Metabolic syndrome and type 2 diabetes

Metabolic syndrome is considered a pro-thrombotic and pro-inflammatory state characterised by a set of clinical findings that include central and abdominal obesity, systemic hypertension, insulin resistance and atherogenic dyslipidaemia, including elevated inflammatory cytokine activity^{(Reference Aziz, Whitehead and Palsson97,Reference Samson and Garber98)} . Therapeutic options involve dietary control, regular exercise and pharmacological treatment for dyslipidaemia, hypertension and hyperglycaemia^{(Reference Samson and Garber98)}.

Gut microbes influence host metabolic balance by modulating energy absorption, intestinal motility, appetite, glucose and lipid metabolism, and hepatic fat storage^{(Reference Festi, Schiumerini and Eusebi99)}. Dysbiosis favours the translocation of bacterial fragments and can lead to systemic inflammation and insulin resistance^{(Reference Festi, Schiumerini and Eusebi99,Reference Li, Zhou and Gan100)} . Administration of pre- and probiotics can reduce low-grade inflammation and improve intestinal barrier integrity, aiding metabolic balance. Zonulin, a family of proteins associated with the permeability of the intestinal barrier^{(Reference Fasano101)}, is a physiological modulator of the tight intercellular junctions of the intestinal epithelium, and the loss of barrier function secondary to its up-regulation can lead to an uncontrolled influx of food and microbial antigens. Pražnikar et al. ^{(Reference Praznikar, Kenig and Vardjan85)} studied the effects of supplementing asymptomatic overweight adults with milk or kefir for 3 weeks, finding that kefir supplementation led to lower serum zonulin levels than milk.

Bellikci-Koyu et al. ^{(Reference Bellikci-Koyu, Sarer-Yurekli and Akyon82)} and Da Silva Ghizi et al. ^{(Reference Da Silva Ghizi, De Almeida Silva and De Andrade Moraes95)} tested the effects of regular kefir consumption in people with metabolic syndrome. The intervention period in both studies was 12 weeks and they used similar dosages, although the kefir preparation methods differed. The bioactive peptide profile of milk kefir is completely different from that of raw milk, including 236 unique peptides produced during the fermentation process, many with antihypertensive (angiotensin-converting enzyme inhibitors), antimicrobial, immunomodulatory, antioxidant and antithrombotic properties^{(Reference Ebner, Asci Arslan and Fedorova46)}. Bellikci-Koyu et al. ^{(Reference Bellikci-Koyu, Sarer-Yurekli and Akyon82)} found no significant differences between milk and kefir groups, while Da Silva Ghizi et al. ^{(Reference Da Silva Ghizi, De Almeida Silva and De Andrade Moraes95)} considered the origin of their fermented beverage key to their more expressive findings than Bellikci-Koyu et al. ^{(Reference Bellikci-Koyu, Sarer-Yurekli and Akyon82)}. Da Silva Ghizi et al. used milk inoculated with kefir grains, which contains more than thirty live bacteria species and twelve yeast and fungi species in a complex symbiotic system, a culture that synthesises several bioactive compounds during the fermentation process, such as organic acids, bioactive peptides, bacteriocins and exopolysaccharides^{(Reference Azizi, Kumar and Yeap39,Reference Ebner, Asci Arslan and Fedorova46,Reference Rosa, Dias and Grzeskowiak51)} . Industrial kefir production, which usually involves commercial starter cultures, allows standardisation of this process, although it results in loss of cell viability. Commercial kefir contains a smaller number and variety of microorganisms, especially yeasts^{(Reference Ebner, Asci Arslan and Fedorova46,Reference Gonzalez-Orozco, Garcia-Cano and Jimenez-Flores102)} . Moreover, in fermented food production (including kefir), the backslopping technique is used to increase production by up to fifty times, maintaining the physico-chemical characteristics and nutritional values, but decreasing the microbiological diversity and producing some consistency deficiencies^{(Reference Farag, Jomaa and El-Wahed31)}. In a randomised, double-blind, placebo-controlled clinical study, Da Silva Ghizi et al. ^{(Reference Da Silva Ghizi, De Almeida Silva and De Andrade Moraes95)} found significant improvement in several clinical parameters in the kefir group compared with controls (who received homemade curd prepared with the same type of milk as the kefir group), including blood pressure, lipid profile blood, fasting glucose and oxidised LDL, which led to lower cardiovascular risk according to Framingham scores. Abd-Alwahab and Al-Dulaimi^{(Reference Abd-Alwahab and Al-Dulaimi78)} administered grain-fermented kefir drink to volunteers, finding significant improvement in the lipid profile, although their control group received water instead of milk, which prevents direct comparison of the results.

