from trial entry (Mean=120 days)

Cough score

1.03 ± 1.82
vs
 0.35 ± 0.89

0.67 ± 1.45

0.38 to 0.98

P<0.001

Fatigue score

21.66 ± 5.55
vs
 17.18 ± 7.20

4.70 ± 6.85

3.13 to 5.82

P<0.001

Subjective wellbeing

23.99 ± 8.04
vs
 27.51 ± 7.03

3.23 ± 9.20

5.33 to -.70

p<0.001

*Early Covid: symptoms within 1 month of trial entry; + Chronic Covid: Participants with symptoms for >1 month prior to  trial entry

Table 2: Changes in Covid symptoms from day 1 to 30 days split into early and chronic cohorts.

Symptom

Number (%)

Symptom

Number (%)

Fatigue

117 (92%)

Sore throat

7 (6%)

Breathlessness

53 (42%)

Anxiety or depression

7 (6%)

Joint, muscle or chest pains

43 (34%)

Altered hearing or vision

6 (5%)

Bowel symptoms, nausea

31 (25%)

Increased BP

6 (5%)

Cough

31 (25%)

Peripheral neuropathy

5 (4%)

Altered sense of smell

31 (25%)

Dizziness

5 (4%)

Headache

24 (19%)

Increased perspiration

4 (3%)

Muscle weakness

22 (17%)

Sneezing

4 (3%)

Fever / chills

18 (14%)

New onset asthma / asthma flare

4 (3%)

Poor appetite, nausea

14 (11%)

Altered voice / hoarseness

3 (2%)

Insomnia

10 (8%)

Hyperesthesia

3 (2%)

Heart palpitations

8 (6%)

Urinary problems

3 (2%)

Brain fog

8 (6%)

Weight loss

3 (2%)

Skin rash / Covid toes

8 (6%)

Period problems

2 (1%)

Table 3: Self-reported symptoms at baseline (any grade of severity).

Symptoms

Number (%)

Symptom

Number (%)

Bowel symptoms

25 of 31 (82%)

Headache

3 of 24 (13%)

Sleep pattern

8 of 10 (80%)

Skin oiliness

1 of 6 (16%)

Brain fog or headache

3 of 8 (38%)

Asthma relief

1 of 4 (25%)

Breathlessness

11 of 53 (21%)

Sneezing

1 of 4 (25%)

Joint or chest pains

7 of 43 (16%)

Decreased palpitations

1 of 8 (12%)

Table 4: Percentage of self-reported symptoms improving at 30 days other than cough and fatigue (reported above).

Symptom scores

Mean score change Day 1 to 30 
SD (number)

Difference
(95% CI)

P value

 

Gender
Male (70) vs Female (56)

 

Cough

1.1 ± 2.0 vs 0.5 ± 1.2

0.6 (0.1 to  1.6)

p=0.04

Fatigue

6.4 ± 7.2 vs 3.2 ± 6.2

3.2 (-0.6 to  0.5)

p=0.01

Subjective wellbeing

5.3 ± 10.6 vs 2.6 ± 8.0

2.7 (0.6 to 5.6)

p=0.10

 

Age
<60  years (89)  vs  >60 years (37)

 

Cough

0.6 ± 1.8 vs 0.9 ± 1.7

0.3 (0.9 to 0.4)

p=0.46

Fatigue

1.6 ± 5.3 vs 6.4 ± 7.0

4.8 (7.2 to 2.5)

p<0.001

Subjective wellbeing

1.4 ± 9.8 vs 5.2 ± 9.4

3.8 (0.2 to 7.5)

p=0.04

 

Ethnic group

White British (92) v other (34)

 

Cough

0.8 ± 1.8 vs 0.7 ± 1.7

0.1 (-0.8 to 0.5)

p=0.64

Fatigue

4.9 ± 7.1 vs 5.3 ± 6.5

0.4-2.4 to 3.3

p=0.74

Subjective wellbeing

4.2 ± 10.3 vs 3.8 ± 7.5

0.4 (-3.4 to 4.2)

p=0.82

 

