The influence of diet and time restricted feeding patterns in maintaining a healthy gut microbiome


An estimated 500 to 1,000 bacterial species reside in each person’s gut, perhaps numbering 100,000 trillion microorganisms. In a new paper, published July 5, 2022 in Cell Reports, researchers at University of California San Diego School of Medicine used mouse models to explore how diet and feeding patterns affect these intestinal microbes – and the health of the hosts, particularly with obesity and type 2 diabetes.

In both mice and men, the ileum is the final stretch of the small intestine, connecting to the cecum, the first part of the large intestine. In the ileum, nutrients are drawn out of liquefied food; in the cecum, which also marks the beginning of the colon, the process of extracting water begins.

Both processes are complex, dynamic and profoundly influenced by factors ranging from the types of foods consumed and when, to the microbial residents of the gut, whose presence and behaviors help dictate digestion, absorption of nutrients, vitamin synthesis and development of the immune system.

“It’s important to realize that the gut microbiome is constantly changing, not only based on what we’re eating, but also based on the time of day,” said senior study author Amir Zarrinpar, MD, Ph.D., assistant professor of medicine at UC San Diego School of Medicine and a gastroenterologist at UC San Diego Health.

“Most researchers are getting snapshots of this constantly shifting environment, which makes it hard to understand what is going on in the gut. With this study, we are trying to get multiple snapshots throughout the day, almost like a movie, to better understand how food and the microbiome interact to affect weight gain and diabetes.

“And what we’ve learned is that cyclical changes in the gut microbiome are quite important for health since they help with the circadian clock, and with that the regulation and control of glucose, cholesterol and fatty acids—and overall metabolic health.”

In their latest work, Zarrinpar and colleagues further elucidate the impact and interplay of these factors, particularly in terms of the ileum and its unique functions related to digestion and absorption. Specifically, they looked at how diet-induced obesity (DIO) and time-restricted feeding (TRF) alter ileal microbiome composition and transcriptome (the protein-coding part of an organism’s genome) in mouse models.

The researchers found that in mouse models, DIO and the absence of TRF (mice could eat as much as they wanted whenever they wanted) resulted in disruptions to gut microbiome rhythms and the signaling pathways that help modulate intestinal clocks. In other words, the mice became fat and unhealthy.

“It is interesting that restricting food access with TRF acts not only through restoration of patterns affected under the unhealthy state, but also through new pathways,” said first author Ana Carolina Dantas Machado, Ph.D., a postdoctoral scholar in Zarrinpar’s lab.

“These findings underscore the influence of diet and time restricted feeding patterns in maintaining a healthy gut microbiome, which in turn modulates circadian rhythms that govern metabolic health,” said Zarrinpar. “It’s a very complicated relationship between the microbiome and the host, with the former helping determine the latter’s gastrointestinal functioning and health.”

Their work, said the authors, can inform future studies, in particular investigations of how the gut works or how drugs act upon the gut function depending upon the state of the microbiome at a particular time or time of day.

Fig. 2 – Effect of different types of fasting regimen on the gut microbiota composition and health parameters

In this systematic review, we provided an overview of the existing literature regarding the gut microbiota during fasting. Most studies have reported the positive effects of fasting diets on modulating intestinal microbiota composition, improving host functions and slowing disease progression.

Current evidence suggests that fasting might be a successful intervention to prevent and manage metabolic disorders with greater reduction in anthropometric parameters, glycemic indices and lipid profile compared with standard continuous energy restriction diets [48–50]. Fasting diets also decrease inflammation, which are believed to protect against metabolic, neurodegenerative and age related diseases [51, 52].

It was demonstrated in animal models that fasting diets can markedly reduce systemic inflammation through decreasing mRNA expression levels of inflammatory cytokines and chemokines in white adipose tissue including IL-6, IL-1Ra, IL-2,MCP-1, and CXCL16 [53]. Regarding the role of microbiome in modulating adiposity and protecting against the development of obesity-related metabolic dysfunction, recently the factors affecting the regulation of gut microbita have received much attention.

Preliminary animal models suggest that intermittent fasting may be one of these modulators [54]. Intermittent fasting in mice induced white adipose tissue (WAT) beiging, weight loss, and changes in the gut microbiota, including a decrease in the Firmicutes to Bacteroidetes ratio [13]. This was associated with improvements in liver steatosis and metabolic syndrome components. However, in microbiota-depleted mice, fasting did not improve obesity or liver steatosis, thus suggesting that the gut microbiota alteration plays a key role as an underlying mechanism in fasting-induced health benefits [55].