One hypothesis about kefir’s mechanism of action on serum cholesterol levels is the deconjugation of bile acids by Lactobacillus spp., while yeasts increase bile acid discharge, which in turn increases cholesterol expenditure during production^{(Reference Abd-Alwahab and Al-Dulaimi78,Reference Brashears, Gilliland and Buck103)} . In addition, colonic microbiota can metabolise dietary and endogenous cholesterol, reducing it mainly to coprostanol (5β-colestan-3β-ol) and coprostanone, both through low intestinal absorption and elimination through faeces^{(Reference Lye, Rusul and Liong104,Reference Ooi and Liong105)} . Higher intake of calcium, which is abundant (about 0·12/100 g) in kefir, can also positively affect the serum lipid profile^{(Reference Ditscheid, Keller and Jahreis106–Reference Denke, Fox and Schulte108)}. St-Onge et al. ^{(Reference St-Onge, Farnworth and Savard54)}, Fathi et al. ^{(Reference Fathi, Ghodrati and Zibaeenezhad71)}, Pražnikar et al. ^{(Reference Praznikar, Kenig and Vardjan85)}, Ostadrahimi et al. ^{(Reference Ostadrahimi, Taghizadeh and Mobasseri68)}, Gezginc and Maranci^{(Reference Gezginc and Maranci79)} and Bashiti and Zabut^{(Reference Bashiti and Zabut84)} investigated kefir’s effects on the lipid profile, but found different results, probably a consequence of the studies’ different methodologies.

The conflicting outcomes of these studies can be explained, at least in part, by the heterogeneity of their populations, especially the floor (baseline) effect (i.e. the lower the baseline level of an outcome, the less likely a treatment will result in a reduction in that outcome level), which was evident in studies such as that by Gezginc and Maranci^{(Reference Gezginc and Maranci79)}, who tested the influence of kefir on the lipid profile of healthy young people.

Hosainzadegn and Hosainzadegan^{(Reference Hosainzadegn and Hosainzadegan92)} reported a case of marked improvement in glycated hemoglobin (HbA1c) levels (from 7·9 to 7·1) and a 4 kg weight loss in a woman with type 2 diabetes after 3 months of using kefir prepared at home. Clinical studies by Judiono et al. ^{(Reference Judiono, Hadisaputro and Indranila67)}, Ostradahimi et al. ^{(Reference Ostadrahimi, Taghizadeh and Mobasseri68)}, Alihosseini et al. ^{(Reference Alihosseini, Moahboob and Farrin72)}, Bellikci-Koyu et al. ^{(Reference Bellikci-Koyu, Sarer-Yurekli and Akyon82)}, Bashiti and Zabut^{(Reference Bashiti and Zabut84)} and Praznikar et al. ^{(Reference Praznikar, Kenig and Vardjan85)} were included in a systematic review with meta-analysis^{(Reference Salari, Ghodrat and Gheflati109)} of randomised clinical trials that assessed the effects of kefir drink on glycaemic control. The authors found significant improvement in fasting glucose and insulin levels in participants who consumed kefir, but no significant difference in HbA1c levels. The results of this meta-analysis, however, can be questioned due to the heterogeneity of study populations, dosages, and intervention times.