BMI

Normal (46) vs OW and O (80)

 

 

Cough

0.8 ± 1.5 vs 0.7 ± 1.9

0.1 (-0.8 ± 1.5)

p=1.00

Fatigue

2.7 ± 10.1 vs 4.7 ± 9.3

2 (2.6 to 4.7)

p=1.00

Subjective wellbeing

-4.2 ± 10.3 vs - 3.8 ± 7.5

0.4 (-2 to 4)

p=0.13

 

Hospitalised

Yes (79) vs No (47)

 

Cough

0.9 ± 1.6 vs 0.7 ± 1.9

0.2 (-0.5 to 0.7)

p=0.77

Fatigue

6.1 ± 7.4. vs 2.9 ± 5.5

3.2 (0.9 to 5.6)

p<0.01

Subjective wellbeing

3.5 ± 9.0 vs 5.1 ± 10.5

1.6 (-2.0 to 5)

p=0.39

 

Prior indigestion

Yes (113) vs No (13)

 

 

Cough

0.8 ± 1.7 vs 1.0 ± 2.1

0.2 (0.8-1.2)

p=0.70

Fatigue

9.4 ± 7.9 vs 4.4 ± 6.6

5 (0.1-11.1)

p<0.01

Subjective wellbeing

9.1 ± 11.5 vs 3.5 ± 9.2

5.6 (8.9-1.1)

p=0.04

 

New GI symptoms at baseline

Yes (41) vs No (85)

 

Cough

0.7 ± 1.9 vs 0.8 ± 1.7

0.1 (-0.5 to 0.8)

p=0.59

Fatigue

5.4 ± 7.0 vs 4.2 ± 6.8

1.2 (-1.5 to 3.8)

p=0.01

Subjective wellbeing

2.7 ± 10.1 vs 4.7 ± 9.3

2 (-5.6 to  1.6)

p=0.274

 

Exercise
3 >hrs/wk  (93) vs <3hrs/wk   (33)

 

Cough

0.5 ± 1.3 vs 1.6 ± 2.4

1.1 (0.2-1.9)

p=0.02

Fatigue

4.1 ± 6.4   vs  7.6 ± 7.8

3.5  (0.3-6.7)

p=0.03

Subjective wellbeing

2.7 ± 6.4  vs  8.0 ± 11.4

5.3 (-9.7to-0.9)

p=0.02

Table 5: Subgroup analysis highlighting who got the greatest benefit from the intervention.

Adverse event

Number (Percentage of 126)

NCI toxicity (Severity)

Increased bloating

2 (1.5%)

1 (Mild)

Increased diarrhea

2 (1.5%)

1 (Mild)

Increased indigestion

2 (1.5%)

1 (Mild)

Table 6: Adverse events attributable to nutritional intervention.