Upon fasting, several beneficial bacteria including Lactobacillus and Bifidobacterium shifted significantly in abundance. Lactobacillus and Bifidobacterium are documented as useful strains for human health in lots of clinical trials on the adult population [56]. Some species such as Escherichia coli that associated with endothelial dysfunction and metabolic syndrome depleted, however, some taxa including Odoribacter which negatively associated with both blood pressure and vascular stiffness bloomed during fasting.

These findings suggest that fasting could promote health through the gut microbiome [41, 57, 58]. Although the complexity of the relationship between fasting and gut microbiota is difficult to interpret, however there are a number of host-driven mechanisms may justify this association.

Fasting can influence microbial community by preventing the production of antimicrobial proteins and other aspects of mucosal immune function in the host [59, 60]. Moreover, fasted animals tend to exhibit higher gut pH compared with fed animals which in turn have effects on microbial growth [61]. Fasting also results in alteration of mucus production which can alter microbial diversity, because several gut microorganisms get rich on mucus and differential production of glycans may support the growth of different types of microorganisms [62, 63].

Another mechanism is the reduction of the intestine size in many fasting animals. Size reduction causes a ‘housing crisis’ for microorganisms that could result in increased competition for space [64]. Over the past decades, human and animal studies have shown that timing of meal intake is as important as the composition of the diet and caloric quantity to prevent obesity and its complications [10, 11]. Studies reveal that changes in daily feeding and fasting rhythms can alter the gut microbiota in animal models [65].

There is a multifaceted relationship between microbiota and meal timing: first, intestinal epithelia cells’ internal circadian clock influences daily glucocorticoid production under the control of the pituitary-adrenal axis, and this rhythm is influenced by microbiota status; second, an alteration of microbiota could lead to a disrupted corticosteroid circadian rhythm influencing food uptake.

Consuming food outside the normal feeding phase may disturb normal peripheral and central clocks resulted in increased risks of metabolic and cardiovascular diseases [66, 67]. So the effect of fasting and feeding patterns on metabolism can be closely associated with alterations in gut microbiota [14, 68].

Nowadays several modifications of fasting diets have gained popularity as they offer impressive health benefits. However, it is unlikely that all fasting diets lead to the same physiological changes because of their different fasting and feeding patterns. A number of recent studies have suggested that fasting diets are effective, as is traditional calorie restriction for weight loss and improving health parameters [69].

However, it is still unclear whether fasting improves gut microbiota and health indicators in the same ways as calorie restriction. This review provides an overview of the effects of different kinds of long or intermittent fasting on the abundance of different gut bacteria. There are various types of fasting programs that restricted meal time or calorie to improve body composition and overall health. One of the common calorie-restricted fasting is the Buchinger program which involves a daily energy intake of about 250 kcal [37].

The other examples of such amodification are alternating eating a day and then fasting the next day or 2 days fasting per week. During the fasting period, one can completely eliminate foods or reduce calorie intake to a minimum [70]. In time-restricted fasting, people abstain from eating for a specific period of time and then eat meals in the feeding window. The periods of fasting or eating windows are various. The most common modification is eating for 8 h, followed by fasting for the next 16 h. Religious fasting is another example, which is a wide range of fasts undertaken for religious or spiritual purposes.

Regarding Buchinger fasting, results of studies showed increase of Proteobacteria abundance and decrease of Firmicutes to Bacteroidetes ratio at phylum level. Besides, Faecalibacterium prausnitzii, Akkermanisa and Bifidobacteria has been reported to increase while results about the butyrate-producing bacteria were contradictory [38–41].

It has been shown that enhancement of Odoribacter abundance following the Buchinger regimen was negatively associated with systolic blood pressure and vascular stiffness [41]. A novel class of sphingolipid compounds, namely sulfonolipids with potential anti-inflammatory effects was identified as a bacterial metabolite which released from odoribacter [71]. It seems that more investigation is needed to determine the functional roles of these bacterial lipids on metabolic health effects of fasting. Moreover, alternate day fasting was associated with metabolic health through enhancing the capacity of short-chain fatty acids production of gut microbiota as well as decreasing lipopolysaccharides release and ameliorating inflammatory status as a consequence [44].

Few research has been done on the gut microbiota alteration following 8-h feeding/16-h fasting as the most common time-restricted fasting regimen up to now [43]. Therefore, the possible mediating effect of gut microbiota in fasting diet-induced metabolic health should be assessed in further clinical trial. In Ramadan, millions of Muslims undertake one month of fasting in observance of this religious obligation and abstain from food and liquids during daylight hours from dawn to sunset [72].