Weight control and exercise are also involved in the prevention and treatment of metabolic syndrome. Studies by O’Brien et al. ^{(Reference O’Brien, Stewart and Forney53)}, Gölünük et al. ^{(Reference Gölünük, Öztaşan and Sözen73)} and Lee et al. ^{(Reference Lee, Jhang and Lee88)} investigated the effects of kefir on post-exercise oxidative stress parameters. The samples of these studies were healthy young people, although the intervention time, kefir type, quantity and tested parameters differed greatly. Kefir improved total oxidant status levels (an indicator of oxidative stress)^{(Reference Gölünük, Öztaşan and Sözen73)}, did not change C-reactive protein levels (which increased in the control group)^{(Reference O’Brien, Stewart and Forney53)}, improved exercise endurance, reduced lactic acid production after exercise, accelerated recovery^{(Reference Lee, Jhang and Lee88)} and did not significantly affect the other parameters.

Regarding weight loss, Fathi et al. ^{(Reference Fathi, Faghih and Zibaeenezhad70)} and Hosainzadegn and Hosainzadegan^{(Reference Hosainzadegn and Hosainzadegan92)} found positive results with kefir, unlike other studies that measured anthropometric parameters such as weight, body mass index and waist circumference^{(Reference O’Brien, Stewart and Forney53,Reference Lee, Jhang and Lee88,Reference Da Silva Ghizi, De Almeida Silva and De Andrade Moraes95)} . Caferoglu and Aytekin Sahin^{(Reference Caferoglu and Aytekin Sahin94)} investigated whether adding kefir to a low or high glycaemic index meal would affect participant appetite and food intake, finding that kefir can help limit appetite and energy intake for high glycaemic index meals but not low glycaemic index meals^{(Reference Caferoglu and Aytekin Sahin94)}.

Gastrointestinal health/disorders

The gastrointestinal tract and its microbiome provide unique metabolic functions to the host and are critical to maintaining health. The abundance of different species of microorganisms, their function and their interaction with organic systems have been the focus of numerous medical studies^{(Reference Hills, Pontefract and Mishcon110)}. Metagenomics and analysis of twin data have shown that environmental factors, such as diet and domestic cohabitation, far outweigh heritable genetic contributions to gut microbiota composition and function^{(Reference Rothschild, Weissbrod and Barkan111)}.

Inflammatory bowel disease is characterised by chronic and relapsing inflammation of the gastrointestinal tract and includes 2 chronic idiopathic inflammatory diseases: Crohn’s disease and ulcerative colitis^{(Reference Yilmaz, Dolar and Ozpinar83,Reference Sairenji, Collins and Evans112,Reference Flynn and Eisenstein113)} . These heterogeneous and complex immune disorders of the gastrointestinal tract share many common clinical features but differ in inflamed areas and are treated differently^{(Reference Hills, Pontefract and Mishcon110,Reference Flynn and Eisenstein113,Reference Lee and Chang114)} . Considered a serious and debilitating condition that affects general health and quality of life, inflammatory bowel disease has been associated with intestinal dysbiosis, which decreases microbial biodiversity and slows or stops important functions of intestinal barrier integrity and immune system regulation, which results in inflammation and increased immune response^{(Reference Lee and Chang114)}. In addition, mucolytic and pathogenic bacteria are also increased, which leads to degradation of the mucosal barrier and greater pathogen penetration into intestinal tissues^{(Reference Lee and Chang114,Reference Chassaing and Darfeuille-Michaud115)} .