References

  1. Kurian SJ, Unnikrishnan MK, Miraj SS, Bagchi D, Banerjee M, et al. (2021) Probiotics in Prevention and Treatment of Covid-19: Current Perspective and Future Prospects. Arch Med Res 52: 582-594.
  2. Lin L, Jiang X, Zhang Z, Huang S, Zhang Z, et al. (2020) Gastrointestinal symptoms of 95 cases with SARS-CoV-2 infection. Gut 69: 997-1001.
  3. Olaimat A, Aolymat A, Al-Holy M, Ayyash M, Abu Ghoush M, et al. (2020) The potential application of probiotics and prebiotics for the prevention and treatment of Covid-19. Sci Food 4: 17.
  4. Dhar D, Mohanty A (2020) Gut microbiota and Covid-19-possible link and implications. Virus Res 285: 198018.
  5. Chen Y, Gu S, Chen Y, Lu H, Shi D, et al. (2021) Six-month follow-up of gut microbiota richness in patients with Covid-19. Gut.
  6. Gu S, Chen Y, Wu Z, Chen Y, Gao H, et al. (2019) Alterations of the Gut Microbiota in Patients With Coronavirus Disease or H1N1 Influenza. Clin Infect Dis 71: 2669-2678.
  7. Ng SC, Tilg H (2020) Covid-19 and the gastrointestinal tract: more than meets the eye. Gut 69: 973-974.
  8. Yeoh YK, Zuo T, Lui GC, Zhang F, Liu Q, et al. (2021) Gut microbiota composition reflects disease severity and dysfunctional immune responses in patients with COVID-19. Gut 70: 698-706.
  9. Wan Y, Li J, Shen L, Zou Y, Hou L, et al. (2020) Enteric involvement in hospitalised patients with COVID-19 outside Wuhan. Lancet Gastroenterol Hepatol 5: 534-535.
  10. Wang L, Zhu L, Qin S (2019) Gut Microbiota Modulation on Intestinal Mucosal Adaptive Immunity. J Immunol Res 2019: 4735040.
  11. Ma C, Gu J, Hou P, Zhang L, Bai Y, et al. (2020) Incidence, clinical characteristics, and prognostic factor of patients with Covid-19: a systematic review and meta-analysis. MedRxiv 2020.03.17.20037572.
  12. Smyk W, Janik MK, Portincasa P, Milkiewicz P, Lammert F, et al. (2020) COVID-19: Focus on the lungs but do not forget the gastrointestinal Eur J Clin Invest 50: e13276.
  13. Budden K, Gellatly S, Wood D, Cooper M, Morrison M, et al. (2017) Emerging pathogenic links between microbiota and the gut-lung axis. Nat Rev Microbiol 15: 55-63.
  14. Dumas A, Bernard L, Poquet Y, Lugo-Villarino G, Neyrolles O (2018) The role of the lung microbiota and the gut-lung axis in respiratory infectious diseases. Cell Microbiol 20: e12966.
  15. Enaud R, Prevel R, Ciarlo E (2020) The gut-lung axis in health and respiratory diseases: a place for inter-organ and inter-kingdom Front Cell Infect Microbiol 10: 9.
  16. Dickson RP (2017) The microbiome and critical illness. Lancet Respir Med 4: 59-72.
  17. Fanos V, Pintus M, Pintus R, Marcialis M (2020) Lung microbiota in the acute respiratory disease: from coronavirus to metabolomics. Journal of Pediatric and Neonatal Individualized Medicine 9: e090139.
  18. Ver Heul A, Planer J, Kau A (2019) The human microbiota and asthma. Clin Rev Allergy Immunol 57: 350-363.
  19. Namasivayam S, Sher A, Glickman MS, Wipperman MF (2018) The microbiome and tuberculosis: early evidence for cross talk. mBio 9: e01418-e01420.
  20. Mammen M, Sethi S (2016) COPD and the microbiome. Respirology 21: 590-599.
  21. Macfarlane S, Cleary S, Bahrami B, Reynolds N, Macfarlane GT (2013) Synbiotic consumption changes the metabolism and composition of the gut microbiota in older people and modifies inflammatory processes:a double-blind, placebo RCT. Aliment Pharmacol Ther 38: 804-816.
  22. Carlson JL, Erickson JM, Lloyd BB, Slavin JL (2018) Health Effects and Sources of Prebiotic Dietary Fiber. Curr Dev Nutr 2: nzy005.