Several health benefits have been attributed to Ramadan fasting as a prevalent type of intermittent fasting. Studies reveal that Ramadan fasting elicits a significant decline in body weight and fat mass which in turn leads to better control of metabolic disorders including diabetes, hypertension, hyperlipidemia and etc. [73–77].

Besides to the reduction in meal frequency, there is a metabolic shift toward the main use of fatty acids as fuel for synthesizing adenosine triphosphate (ATP) during Ramadan fasting causing body fat reduction, improving functional capacity, resting energy expenditure and blood glucose homeostasis [78]. The optimization of energy reserves, decreased secretion of anabolic hormones and increased secretion of catabolic hormones such as adrenaline and glucagon have been proposed as underlying mechanisms for beneficial effect of Ramadan fasting on metabolism [79].

Moreover, Ramadan fasting had considerable effects on the gut microbiota composition. According to the results of studies, A. muciniphila, B. fragilis, Bacteroides and butyric acid–producing Lachnospiraceae which have been largely accepted as the major members of the healthy gut microbiome increased after Ramadan fasting [46, 47]. The relative abundance of A. muciniphila as a mucin-degrading bacterium which resides in the mucus layer is inversely correlated with body weight [80, 81].

Human studies have demonstrated an increased abundance of A. muciniphila after calorie restriction in obese patients along with the healthier metabolic outcomes [38, 82]. A. muciniphila strongly adheres to the mucosal layer, so it may remain relatively stable during the dietary modifications and subsequent changes in intestinal passage/flow rates and alteration of defecation regimens [83]. Regarding B. fragilis, its increase in overweight adolescents after reduction in energy intake has been reported [85].

Bacteroides genus, as an important member of healthy gut microbiota, could increase the tolerance to changes in the intestinal tract and has high capability to decrease oxygen levels in the gut lumen and high potency to metabolize complex polysaccharides and fatty acids. This genus has the unique ability to switch their transcriptional profile to use host-derived glycans in the absence of polysaccharides and glycoproteins, such as the fasting periods [85].

The property of rapid adaptation to nutrient availability and high survival of Bacteroides may contribute to its resistance to time-restricted energy intake and may lead to increased dominance after the depletion of the other bacterial groups during fasting. Furthermore, Ramadan fasting provides an obvious possible mechanistic explanation for health effects associated with intermittent fasting via upregulating the butyric acid–producing Lachnospiraceae [47].

Evidence presented that butyrate has immunomodulatory properties and could regulate energy homeostasis[86]. After Ramadan fasting, a decreasing trend was observed in Firmicutes and Enterobacteriaceae abundance. Firmicutes is responsible for increased energy harvest from foods and mostly is associated with obesity despite its anti-inflammatory and butyrate source features [87]. Besides, Enterobacteriaceae is also known as a source of endotoxin production, and its abundance is closely related with decreased gut permeability [88].

This study comprehensively reviewed existing animal and human surveys regarding the effect of different types of fasting diets on gut microbiota alterations. However, it has some limitations; the human studies consisted of generally small size and they were disparate in their purposes, methodologies and studied population in terms of diet, weight, geographic location, and host genetics which can affect the pattern of the gut microbiome.

There are substantial differences in gut microbiota composition between various ethnic groups that were only partly explained by sociodemographic status, lifestyle, and dietary patterns. Therefore, ethnic differences should be taken into account when studying associations between fasting or other dietary regimens and the gut microbiota composition.

Moreover, many of the studies failed to account for common confounders, such as the effects of smoking, and physical activity. Furthermore, in the case of Islamic fasting, the timing of Ramadan moves throughout the year, in accordance with the phases of the moon which can have different effects on gut microbiota composition and health parameters.

Regarding the quality of included clinical trials, only 4 studies had good quality based on Jadad score. However, it should be noted that due to the nature of this intervention, it is too hard or sometimes impossible that participants or staff be blinded to allocation. Moreover, most of the studies were pilot and they included no control groups. So, further well-designed randomized controlled trials are needed to have a conclusion about the effects of various fasting regimens on microbiota composition and overall well-being.

It was shown that both time and calorie restriction fasting regimens can be able to alter the taxonomic composition of gut microbiota. However, due to the using various animal models and different biospecimens regarding microbiota composition in animal studies, interpretation of the results should be done with caution. Further studies considering these issues are warranted for evaluating the exact effect of each type of fasting diets on microbiota composition of different body sites.

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More information: Ana Carolina Dantas Machado et al, Diet and feeding pattern modulate diurnal dynamics of the ileal microbiome and transcriptome, Cell Reports (2022). DOI: 10.1016/j.celrep.2022.111008


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