Probiotics and faecal microbial transplantation, both aimed at reintroducing beneficial microbes into dysbiotic guts, are currently being used to treat inflammatory bowel disease^{(Reference Lee and Chang114,Reference Jeong, Kim and Son116)} . Since kefir contains a diverse range of microorganisms, many of which have already been studied as probiotics^{(Reference Slattery, Cotter and O’Toole117)}, it has promise as an alternative treatment for intestinal dysbiosis. Wang^{(Reference Wang, Zaydi and Lin87)} found that 21 d of freeze-dried (industrialised) kefir had positive effects on gastrointestinal symptoms, such as abdominal pain and bloating, and increased abundance of bifidobacteria. Forejt et al. ^{(Reference Forejt, Šimůnek and Brázdová57)} found significant improvement in gastrointestinal discomfort and lower Enterococcus faecalis after 2 weeks of kefir therapy in a sample of women. Figler et al. ^{(Reference Figler, Mozsik and Schaffer56)} investigated how consuming two types of kefir influenced the levels of primary probiotic Streptococcus, Lactobacillus and Bifidobacterium among the total number of microbes, finding that these populations increased in both groups after 4 weeks, with a more expressive increase in the intervention group (Biofir^® kefir). In contrast, Sepp^{(Reference Sepp, Smidt and Štšepetova80)} found increased diversity of Lactobacillus spp. after 8 weeks only in the group who received kefir (industrialised) with added L. fermentum ME-3. The studies’ samples, however, were healthy people with no diagnosed gastrointestinal disease, and different intervention times were used. In a sample of patients with Crohn’s disease, Yilmaz et al. ^{(Reference Yilmaz, Dolar and Ozpinar83)} found that regular kefir use can improve both symptoms and short-term quality of life and has a positive effect on biochemical parameters (such as haemoglobin, C-reactive protein and erythrocyte sedimentation rate).

Kefir has also been studied as an adjuvant treatment in two other gastrointestinal pathologies, Helicobacter pylori infection and recurrent Clostridioides difficile infection. Among patients who received kefir, Bekar et al. ^{(Reference Bekar, Yilmaz and Gulten61)} found a lower prevalence of side effects, such as headache, nausea, diarrhoea and abdominal pain, in a group that received a triple therapy consisting of lansoprazole (30 mg), amoxicillin (1000 mg) and clarithromycin (500 mg). This may have important implications for increasing treatment adherence. In a case series of patients at risk of recurrent Clostridioides difficile infection, Bakken^{(Reference Bakken64)} used continuous kefir ingestion in association with a regimen of staggered and tapered antibiotic withdrawal, finding the same efficacy as faecal microbial transplantation.

Microorganisms present in kefir, such as Lactococcus spp., Lactobacillus spp. and some strains of Kluyveromyces spp. hydrolyse lactose to glucose and galactose^{(Reference Leite, Leite and Del Aguila118)}. During the fermentation process, milk proteins are also extensively hydrolysed, releasing functional peptides and improving digestibility^{(Reference Dallas, Citerne and Tian119)}. Two studies tested kefir for digestibility in healthy adults with poor digestion^{(Reference Hertzler and Clancy55)} or lactose intolerance^{(Reference Mądry, Krasińska and Woźniewicz63)}, both using a single intervention dose. They concluded that milk fermented with kefir, as well as yogurt, causes less severe discomfort than normal milk.

Turan et al. ^{(Reference Turan, Dedeli and Bor66)} and Maki et al. ^{(Reference Maki, Matsukawa and Matsuduka77)} studied the effects of kefir on chronic intestinal constipation, a highly prevalent condition for which diet is a possible treatment^{(Reference Aziz, Whitehead and Palsson97)}. The first study enrolled patients who met Rome II criteria for chronic constipation, without metabolic or structural disorders that could be responsible for the disease; the second enrolled patients with some physical or mental disability who were admitted to a Japanese hospital. In addition to the different study populations, the type and amount of kefir used were completely different. Turan et al. ^{(Reference Turan, Dedeli and Bor66)} used a higher dose of kefir (250 ml twice per day) for 28 d, while Maki et al. ^{(Reference Maki, Matsukawa and Matsuduka77)} used lyophilised kefir at a much lower dose (about 1/8 of Turan et al.) for 84 d. Turan et al. found that kefir supplementation was associated with a statistically significant decrease in laxative use, increased defecation frequency, higher bowel satisfaction scores and shortened colonic transit times. Maki et al. ^{(Reference Maki, Matsukawa and Matsuduka77)} found that kefir worked better in patients with non-severe chronic constipation and suggested identifying individuals who could benefit from its use. Clinical trials with larger sample sizes and a control group are highly recommended to determine kefir’s benefits in preventing and/or treating these gastrointestinal disorders.