  23. Nobaek S, Johansson M, Molin G, Ahrne S, Jeppsson B (2000) Alteration of intestinal microflora is associated with reduction in abdominal bloating and pain in patients with irritable bowel syndrome. Am J Gastroenterol 95: 1231-1238.
  24. Azad MAK, Sarker M, Wan D (2018) Immunomodulatory effects of probiotics on cytokine profiles. Biomed Res Int.
  25. Morshedi M, Hashemi R, Moazzen S, Sahebkar A, Hosseinifard ES (2019) Immunomodulatory and anti-inflammatory effects of probiotics in multiple sclerosis: a systematic review. J Neuroinflammation 16:
  26. Gill HS, Rutherfurd KJ, Cross ML (2001) Dietary probiotic supplementation enhances natural killer cell activity in the elderly: an investigation of age-related immunological changes. J Clin Immunol 21: 264-271.
  27. Livingston M, Loach D, Wilson M, Tannock GW, Baird M (2019) Gut commensal Lactobacillus stimulates an immunoregulatory response.Immunol Cell Biol 88: 99-102.
  28. Dehghan P, Gargari B, Jafar-Abadi M, Aliasgharzadeh A (2014) Inulin controls inflammation and metabolic endotoxemia in women with type 2 diabetes mellitus: a randomized-controlled clinical trial. Int J Food Sci Nutr 65: 117-123.
  29. Hempel S, Newberry S, Ruelaz A, Wang Z, Miles JNV, et al. (2011) Safety of probiotics used to reduce risk and prevent or treat disease. Evid Rep Technol Assess 1-645.
  30. Turnbaugh P, Hamady M, Yatsunenko T, Cantarel BL, Duncan A, et (2009) A core gut microbiome in obese and lean twins. Nature 457: 480-484.
  31. Dabke K, Hendrick G, Devkota S (2019) The gut microbiome and metabolic syndrome. J Clin Invest 129: 4050-4057.
  32. Foster JA, McVey Neufeld KA (2013) Gut-brain axis: how the microbiome influences anxiety and depression. Trends Neurosci 36: 305-312.
  33. Nishida A, Inoue R, Inatomi O, Bamba S, Naito Y, et al. (2018) Gut microbiota in the pathogenesis of inflammatory bowel disease. Clin J Gastroenterol 11: 1-10.
  34. Gurung M, Li Z, You H, Rodrigues R, Jump DB, et al. (2020) Role of gut microbiota in type 2 diabetes pathophysiology. EBioMedicine 51:
  35. Tang W, Kitai T, Hazen S (2017) Gut microbiota in cardiovascular health and disease. Circ Res 120: 1183-1196.
  36. Meijnikman A, Gerdes V, Nieuwdorp M, Herrema H (2018) Evaluating causality of gut microbiota in obesity and diabetes in humans. Endocr Rev 39: 133-153.
  37. Jiang C, Li G, Huang P (2017) The gut microbiota and Alzheimer’s J Alzheimers Dis 58: 1-15.
  38. Fujita R, Iimuro S, Shinozaki T, Sakamaki K, Uemura Y, et al. (2013) Decreased duration of acute upper respiratory tract infections with daily intake of fermented milk: a multicenter, double‐blinded, randomized comparative study in users of day care facilities for the elderly population. Am J Infect Control 41: 1231‐1235.
  39. Rerksuppaphol S, Rerksuppaphol L (2012) Randomized controlled trial of probiotics to reduce common cold in schoolchildren. Pediatr Int 54: 682‐687.
  40. Waki N, Matsumoto M, Fukui Y, Suganuma H (2014) Effects of probiotic Lactobacillus brevis KB290 on incidence of influenza infection among schoolchildren: an open-label pilot study. Lett Appl Microbiol 59: 565
  41. Kang EJ, Kim SY, Hwang IH, Ji YJ (2013) The effect of probiotics on prevention of common cold: a meta-analysis of randomized controlled trial studies. Korean J Fam Med 34: 2-10.
  42. Eguchi K, Fujitani N, Nakagawa H (2019) Prevention of respiratory syncytial virus infection with probiotic lactic acid bacterium Lactobacillus gasseri Sci Rep 9: 4812.