Maternal/child health and paediatrics

Intestinal bacterial colonisation in the first years of life (generally the first three) has a major impact on the immune system, and the immunological influences of microbiota during this specific window can determine resistance or susceptibility to diseases, affecting the host’s health throughout life^{(Reference Kim and Kim120–Reference Gensollen and Blumberg122)}. Breast milk is a critical factor in the development and composition of intestinal microbiota in neonates. One possible origin of the bacteria in this fluid, many of which are potentially probiotic, is the maternal gastrointestinal tract via bacterial translocation through the lymphatic system^{(Reference Stinson, Sindi and Cheema123)}. Tunay et al. ^{(Reference Tunay and Taş96)} tracked transmission of bacteria unique to kefir grains (Lactobacillus kefiranofaciens, Lentiactobacillus kefiri, Lentiactobacillus parakefiri) in breast milk and the faeces of newborns, finding that these microorganisms were transmitted to milk through maternal consumption of kefir, resulting in infant intestinal colonisation. Kurt et al. assessed the effects of milk kefir in nursing mothers in relation to the carbohydrate profile of their breast milk^{(Reference Kurt, Gökırmaklı and Guzel-Seydim91)}. The authors detected a trend towards more carbohydrates, including galactoligosaccharides (structures with prebiotic properties), in the milk of mothers who consumed kefir. They also reported that neither the mothers nor their infants experienced abdominal discomfort from using kefir. While a good body of evidence about the effects of probiotics on paediatric populations already exists^{(Reference Guo, Goldenberg and Humphrey124–Reference Jiang, Ni and Liu126)}, studies about the benefits of kefir in children are still incipient.

Merenstein et al. ^{(Reference Merenstein, Foster and D’Amico60)} tested kefir’s effects on prevention of antibiotic-associated diarrhoea, a disease with a high morbidity rate and low treatment adherence^{(Reference Turck, Bernet and Marx127)}. The sample consisted of children aged between 1 and 5 years who received antibiotics to treat upper airway infections. Although they found no difference in diarrhoea rates between the intervention and control groups, they did find different absolute numbers of diarrhoea incidents in children aged 3–5 years (14% in the control group versus 6% in the kefir group) and in boys (32% in the control group versus 24% in the kefir group, compared with a 2% difference among girls in these groups). The differences in absolute numbers of diarrhoea incidents in the older groups were quite expressive (57% higher in the placebo group), which suggests that a study with a larger sample in this population could help elucidate the promising role of kefir for preventing antibiotic-associated diarrhoea. The authors further reported that patient safety was excellent, as expected for a food.

De Araújo et al. studied the effects of lyophilised kefir on the clinical parameters of wheezing among infants aged 6–24 months and on cytokine expression via T-helper 1 and T-regulatory cells^{(Reference De Araujo, De Lorena and Montenegro75)}, finding no significant decrease in the clinical parameters of wheezing, only a trend towards lower recurrence (perhaps the sample was too small to demonstrate significance). However, they suggested that this probiotic mixture triggers immunomodulation due to the production of T-helper 1 and T-regulatory cell cytokines, including IL-10 and IL-12, since there they increased significantly in the intervention group. Intestinal bacteria contribute to proper development of the immune system in the first years of life, and the intestinal flora and its metabolites (such as short-chain fatty acids) actively participate in the proliferation and differentiation of B cells and T cells, inducing a protective antibody response^{(Reference Nguyen, Himes and Martinez128)}.