  43. Hao Q, Dong B, Wu T (2015) Probiotics for preventing acute upper respiratory tract infections. Cochrane Database Syst Rev CD006895.
  44. Su M, Jia Y, Li Y, Zhou D, Jia J (2020) Probiotics for the prevention of ventilator-associated pneumonia: a meta-analysis of randomized controlled trials. Respir Care 65: 673-685.
  45. Hemarajata P, Versalovic J (2013) Effects of probiotics on gut microbiota: mechanisms of intestinal immunomodulation and Therap Adv Gastroenterol 6: 39-51.
  46. Plaza-Diaz J, Ruiz-Ojeda FJ, Gil-Campos M, Gil A (2019) Mechanisms of action of probiotics. Adv Nutr 10: S49-S66.
  47. Thomas C, Versalovic J (2010) Probiotics-host communication: modulation of signalling pathways in the intestine. Gut Microbes 1: 148-163.
  48. Van Baarlen P, Troost F, Van Der Meer C, Hooiveld G, Boekschoten M, et al. (2010) Human mucosal in vivo transcriptome responses to three Lactobacilli indicate how probiotics may modulate human cellular Proc Natl Acad Sci USA 108: 4562-4569.
  49. Hiippala K, Jouhten H, Ronkainen A, Hartikainen A, Kainulainen V, et (2018) The Potential of Gut Commensals in Reinforcing Intestinal Barrier Function and Alleviating Inflammation. Nutrients 10: 988.
  50. Morrison DJ, Preston T (2016) Formation of short chain fatty acids by the gut microbiota and their impact on human metabolism. Gut Microbes 7: 189-200.
  51. Koh A, De Vadder F, Kovatcheva-Datchary P, Bäckhed F (2016) From dietary fibre to host physiology: short-chain fatty acids as key bacterial Cell 165: 1332-1345.
  52. Thomas R, Williams M, Sharma H, Chaudry A, Bellamy P (2014) A double-blind, placebo-controlled randomised trial evaluating the effect of a polyphenol-rich whole food supplement on PSA progression in men with prostate cancer-the U.K. NCRN Pomi-T study. Prostate Cancer Prostatic Dis 17: 180-186.
  53. Thomas R, Yang D, Zollaman C (2017) Phytochemicals in Cancer Current Research in Compl and Alt therapy 105: 2-8.
  54. Powanda MC, Whitehouse MW, Rainsford KD (2015) Celery Seed and Related Extracts with Antiarthritic, Antiulcer, and Antimicrobial Prog Drug Res 70: 133-153.
  55. Hu F, Yi BW, Zhang W, Liang J, Lin C, et al. (2012) Carotenoids and breast cancer risk: a meta-analysis and meta-regression. Breast Cancer Res Treat 131: 239-253.
  56. Lin C, Tsai F, Tsai C, Lai C, Wan L, et al. (2005) Anti-SARS coronavirus 3C-like protease effects of plant-derived phenolic compounds. Antivir Res 68: 36-42.
  57. Singh K, Rao A (2021) Probiotics: A potential immunomodulator in Covid-19 infection management. Nutr Res 87: 1-12.
  58. Li SY, Chen C, Zhang HQ, Guo HY, Wang H, et al. (2005) Identification of natural compounds with antiviral activities against SARS-associated Antivir Res 67: 18-23.
  59. Wang Y, Wu Y, Wang Y, Xu H, Mei X, Yu D, et al. (2017) Antioxidant properties of probiotic bacteria. Nutrients 9: 521.
  60. Cecchini R, Cecchini AL (2020) SARS-CoV-2 infection pathogenesis is related to oxidative stress as a response to aggression. Med Hypotheses 143: 110102.
  61. Jones ML, Martoni CJ, Prakash S (2013) Oral supplementation with probiotic L. reuteri increases mean circulating 25-hydroxyvitamin D: a post hoc analysis of a randomized controlled trial. J Clin Endocrinol Metab 98: 2944-2951.
  62. Singh P, Rawat A, Alwakeel M, Sharif E, Al Khodor S (2020) The potential role of vitamin D supplementation as a gut microbiota modifier in healthy individuals. Sci Rep 10: 21641.