Dentistry

The human mouth harbours a complex microbiome whose imbalance can lead to dental caries and periodontal disease^{(Reference Mosaddad, Tahmasebi and Yazdanian129)}. When metabolising carbohydrates, cariogenic microorganisms produce lactic, formic, acetic and propionic acids, which decrease the mouth’s pH to below 5·5, resulting in demineralisation of enamel hydroxyapatite crystals and proteolytic breakdown of the hard tissue structure of the teeth. Streptococcus mutans is the most important bacterial species related to oral health^{(Reference Dashper, Mitchell and Le Cao130)}; it is more abundant in disease and is the main bacteria involved in early childhood caries^{(Reference Patidar, Sogi and Singh131)}. Three included studies analysed the effects of kefir on the salivary count of S. mutans. Nevertheless, the results differed depending on the population, intervention time and dosage. The results showed that kefir was as effective as sodium fluoride for reducing salivary S. mutans counts in young adults^{(Reference Ghasempour, Sefdgar and Moghadamnia65)}. Daily consumption of kefir and the use of probiotic toothpaste decreased salivary microbial colonisation in orthodontic patients^{(Reference Alp and Baka76)}; probiotic products together with dental restorations effectively reduced S. mutans in children aged 8–12 years^{(Reference Reddy, Madhu and Punithavathy89)}.

Oncology

In vitro and animal studies have found positive results with probiotic dietary products like kefir in the prevention and treatment of various types of cancer^{(Reference Sharifi, Moridnia and Mortazavi40,Reference Fatahi, Soleimani and Afrough132,Reference Rafie, Golpour Hamedani and Ghiasvand133)} . Studies by Topuz et al. ^{(Reference Topuz, Derin and Can58)} and Can et al. ^{(Reference Can, Topuz and Derin59)} explored the use of kefir in very similar populations, using the same dose in almost identical intervention times, although their objectives differed. Topuz et al. measured serum levels of pro-inflammatory cytokines, the antimicrobial effects of kefir and the mucositis rate in patients with colorectal cancer receiving chemotherapy (5-fluorouracil or oral fluoropyrimidine), but found no statistically significant differences between the intervention and control groups. Can et al. ^{(Reference Can, Topuz and Derin59)} explored kefir’s ability to prevent treatment-related gastrointestinal symptoms and its effects on the quality of life of cancer patients. They detected no differences in quality-of-life indices and reported more gastrointestinal complaints, but found better sleep quality in patients who used kefir. The amount of fermented milk used in the intervention may explain the increased complaints, since the ingestion of 250 ml of any liquid can be uncomfortable and increase symptoms such as nausea, vomiting and diarrhoea. Furthermore, the control group did not receive any type of similar liquid.

Smoak et al. ^{(Reference Smoak, Harman and Flores93)} studied patients with cancer who had undergone chemotherapy or radiotherapy in the previous 2 years and were enrolled in an exercise programme at the University of Northern Colorado Cancer Rehabilitation Institute. The intervention group drank approximately 240 ml of kefir up to 30 min after the exercise sessions, which took place three times a week for 12 weeks. The control group performed the same exercises but received no placebo. The kefir group improved in lean body mass, depression symptoms, fatigue, gastric discomfort and a biomarker of intestinal dysbiosis, which suggests that including kefir as part of a post-exercise diet can have significant psychological and physical benefits for cancer survivors^{(Reference Smoak, Harman and Flores93)}.

Women’s and geriatric health

Özcan et al. ^{(Reference Ozcan, Oskay and Bodur81)} studied perimenopause middle-aged women, in whom hormonal changes can lead to sleep and mood disturbances, sexual problems and, in the long term, decreased bone density^{(Reference Gracia and Freeman134,Reference Potter, Schrager and Dalby135)} . The authors used the Women’s Health Insomnia Rating Scale, the Menopause-Specific Quality of Life Questionnaire and the Beck Depression Inventory to determine whether kefir benefitted post-menopausal women suffering from sleep disorders. After 1 month of intervention there was significant improvement in the first two parameters but not in Beck Depression Inventory results, which showed a non-significant trend towards improvement. Despite the study’s small sample size, the authors found kefir to be a non-pharmacological alternative for minimising some of the discomforts of the menopausal transition period.

Tu et al. ^{(Reference Tu, Chen and Tung69)} studied patients with osteoporosis, a disorder especially prevalent in postmenopausal women and older men, characterised by decreased bone mass and increased fracture risk^{(Reference Lane, Russell and Khan136)}. Therapy for patients with osteoporosis includes non-pharmacological measures (exercise, adequate calcium intake, etc.), medications to increase bone density and improve bone strength, and strategies to reduce the risk of falling^{(Reference Lane, Russell and Khan136,137)} . In their controlled, parallel, double-blind intervention study, Tu et al. ^{(Reference Tu, Chen and Tung69)} divided participants into an intervention group, which received 1600 mg of freeze-dried milk kefir plus CaCO₃ (1500 mg) daily, while the control group received the same amount of CaCO₃ plus placebo (1600 mg of freeze-dried unfermented raw milk) daily for 6 months. By 6 months, the intervention had promoted short-term changes in bone turnover markers and greater increases in hip bone mineral density.

In the field of neurodegenerative diseases, Ton et al. ^{(Reference Ton, Campagnaro and Alves86)} conducted an uncontrolled clinical investigation to explore the antioxidant effects of milk fermented by kefir grains in patients with Alzheimer’s disease. Alzheimer’s disease causes progressive functional and cognitive decline in older adults and is the most common cause of dementia worldwide^{(Reference Lopez and Kuller138)}. From a pathological point of view, it is characterised by extracellular deposition of β-amyloid peptides and intracellular accumulation of hyperphosphorylated and aggregated hyperphosphorylated tau (a protein abundant in neurons), forming neurofibrillary tangles^{(Reference Querfurth and LaFerla139)}. The central mediators in the pathogenesis of Alzheimer’s disease are oxidative stress and neuroinflammation^{(Reference Kinney, Bemiller and Murtishaw140–Reference Chen and Zhong142)}. Numerous studies have shown that gut microbiota play an important role in brain function^{(Reference Megur, Baltriukiene and Bukelskiene143–Reference Doifode, Giridharan and Generoso145)}. The brain and microbiota communicate through a complex bidirectional connection known as the ‘microbiota–gut–brain axis’, which involves the immune system, neuroendocrine mechanisms, tryptophan metabolism, vagus nerve and enteric nervous system.^{(Reference Yue, Cai and Xiao3,Reference Megur, Baltriukiene and Bukelskiene143,Reference Cryan, O’Riordan and Cowan146)} . Lipopolysaccharides (endotoxins) and bacterial amyloids synthesised by the gut microbiota can activate brain immune response and lead to neuroinflammation^{(Reference Megur, Baltriukiene and Bukelskiene143,Reference Jiang, Li and Huang144)} . Neuroinflammatory cytokines may compromise β-amyloid clearance, leading to its accumulation in the brain^{(Reference Pereira, Coco and Ton8,Reference Alasmari, Alshammari and Alasmari147)} . Ton et al. ^{(Reference Ton, Campagnaro and Alves86)} evaluated the benefits of kefir supplementation for 90 d at a dose of 2 ml/kg/d on cognitive function and biomarkers of oxidative stress, inflammation and cell damage in older adults with Alzheimer’s disease. They found improvement in every test (memory, visual–spatial function and abstraction skills, executive and language functions, constructive skills and attentive function), a protective effect for mitochondria, and cytoprotective and anti-apoptotic action, whose effects slow neurodegeneration.