  63. Singh PK, Chopra K, Kuhad A, Kaur IP (2012) Role of Lactobacillus acidophilus loaded floating beads in chronic fatigue syndrome: Behavioral and biochemical evidences. Neurogastroenterol Motil 24: 366-e170.
  64. Shang M, Sun J (2017) Vitamin D/VDR, Probiotics and Gastrointestinal Curr Med Chem 24: 876-887.
  65. Yoon S, Yong-Guo Z, Rong L (2011) Probiotic regulation of vitamin D receptor in intestinal inflammation. Gastroenterology 140.
  66. Wu S, Yoon S, Zhang Y (2015) Vitamin D receptor pathway is required for probiotic protection in colitis. Am J Physiol Gastrointest Liver Physiol 309: G341-G349.
  67. Jamilian M, Amirani E, Asemi, Z (2019) The effects of vitamin D and probiotic co-supplementation on glucose homeostasis, inflammation, oxidative stress and pregnancy outcomes in gestational diabetes: A randomized, double-blind, placebo-controlled trial. Clin Nutr 38: 2098
  68. Daneshkhah A, Agrawal V, Eshein A, Subramanian H, Roy HK, et al. (2021) The possible role of vitamin D in suppressing cytokine storm and associated mortality in Covid-19 patients. MedRxiv.
  69. Weir EK, Thenappan T, Bhargava M, Chen Y (2020) Does vitamin D deficiency increase the severity of COVID-19? Clin Med (Lond) 20: e107-e108.
  70. Demir M, Demir F, Aygun H (2021) Vitamin D deficiency is associated with Covid-19 positivity and severity of the disease. J Med Virol 93: 2992-2999.
  71. Al Kassaa I, Hober D, Hamze M, Chihib NE, Drider D (2014) Antiviral potential of lactic acid bacteria and their bacteriocins. Probiotics Antimicrob Proteins 6: 177-185.
  72. Salaris C, Scarpa M, Elli M, Bertolini A, Guglielmetti S, et al. (2021) Lacticaseibacillus paracasei DG enhances the lactoferrin anti-SARSCoV-2 response in Caco-2 cells. Gut Microbes 13: 1961970.
  73. Chang, R, Ng, T, Sun W (2020) Lactoferrin as potential preventative and adjunct treatment for COVID-19. Int J Antimicrob Agents 56:
  74. Kotwal G (2014) Natural Antivirals against Human Viruses. Virol Mycol 3: e107.
  75. Jassim SAA, Naji MA (2003) Novel antiviral agents: a medicinal plant J Appl Microbiol 95: 412-427.
  76. Sudre C, Lee K, Lochlainn M, Varsavsky T, Murray B, et al. (2021) Symptom clusters in COVID-19: A potential clinical prediction tool from the COVID Symptom Study app. Sci Adv 7: eabd4177.
  77. Louca P, Murray B, Klaser K, Graham MS, Mazidi M, et al. (2021) Modest effects of dietary supplements during the COVID-19 pandemic: insights from 445 850 users of the Covid-19 Symptom Study app. BMJ Nutrition, Prevention & Health.
  78. Huang C, Huang L, Wang Y, Li X, Ren L, et al. (2021) 6-month consequences of COVID-19 in patients discharged from hospital: a cohort study. Lancet 397: 220-232.
  79. Xu K, Cai H, Shen Y, Ni Q, Chen Y, et al. (2020) Management of corona virus disease-19 (COVID-19): the Zhejiang experience. Zhejiang Da Xue Xue Bao Yi Xue Ban 49: 147-157.
  80. Anand S, Mande S (2018) Diet, microbiota and gut-lung connection.Front Microbiol 9: 2147.
  81. Baud D, Dimopoulou A, Gibson GR, Reid G, Giannoni E (2020) Using Probiotics to Flatten the Curve of Coronavirus Disease COVID-2019 Front Public Health 8: 186.
  82. Pourhossein M, Moravejolahkami A (2020) Probiotics in viral infections, with a focus on COVID-19: A systematic review. Authorea.
  83. Pontin E, Schwannauer M, Tai S, Kinderman P (2013) A UK validation of a general measure of subjective well-being: the modified BBC subjective well-being scale. Health Qual Life Outcomes 11: 150.