Dermatology

The skin and gut appear to share a series of indirect bidirectional metabolic pathways known as the ‘gut–skin axis’^{(Reference Alves, Gregorio and Baby90)}. Patients with atopic dermatitis, a highly prevalent inflammatory skin disease worldwide, present with intestinal and cutaneous dysbiosis^{(Reference Kim and Kim120,Reference Watanabe, Narisawa and Arase148,Reference Fieten, Totte and Levin149)} . This condition of microbiome imbalance, along with skin barrier dysfunction, immune dysregulation and environmental risk factors, contributes to disease onset and the atopic march^{(Reference Yu, Dunaway and Champer11,Reference Lee, Lee and Park150)} . In their controlled crossover intervention study, Alves et al. ^{(Reference Alves, Gregorio and Baby90)} compared the effects of kefir ingestion (grain-fermented at home) on the skin of adults with and without atopic dermatitis. The primary outcomes were transepidermal water loss and stratum corneum hydration in all participants and the severity scoring of atopic dermatitis (SCORAD) index in patients with atopic dermatitis. Significant improvements were found in both groups, including a significant SCORAD index decrease in the atopic dermatitis group.

Kefir production and dosage

Commercially produced kefir models may contain different species of Lactobacillus than those produced with the inoculation of the grains, which can make an important difference, because species exclusive to kefir grains such as L. kefiranofaciens and L. kefiri have already demonstrated beneficial health effects^{(Reference Carasi, Racedo and Jacquot151–Reference Chen, Hsiao and Hong154)}. Furthermore, commercial kefir samples usually do not contain acetic acid bacteria, which are abundant in traditionally prepared kefir^{(Reference Dobson, O’Sullivan and Cotter155–Reference Walsh, Crispie and Kilcawley157)}. Another noteworthy difference between commercially and traditionally prepared kefir is the variety of yeasts, radically smaller in commercial models^{(Reference Marsh, O’Sullivan and Hill156)}. Bourrie et al. ^{(Reference Bourrie, Cotter and Willing158,Reference Bourrie, Ju and Fouhse159)} demonstrated the impact of these microbial differences on kefir’s ability to improve metabolic parameters in obese mice.

On the basis of these animal studies and on the analysed intervention studies, our suggestion is to use a therapeutic dose pattern in millilitres of traditionally prepared kefir (kefir grains inoculated in milk), due to its greater microbiological complexity and potential bioactive compounds.

The randomised, double-blind, placebo-controlled trial by Da Silva Ghizi et al. ^{(Reference Da Silva Ghizi, De Almeida Silva and De Andrade Moraes95)} was the only one to use individualised dose per kilogram (1·6 ml/kg for males and 1·9 ml/kg for females), calculated on the basis of studies by Reagan-Shaw et al. ^{(Reference Reagan-Shaw, Nihal and Ahmad160)} and Rosa et al. ^{(Reference Diniz Rosa, Gouveia Peluzio do and Pérez Bueno161)}. This dose was close to the lowest standardised doses used in other studies that showed benefits. So, we suggest this individualised dose to be used in future studies avoiding underdose/overdose error. For example, a dose of 1·6 ml/kg for a man weighing 90 kg would be 144 ml of kefir per day, making routine consumption much more viable. When such individualisation is not possible, doses of 100–200 ml/d are suggested.

These doses were determined by the perception that a minimum amount necessary is better tolerated by people and is more economically viable, increasing the probability of the consumption of this food to become a habit and its possible benefits to extend over time. Such doses would also make the methodology of future studies closer to the reality of the population. Very high amounts of kefir can hamper the viability of longer-term use due to palatability and maintenance costs, even when prepared at home. Daily doses of 500 or 600 ml, used in some studies, are not feasible long term for the general population, thus preventing any possible benefits.