  84. Chalder T, Berelowitz G, Pawlikowska T, Watts L, Wessely S, et al. (1993) Development of a fatigue scale. J Psychosom Res 37: 147
  85. Birring SS, Prudon B, Carr A, Singh SJ, organ MDL, et al. (2003) Development of a symptom specific health status measure for patients with chronic cough: Leicester Cough Questionnaire (LCQ) Thorax 58: 339-343.
  86. Meijvis SCA, Hardeman H, Remmelts HF, Heijigenberg R, Rijkers GT, et al. (2011) Dexamethasone and length of hospital stay in patients with community-acquired pneumonia: a randomised, double-blind, placebo-controlled trial. Lancet 377: 2023-2030.
  87. Conlon MA, Bird AR (2014) The impact of diet and lifestyle on gut microbiota and human health. Nutrients 7: 17-44.
  88. Bwire GM (2020) Coronavirus: Why Men are More Vulnerable to Covid-19 Than Women? SN Compr Clin Med 1-3.
  89. Hassan NE, Wahba SA, El-Masry SA, Abd Elhamid ER,Boseila SAW, et al. (2015) Eating Habits and Lifestyles among a Sample of Obese Working Egyptian Women. Open Access Maced J Med Sci 3: 12-17.
  90. Yurkovetskiy L, Burrows M, Khan A, Graham L, Volchkov P, et al. (2013) Gender bias in autoimmunity is influenced by microbiota. Immunity 39: 400-412.
  91. Dantzer R, Heijnen CJ, Kavelaars A, Laye S, Capuron L (2014) The neuroimmune basis of fatigue. Trends Neurosci 37: 39-46.
  92. Giloteaux L, Goodrich J, Walters W, Levine SM, Ley RE, et al. (2016) Reduced diversity and altered composition of the gut microbiome in individuals with myalgic encephalomyelitis chronic fatigue syndrome. Microbiome 4: 30.
  93. Williamson CB, Burns C, Gossard C, Pizano JM, Dolan KE, et al. (2017) Probiotics and Disease: A Comprehensive Summary, Cardiometabolic Disease and Fatigue Syndromes. Integr Med 16: 30-41.
  94. Sullivan A, Nord CE, Evengard B (2009) Effect of supplement with lactic-acid producing bacteria on fatigue and physical activity in patients with chronic fatigue syndrome. Nutr J 8: 4.
  95. Doron S, Snydman DR (2015) Risk and safety of probiotics. Clin Infect Dis 60: S129-S134.
  96. Galland L (2014) The gut microbiome and the brain. J Med Food 17: 1261-1272.
  97. Gagliardi A, Totino V, Cacciotti F, Iebba V, Neroni B, et al. (2018) Rebuilding the Gut Microbiota Ecosystem. Int J Environ Res Public Health 15: 1679.
  98. Bernardeau M, Vernoux J, Henri-Dubernet S, Gueguen M (2008) Safety assessment of dairy microorganisms: the Lactobacillus genus. Int J Food Microbiol 126: 278-285.
  99. Bernardeau M, Guguen M, Vernoux JP (2006) Beneficial lactobacilli in food and feed: long-term use, biodiversity and proposals for specific and realistic safety assessments. FEMS Microbiol Rev 30: 487-513.
  100. Preidis GA, Weizman AV, Kashyap PC, Morgan RL (2020) AGA Technical Review on the Role of Probiotics in the Management of Gastrointestinal Disorders. Gastroenterology 159: 708-738.
  101. Rao S, Rehman S, Yu S, de Andino NM (2018) Brain fogginess, gas and bloating: a link between SIBO, probiotics and metabolic acidosis. Clin Transl Gastroenterol 9: 162.
  102. Sanders ME, Akkermans LM, Haller D, Hammerman C, Heimbach J, et al. (2010) Safety assessment of probiotics for human use. Gut Microbes 1: 164-185.
  103. Borriello SP, Hammes WP, Holzapfel W, Marteau P, Schrezenmeir J, et (2003) Safety of probiotics that contain lactobacilli or bifidobacteria. Clin Infect Dis 36: 775-780.
  104. Lu D, Yan J, Liu F, Ding P, Chen B, et al. (20191) Probiotics in preventing and treating chemotherapy-induced diarrhoea: a meta Asia Pac J Clin Nutr 8: 701-710.

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